New Non-steroidal Anti-inflammatory Drug Research Articles

Nonsteroidal Antiinflammatory Drugs During Lactation

In Response: We thank Paech et al. for their close attention to detail in reading our recent review article [1]. We cited a chapter by Dailland [2], which recommends against the use of indomethacin during breast feeding because of the risk of neonatal seizures and nephrotoxicity. This chapter refers only to the single case report discussed above as evidence for the risk of associated seizures [3]. Indeed, the manufacturer has questioned the causal link between indomethacin therapy and convulsions [4] while reminding us that the manufacturer's prescribing information states that indomethacin use is contraindicated during pregnancy and lactation (based on lack of available toxicity data). Renal failure has been reported after in utero exposure to indomethacin [5], and intestinal perforation has been reported in neonates receiving indomethacin for closure of a patent ductus arteriosus [6]. Neither complication has been associated with maternal indomethacin ingestion during breast feeding. We agree with the analysis presented-there is scant evidence that indomethacin use by breast-feeding mothers poses appreciable risk to the infant. However, newer nonsteroidal antiinflammatory drugs are generally better tolerated, with less upper gastrointestinal bleeding and fewer central nervous system effects (headaches, drowsiness, tinnitus, and dizziness) [7]. James P. Rathmell, MD Department of Anesthesiology; University of Vermont College of Medicine; Burlington, VT Christopher M. Viscomi, MD Michael A. Ashburn, MD, MPH Department of Anesthesiology; University of Utah Medical Center; Salt Lake City, UT

Nonsteroidal Antiinflammatory Drugs During Lactation

In Response: We thank Paech et al. for their close attention to detail in reading our recent review article [1]. We cited a chapter by Dailland [2], which recommends against the use of indomethacin during breast feeding because of the risk of neonatal seizures and nephrotoxicity. This chapter refers only to the single case report discussed above as evidence for the risk of associated seizures [3]. Indeed, the manufacturer has questioned the causal link between indomethacin therapy and convulsions [4] while reminding us that the manufacturer's prescribing information states that indomethacin use is contraindicated during pregnancy and lactation (based on lack of available toxicity data). Renal failure has been reported after in utero exposure to indomethacin [5], and intestinal perforation has been reported in neonates receiving indomethacin for closure of a patent ductus arteriosus [6]. Neither complication has been associated with maternal indomethacin ingestion during breast feeding. We agree with the analysis presented-there is scant evidence that indomethacin use by breast-feeding mothers poses appreciable risk to the infant. However, newer nonsteroidal antiinflammatory drugs are generally better tolerated, with less upper gastrointestinal bleeding and fewer central nervous system effects (headaches, drowsiness, tinnitus, and dizziness) [7]. James P. Rathmell, MD Department of Anesthesiology; University of Vermont College of Medicine; Burlington, VT Christopher M. Viscomi, MD Michael A. Ashburn, MD, MPH Department of Anesthesiology; University of Utah Medical Center; Salt Lake City, UT

Synthesis of new 1,2-Benzothiazin-3-one Derivatives Designed as Dual Cyclooxygenase-2 and 5-Lipooxygenase Inhibitors

In the scope of a research program aiming at the synthesis of new nonsteroidal anti-inflammatory drugs (NSAIDs) acting on the enzymes of the arachidonic acid cascade, we describe in this paper the synthesis of two new series of functionalized a,b-unsaturated 1,2-benzothiazin-3-one derivatives (3a-10a) and (3b-10b), structurally designed as dual cyclooxigenase-2 and 5-lipooxygenase inhibitors by applying rational principles of molecular modification and hybridization. The target compounds (3a-10a) and (3b-10b) were prepared in good overall yields, exploring as the key step of the synthetic route a Knoevenagel-Doebner condensation between substituted benzaldehydes (e.g. 4-methoxy-benzaldehyde) and corresponding 1,2-benzothiazin-3(4H)-one 1,1-dioxide derivatives (17a) and (17b).

