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PubMed2004

Naproxen affects Ca(2+) fluxes in mitochondria, microsomes and plasma membrane vesicles.

There is substantial evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) affect cellular processes regulated by Ca(2+) ions, including the metabolic responses of the liver to Ca(2+)-dependent hormones. The aim of the present study was to determine whether the effects of naproxen are mediated by a direct action on cellular Ca(2+) fluxes. The effects of naproxen on 45Ca(2+) fluxes in mitochondria, microsomes and inside-out plasma membrane vesicles were examined. Naproxen strongly impaired the mitochondrial capacity to retain 45Ca(2+) and inhibited also ATP-dependent 45Ca(2+) uptake by microsomes. Naproxen did not modify 45Ca(2+) uptake by inside-out plasma membrane vesicles, but it inhibited the hexokinase/glucose-induced Ca(2+) efflux from preloaded vesicles. Additional assays performed in isolated mitochondria revealed that naproxen causes mitochondrial uncoupling and swelling in the presence of Ca(2+) ions. These effects were prevented by EGTA, ruthenium red and cyclosporin A, indicating that naproxen acts synergistically with Ca(2+) ions by promoting the mitochondrial permeability transition. The experimental results suggest that naproxen may impair the metabolic responses to Ca(2+)-dependent hormones acting by at least two mechanisms: (1) by interfering with the supply of external Ca(2+) through a direct action on the plasma membrane Ca(2+) influx, and (2) by affecting the refilling of the agonist-sensitive internal stores, including endoplasmic reticulum and mitochondria.

Animals↗

PubMed2004

Effect of binary and ternary polyethyleneglycol and/or beta-cyclodextrin complexes on the photochemical and photosensitizing properties of Naproxen.

The effect of the polyethylene glycol and/or beta-cyclodextrin on the photolability of aqueous solutions of the anti-inflammatory drug Naproxen was studied. In all systems studied, the photodegradation process followed zero-order kinetics, leading to the same photoproducts as in the absence of these additives. Kinetic studies revealed that the presence of polyethylene glycol (PEG) reduced drug photodegradation (phi=0.11 in water and phi=0.045 in the presence of 1% of PEG). By contrast, the binary inclusion complex, Naproxen:beta-CD, did not protect the drug from degradation, phi=0.11. However, the ternary complex, Naproxen:beta-CD:PEG, reduced the efficiency of the photodegradative process to a considerable extent, with phi=0.022 in this system. In all cases the presence of the different additives elicited a change in the photomixture composition, the alcoholic derivative being the major photoproduct formed. Nevertheless, the change in the efficiency of the process and the amount of the photoproducts formed in the different systems were not related with the biodamage produced by the drug. In this sense, the presence of free Naproxen clearly sensitized the photoperoxidation of linoleic acid. The photosensitizing effect decreased as the PEG concentration increased and was completely abolished by both the binary (Naproxen:beta-CD) and ternary (Naproxen:beta-CD:PEG) complexes. In light of these observations, it is possible to speculate that in these systems the prevention of biodamage would be due to a decrease in the contact between the short-lived species generated during Naproxen photodegradation and biological structures, rather than to the nature or amount of the photoproducts.

Kinetics↗

PubMed1999

Uniform-sized molecularly imprinted polymer for (S)-naproxen selectively modified with hydrophilic external layer.

A uniform-sized molecularly imprinted polymer (MIP) for (S)-naproxen selectively modified with hydrophilic external layer has been prepared. First, the molecularly imprinted polymer for (S)-naproxen was prepared using 4-vinylpyridine and ethylene glycol dimethacrylate (EDMA) as a functional monomer and cross-linker, respectively, by a multi-step swelling and thermal polymerization method. Next, a 1:1 mixture of glycerol monomethacrylate (GMMA) and glycerol dimethacrylate (GDMA) was used for hydrophilic surface modification, and it was added directly to the molecularly imprinted polymer for (S)-naproxen 4 h after the start of molecular imprinting. The retention factors of all solutes tested were decreased with the surface modified molecularly imprinted polymer, compared with the unmodified molecularly imprinted polymer. However, chiral recognition of racemic naproxen was attained with the surface modified molecularly imprinted polymer as well as the unmodified molecularly imprinted polymer. Further, bovine serum albumin was completely recovered from the surface modified molecularly imprinted polymer. These results revealed that the chiral recognition sites of (S)-naproxen remained unchanged with hydrophilic surface modification, and that the molecularly imprinted polymer for (S)-naproxen was selectively modified with hydrophilic external layer. Preliminary results reveal that the surface modified molecularly imprinted polymer could be applicable to direct serum injection assays of (S)-naproxen.

Chromatography, High Pressure Liquid↗

PubMed2002

A randomized, double-blind, multicenter trial of nimesulide-beta-cyclodextrin versus naproxen in patients with osteoarthritis.