Anti-inflammatory, Analgesic and Anti-pyretic Effects of d-2-[4-(3-Methyl-2-thienyl)phenyl]propionic Acid (M-5011), a New Non-steroidal Anti-inflammatory Drug, in Rats and Guinea Pigs

Anti-inflammatory, analgesic and anti-pyretic effects of d-2-[4-(3-methyl-2-thienyl)phenyl]-propionic acid (M-5011), a new non-steroidal anti-inflammatory drug (NSAID), were compared with those of indomethacin, diclofenac sodium and ketoprofen in rats and guinea pigs. Anti-inflammatory effect of M-5011 on ultraviolet-induced erythema in guinea pigs was 11.7 and 1.8 times more potent than that of indomethacin and ketoprofen, respectively. Inhibitory effect of M-5011 on carrageenin-induced paw edema was 2 and 1.5 times more potent than that of indomethacin and diclofenac sodium, respectively. Analgesic effect of M-5011 on dry yeast-induced hyperalgesia or adjuvant-induced arthritic pain was equipotent to that of indomethacin, diclofenac sodium or ketoprofen. Anti-pyretic effect of M-5011 on yeast-induced pyrexia in rats was 4.2 and 4.6 times more potent than that of indomethacin and ketoprofen, respectively. Inhibitory effect of M-5011 on prostaglandin E2 production in the exudate of air-pouch inflammation induced by carrageenin was 1.75 times more potent than that in the non-inflamed site (stomach). As a result, gastric ulcerogenic activity of M-5011 was half that of indomethacin in rat. These results suggest that M-5011 shows more potent anti-inflammatory and anti-pyretic effects and equipotent analgesic effect with low gastro-ulcerogenic activity compared with classical NSAIDs.

A double-blind, randomized, placebo-controlled study of efficacy and tolerance of meloxicam treatment in patients with osteoarthritis of the knee

Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID), with a favourable ratio of inhibition of cyclooxygenase-2 (COX-2)/cyclooxygenase-1 (COX-1), giving the drug the potential to produce few gastric adverse effects. The aim of this study was to investigate the efficacy and safety of meloxicam in patients with osteoarthritis (OA) of the knee. Five hundred and thirteen patients were treated in a double-blind trial comparing once-daily meloxicam 7.5 mg, 15 mg, 30 mg, or placebo (140, 134, 102 and 137 patients, respectively). Outcome measures included scores on Visual Analogue Scales (VAS) for pain on movement (primary endpoint) and pain at rest in the target joint as well as global efficacy. Lesquesne's index of severity and paracetamol consumption were also measured. Global tolerability and the occurrence of adverse events were monitored. Both meloxicam 7.5 mg and 15 mg were significantly more effective than placebo with respect to pain on movement (p<0.01 and p<0.03, respectively). Both doses of meloxicam compared favourably with placebo with respect to pain of the target joint at rest, although only the 15 mg dose achieved statistical significance (p<0.02). Global efficacy showed a significant difference for both doses of meloxicam (p<0.05 and p<0.002 for 7.5 mg and 15 mg doses, respectively). Once daily meloxicam 7.5 and 15 mg is effective and well tolerated in the short term symptomatic treatment of OA of the knee. Birger Lund, SAXO, Det Kliniske Behandlings - og Forskningscenter, Oesterbrogade 70, DK-2100 Copenhagen Ø, Denmark

A double-blind, randomized trial to compare meloxicam 15 mg with diclofenac 100 mg in the treatment of osteoarthritis of the knee

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID), which, in animal tests, displays a high potency for anti-inflammatory and analgesic action. The aim of this study was to investigate the efficacy and tolerability of 15 mg meloxicam in comparison with 100 mg slow-release diclofenac in patients with osteoarthritis of the knee. Two hundred and fifty-eight patients were included in the intent-to-treat analysis; these were randomized into two groups to receive either 15 mg meloxicam (N = 128) or 100 mg diclofenac (N = 130) for a period of 6 weeks. The results with respect to efficacy showed a trend in favor of meloxicam regarding pain on movement, global efficacy and paracetamol consumption, although these differences did not reach statistical significance. The most frequently-occurring adverse events in both groups were of a gastrointestinal (GI) nature. However, there was a higher incidence (26 vs 16%) of GI adverse events in the diclofenac group compared with the meloxicam group. Both drugs were well tolerated when assessed by the patients on a visual analog scale (VAS). Thus, 15 mg meloxicam is an effective and well-tolerated therapy for osteoarthritis and compares favorably with diclofenac 100 mg, a well-established treatment for this indication.

Nonsteroidal antiinflammatory drugs, ulcers and risk:A collaborative meta-analysis

Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with a high prevalence of gastrointestinal toxicity. Comparisons of the risks associated with individual NSAIDs are needed, but most clinical studies in this area are not ideally suited for use in meta-analyses. These difficulties can be overcome by using strict criteria for the inclusion of studies, and by reanalyzing previous data, updated by authors where possible. In doing so, this meta-analysis compared the relative risk of serious toxicity associated with 14 NSAIDs from 12 studies with the risks of ibuprofen. These results were supported by a novel “summary ranking” analysis, which was weighted to limit the influence of smaller studies. Wide variations in relative risk among NSAIDs were observed with piroxicam and azapropazone being the most toxic. Ibuprofen was associated with the least risk, probably because of its widespread use as a low-dose analgesic. Five studies provided comparative data on NSAIDs at “high” and “low” doses (as defined in the original reports), showing that the risk of toxicity was dose related. Furthermore, at full antiinflammatory doses, the risk associated with ibuprofen was similar to that of naproxen and diclofenac. These analyses show that NSAIDs vary more in toxicity than in efficacy. First-line therapy should be started with the lowest effective dose of a less toxic NSAID, moving to higher doses or a more toxic NSAID only if the clinical situation demands it. Newer NSAIDs, such as selective cyclooxygenase-2 inhibitors, may provide safer antiinflammatory therapy.

Efficacy and Tolerability of Meloxicam versus Piroxicam in Patients with Osteoarthritis of the Hip or Knee

This study compared the efficacy and tolerability of meloxicam, a new non-steroidal anti-inflammatory drug (NSAID), with piroxicam in a randomised, double-blind, parallel-group trial. 455 patients with proven osteoarthritis of the knee or hip were randomised in a ratio of 2:1 to receive meloxicam 15mg once daily (n = 306) or piroxicam 20mg once daily (n = 149) for a 6-month period. In the evaluation of efficacy end-points (overall pain, pain on movement, joint stiffness, global efficacy and quality of life), both drug treatments were shown to be effective and comparable. The incidence and type of adverse events were similar in both groups. The most frequently reported adverse events were gastrointestinal disorders, reported in 24.2% of meloxicam-treated patients and 30.2% of piroxicam-treated patients. Both drugs were well tolerated. In conclusion, meloxicam is an effective and well tolerated drug for the symptomatic treatment of osteoarthritis and is comparable in efficacy to piroxicam.

Meloxicam:a selective COX-2 inhibitor non-steroidal anti-inflammatory drug

Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits the inducible isoform of the cyclo-oxygenase (COX)-2 enzyme. This enzyme has a major role in mediating the inflammatory response, while synthesis of prostaglandins required for normal physiological functioning of the stomach and kidneys is under the control of the constitutive isoform, COX-1. Other NSAIDs in clinical use show varying degrees of selectivity towards COX-1. Only meloxicam and (albeit to a lesser extent) nimesulide could be described as selective for COX-2. In comparative trials of patients with osteo- and rheumatoid arthritis, meloxicam has been found to be at least as effective as other NSAIDs, but with a greatly reduced incidence of gastrointestinal side-effects. There is no evidence that meloxicam causes any deterioration in renal function in patients with moderate degrees of renal failure, and no evidence of drug accumulation with continued use. Meloxicam’s half-life of 20 h makes it ideal for once daily administration, and it is 99% converted to inactive metabolites prior to excretion. No clinically significant drug interactions have been detected, making it suitable for use in patients with co-existing pathology. Meloxicam’s safety and tolerability make it a significant advance in the treatment of rheumatic disease.

Lack of interaction between meloxicam and warfarin in healthy volunteers.

The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days. Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUCss values for the more potent S-enantiomer were 5.07 mg.h.l-1 (27.5%) for warfarin alone and 5.64 mg.h.l-1 (28.1%) during the interaction phase. Respective AUCss values for R-warfarin were 7.31 mg.h.l-1 (43.8%) and 7.58 mg.h.l-1 (39.1%). The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory.

NSAID Gastropathy

Nonsteroidal anti-inflammatory drug (NSAID) gastropathy is associated with substantial morbidity and mortality, which result in high costs to both the patient and society. The subset of patients who are at greatest risk for developing NSAID gastropathy continues to be better defined, but various risk factors, such as age and previous gastrointestinal tract disease, have been identified. In patients receiving older NSAIDs, the choice of NSAID should be based on differences in formulations at the lowest effective dose. Gastroprotective cotherapy should be instituted if treatment with older NSAIDs is continued in at-risk patients; misoprostol is currently the only agent approved for this indication. The impact of misoprostol on clinical gastrointestinal tract end points has recently been documented. Newer NSAIDs may have an improved safety profile over older NSAIDs; some have a clinically documented reduction in the incidence of adverse gastrointestinal tract effects. An understanding of these issues should enable the informed clinician to choose an NSAID on the basis of risk-benefit and cost-benefit considerations.

General pharmacology of meloxicam-part I: Effects on CNS, gastric emptying, intestinal transport, water, electrolyte and creatinine excretion

The general pharmacodynamic properties of meloxicam, a new nonsteroidal antiinflammatory drug (NSAID), were examined. Characteristics that distinguish meloxicam from conventional NSAIDs were investigated. No central-nervous-system effects were observed in the mouse at oral doses up to 100 mg/kg. In vitro studies showed meloxicam had no antagonistic properties against mediators such as histamine, PGE 2 and angiotensin II. The rate of gastric emptying or intestinal transport in the rat was not influenced by therapeutic doses of meloxicam and, of all the NSAIDs investigated, meloxicam showed the mildest effect on gastric acidity. In doses well above those required for antiinflammatory action, meloxicam had no influence on water, electrolyte or creatinine excretion.

General pharmacology of meloxicam-part II: Effects on blood pressure, blood flow, heart rate, ECG, respiratory minute volume and interactions with paracetamol, pirenzepine, chlorthalidone, phenprocoumon and tolbutamide

The pharmacodynamic properties of meloxicam, a new nonsteroidal antiinflammatory drug (NSAID), that go beyond those typical of an NSAID were examined. The extent to which meloxicam shows NSAID-like interactions with paracetamol, pirenzepine, chlorthalidone, phenprocoumon and tolbutamide was also investigated. In the dose range studied, meloxicam had no influence on the blood pressure of the unanaesthetized rat, blood flow, heart rate, ECG and respiratory minute volume of the anaesthetized cat or on the blood pressure, heart rate and respiratory minute volume of the anaesthetized dog. The acute toxicity level of meloxicam after oral and parenteral administration to the rat and mouse proved considerably lower than that of indomethacin. Meloxicam showed excellent tissue tolerability following parenteral administration. The effects against inflammatory pain and acute antiexudative effects of meloxicam were enhanced by simultaneous low doses of paracetamol. Pirenzepine showed an antagonistic effect on the ulcerogenicity of meloxicam in the rat stomach. The diuretic effect of chlorthalidone in the rat was not influenced by high doses of meloxicam. The effect of phenprocoumon in the rat was enhanced by high doses of meloxicam. However, the hypoglycaemic effect of tolbutamide in the rabbit was not influenced by meloxicam.

Lornoxicam. A review of its pharmacology and therapeutic potential in the management of painful and inflammatory conditions.

Lornoxicam (chlortenoxicam), a new nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class with analgesic, anti-inflammatory and antipyretic properties, is available in oral and parenteral formulations. It is distinguished from established oxicams by a relatively short elimination half-life (3 to 5 hours), which may be advantageous from a tolerability standpoint. Data from preliminary clinical trials suggest that lornoxicam is as effective as the opioid analgesics morphine, pethidine (meperidine) and tramadol in relieving postoperative pain following gynaecological or orthopaedic surgery, and as effective as other NSAIDs after oral surgery. Lornoxicam was also as effective as other NSAIDs in relieving symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute sciatica and low back pain. Lornoxicam has a tolerability profile characteristic of an NSAID, with gastrointestinal disturbances being the most common adverse events. Limited clinical experience to date suggests that, as with a number of other NSAIDs, lornoxicam may provide a better-tolerated alternative or adjuvant to opioid analgesics for the management of moderate to severe pain. It has also demonstrated potential as an alternative to other NSAIDs for the management of arthritis and other painful and inflammatory conditions. These preliminary findings require confirmation in further comparative and long term studies.

A long-term study to evaluate the safety and efficacy of meloxicam therapy in patients with rheumatoid arthritis.

Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID), which has a higher activity against cyclooxygenase-2 (COX-2) than against cyclooxygenase-1 (COX-1), with potentially high anti-inflammatory and analgesic action. This study was designed to assess the long-term safety and efficacy of meloxicam 15 mg daily. Three hundred and fifty-seven patients (aged 19-84 yr, mean 56 yr) with rheumatoid arthritis (RA) received meloxicam 15 mg orally once daily, for up to 18 months. Sixty-six per cent of patients remained on therapy for 18 months. Mean global efficacy, assessed by each patient on a visual analogue scale (0 cm = excellent, 10 cm = useless), was 3.32 +/- 3.1 cm at the last study visit (all patients included) and 2.33 +/- 2.25 cm after 18 months. Health status, general condition, morning stiffness, grip strength of right hand, Ritchie joint index, pain in the morning and pain at night all improved significantly. Efficacy was maintained through the study. Only 11.4% of patients discontinued prematurely due to lack of efficacy. Mean global tolerance was good. Twenty-eight per cent of patients experienced gastrointestinal (GI) adverse events, 21% musculoskeletal system disorders, 18% skin disorders and 15% respiratory disorders. Only 13.7% of patients discontinued due to adverse events. Severe GI effects, such as perforation, ulcer and bleeding, occurred in only three patients (0.8%). Withdrawals due to GI adverse events occurred in 3.9% of patients. Meloxicam 15 mg once daily was effective and compared favourably with standard NSAIDs regarding tolerance when administered to patients with RA over an 18 month period.

An Open Study to Assess the Safety and Tolerability of Meloxicam 15 mg in Subjects with Rheumatic Disease and Mild Renal Impairment

Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID) which has shown potent anti-inflammatory properties but good gastrointestinal (GI) renal tolerability. The safety and tolerability profile of orally administered meloxicam 15 mg given once daily over a 28 day treatment period in renally impaired patients with rheumatic disease is presented here. A total of 25 patients (aged 43-78 yr, mean age 70 yr) with rheumatic disease and mild renal impairment were enrolled in this multicentre, open-label study, with 22 patients completing the 28 day treatment period. The median estimated creatinine clearance and N-acetyl-beta-glucosaminidase/creatinine ratios (a marker of renal tubular damage) recorded at day 14, day 28 or 4-7 days after meloxicam treatment was terminated, were not statistically significantly different from baseline values. There was no evidence of accumulation of meloxicam. Overall, meloxicam was well tolerated. The most common adverse events were GI complaints of abdominal pain and dyspepsia. No adverse events related to the urinary system, or increases in serum urea or potassium were recorded. The results suggest that meloxicam, 15 mg once daily, does not further compromise renal function or result in accumulation of meloxicam over this treatment period in patients with pre-existing mild renal impairment.

Meloxicam.

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID) developed for the treatment of rheumatoid arthritis and osteoarthritis. It has greater in vitro and in vivo inhibitory action against the inducible isoform of cyclo-oxygenase (COX-2), which is implicated in the inflammatory response, than against the constitutive form of this enzyme (COX-1), inhibition of which is associated with gastric, renal and other adverse effects. It has anti-inflammatory effects similar to or better than those of other NSAIDs in animal models, and a greater therapeutic ratio (ulcerogenic potential:efficacy in adjuvant arthritis). In healthy volunteers meloxicam 7.5 or 15 mg caused less gastrointestinal mucosal damage on endoscopy than piroxicam 20 mg, with a significant difference between meloxicam 7.5 mg and piroxicam. In comparative clinical trials, meloxicam was at least as effective as piroxicam and naproxen in patients with rheumatoid arthritis, and diclofenac and piroxicam in patients with osteoarthritis. Meloxicam was at least as well tolerated as piroxicam, diclofenac or naproxen overall but had improved gastrointestinal tolerability compared with these agents.

Meloxican: Influence on arachidonic acid metabolism: Part 1. In vitro findings

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID) derived from enolic acid. Meloxicam has shown potent anti-inflammatory activity in animal models together with low gastrointestinal and renal toxicity. Studies were undertaken to compare meloxicam to other NSAIDs in their ability to inhibit either constitutive cyclooxygenase (COX-1) or inducible cyclooxygenase (COX-2). COX-1 was isolated as a cell-free enzyme from bovine seminal vesicles or bovine brain or was present in nonstimulated macrophages derived from the guinea-pig peritoneum. COX-2 was induced in peritoneal macrophages stimulated by lipopolysaccharide (LPS) or isolated as a cell-free enzyme from sheep placenta. Of all NSAIDs tested, meloxicam was the most selective inhibitor of COX-2 in intact cells. In cell-free enzyme preparations, however, meloxicam showed the same activity against COX-1 and COX-2. All other NSAIDs tested were more potent inhibitors of COX-1 than of COX-2. The inducible cyclooxygenase COX-2 has been implicated in the mediation of the inflammatory reaction, whereas the products of the constitutive cyclooxygenase COX-1 have cytoprotective effects in the gastric mucosa, support microcirculation in the kidney, and are antithrombogenic. Therefore, differential inhibitory effects of NSAIDs on COX-1 and COX-2 may have a bearing on the risk-benefit profile displayed in clinical practice. Meloxicam shows a preferential inhibitory effect on COX-2 over COX-1, which may be directly related to the favorable tolerability profile with potent anti-inflammatory effects observed in animal studies.

Meloxican: Influence on arachidonic acid metabolism: Part II. In vivo findings

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID) derived from enolic acid. Preclinical studies have indicated that meloxicam has potent anti-inflammatory activity, together with a good gastrointestinal and renal tolerability profile. This report summarizes studies undertaken to compare meloxicam to other NSAIDs in the inhibition of the inducible cyclooxygenase (COX-2) in inflamed areas (pleurisy of the rat, peritonitis of mice) and their influence on the activity of the constitutive cyclooxygenase (COX-1) in stomach, kidney, brain, and blood. In pleurisy of the rat, meloxicam was twice as potent as tenoxicam, 3 times as potent as flurbiprofen, 8 times as potent as diclofenac, and 20 times as potent as tenidap at inhibiting prostaglandin E 2 (PGE 2) biosynthesis. In the peritonitis model in mice, meloxicam was approximately twice as active as piroxicam, and more than 10 times as active as diclofenac in the suppression of PGE biosynthesis. Doses of meloxicam sufficient to inhibit PGE 2 biosynthesis in the pleural exudate and peritoneal exudate had no influence on leukotriene-B 4 (LTB 4) or leukotriene-C 4 (LTC 4) content. The effect of meloxicam on the PGE 2 content of rat gastric juice and rat urine was weaker than that of piroxicam or diclofenac. Meloxicam was a weaker inhibitor of the increased PGE 2 concentration in brain of rats and mice (induced by convulsant doses of pentetrazole) than piroxicam, diclofenac, or indomethacin. Meloxicam had a weaker effect on serum thromboxane-B 2 (TXB 2) concentration in rats than piroxicam or tenoxicam. The in vivo findings confirm the results of in vitro tests, conducted separately, showing that meloxicam preferentially inhibits COX-2 over COX-1. COX-2 is the inducible isoenzyme implicated in the inflammatory response, whereas COX-1 has cytoprotective effects in the gastric mucosa. Therefore, a preferential selectivity for one isoenzyme over another, as displayed by meloxicam, may have implications in the clinical setting in terms of a more favorable risk: benefit profile.

Mechanisms of Mucosal Injury and Healing: the Role of Non-steroidal Anti-inflammatory Drugs

Biological insights into injurious effects of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin (ASA), on mucosal protection and repair, are largely from studies of acute injury. That chronic ulceration is similar is not established. NSAIDs directly injure tissues, including endothelia, and at the same time impair the operation of many of the processes that normally contribute to mucosal protection, whatever the injurious agent. Many protective processes are mediated through prostaglandins, whose synthesis is abolished by inhibition of the constitutive isoenzyme, cyclooxygenase I (COX I) or Prostaglandin H-Synthase1 (PGHS1). The aims of therapy are aimed at inhibiting the inducible isozyme cyclooxygenase II (COX II) or prostaglandin-H Synthase2 (PGHS2), which contributes to prostanoid synthesis at sites of inflammation. Newer NSAIDs, selectively inhibiting COX II, promise to revolutionize the treatment of inflammatory disease while reducing mucosal injury. Meanwhile, there is increasing evidence that direct injury to both mucosae and endothelia is mediated by free-radical species, exacerbated by reduced blood flow, and by the local release of inflammatory and other mediators, which accentuate vascular leakage and hemorrhage, and cause intravascular aggregation of blood elements, stasis, hypoxia, and additional free-radical injury. The NSAIDs also inhibit epithelial cell division and the angiogenesis critical to healing and repair.