BACKGROUND: Nonsteroidal anti-inflammatory drugs are the most widely used agents in the symptomatic treatment of osteoarthritis (OA). No data are presently available on the medium-term management of this disease with an on-demand treatment regimen, which nevertheless reflects medical practice. OBJECTIVES: The aim of this study was to compare nimesulide-beta-cyclodextrin and naproxen in terms of short-term (2 weeks) pain control with scheduled dosing and medium-term (5.5 months) pain control with on-demand dosing in patients with OA. METHODS: In this multicenter, randomized, double-blind, controlled study, we compared 2 weeks of scheduled treatment plus 5.5 months of on-demand treatment in patients with OA of the hip and/or knee and moderate to severe pain, with no important concomitant disorders. Treatment consisted of nimesulide-beta-cyclodextrin (400 mg BID, orally = 100 mg nimesulide BID) or naproxen (500 mg BID). The primary outcome measures for scheduled dosing were pain on movement (measured by visual analog scale), morning stiffness score, Lequesne index, and adverse events. For on-demand dosing, the measures were the same as for scheduled dosing, plus duration of treatment and global assessment of efficacy and tolerability by patient and physician. RESULTS: After 2 weeks, there was equivalent reduction from baseline in pain on movement in the 2 treatment groups (nimesulide-beta-cyclodextrin, -41.5%; naproxen, -40.5%); the reduction was significant after 1 week (P < 0.001). The findings were also similar for the morning stiffness score and Lequesne index. There were no significant differences in mean duration of on-demand treatment (nimesulide-beta-cyclodextrin, 163.03 days; naproxen, 166.3 days) or in mean consumption of study drug (nimesulide-beta-cyclodextrin, 0.85 +/- 0.61 sachets/d; naproxen, 0.74 +/- 0.42 sachets/d). Withdrawal due to intolerance occurred in 8 patients given nimesulide-beta-cyclodextrin and 13 patients given naproxen, with no significant difference between groups; 3 and 12 patients, respectively, withdrew due to gastrointestinal intolerance, a finding that was significantly different between groups (P < 0.01). Global assessment of efficacy by patient and physician was similar for both drugs. Assessment of tolerability significantly favored nimesulide-beta-cyclodextrin on the physician assessments (P < 0.05) but was similar for the 2 drugs on the patient assessments (physicians, 46.9% vs 30.9%; patients, 43.5% vs 33.3%). CONCLUSIONS: The results suggest that nimesulide-beta-cyclodextrin provides similar pain relief to naproxen in the management of OA of the hip and/or knee and is associated with fewer gastrointestinal adverse reactions. On-demand dosing may be an effective and well-tolerated low-dose regimen of nonsteroidal anti-inflammatory drugs for the maintenance of pain control in OA in the medium term.

Aged↗

PubMed1998

Bone mineral density and biomechanical properties of spine and femur of ovariectomized rats treated with naproxen.

Prostaglandins have been reported to mediate the effects of ovariectomy on bone loss. We studied the effect of naproxen, an inhibitor of production of prostaglandins, on ovariectomy-induced bone loss. One hundred forty female Wistar rats 4.5 months of age were divided into groups of baseline, sham operation (sham), sham treated with naproxen at 10 mg/kg per day (in food), and ovariectomy treated with naproxen or estrogen as intramuscular injection of estradiol at 0.2 mg/kg body weight per week. They were killed 3, 6, and 9 months postsurgery. Bone mineral density (BMD) of the lumbar spine (L1-4), femoral neck, midshaft, and distal metaphysis was determined using dual-energy X-ray absorptiometry (DXA) in vitro. The compressive test of the L1 vertebral body and torsional test of the left femur were performed. The right femoral neck and femoral midshaft were processed undecalcified for determining cross-sectional moments of inertia. Naproxen treatment partially prevented ovariectomy-induced loss or less gain in BMD, in a significant manner, in the femoral neck cortical area, and also in L1 compressive strength and stiffness. Estrogen fully prevented these ovariectomy-induced effects. Naproxen showed no effect on ovariectomy-induced improvement in femoral torsional strength and stiffness and cross-sectional moments of inertia. No statistically significant difference was found between naproxen-treated sham rats and untreated sham rats. The data suggest that naproxen partially prevents ovariectomy-induced osteopenia.

Absorptiometry, Photon↗

PubMed2000

Synthesis and in vitro evaluation of novel morpholinyl- and methylpiperazinylacyloxyalkyl prodrugs of 2-(6-methoxy-2-naphthyl)propionic acid (Naproxen) for topical drug delivery.

Various novel morpholinyl- (3a,b) and methylpiperazinylacyloxyalkyl (3c-f) esters of 2-(6-methoxy-2-naphthyl)propionic acid were synthesized and evaluated in vitro for topical drug delivery as potential prodrugs of naproxen (1). Compounds 3a-f were prepared by coupling the corresponding naproxen hydroxyalkyl ester with the morpholinyl- or (4-methyl-1-piperazinyl)acyl acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP) and quantitatively hydrolyzed (t(1/2) = 1-26 min) to naproxen in human serum. Compounds 3c-f showed higher aqueous solubility and similar lipophilicity, determined by their octanol-buffer partition coefficients (log P(app)), at pH 5.0 when compared to naproxen. At pH 7.4 they were significantly more lipophilic than naproxen. The best prodrug 3c led to a 4- and 1.5-fold enhancement of skin permeation when compared to naproxen at pH 7.4 and 5.0, respectively. The present study indicates using a methylpiperazinyl group yields prodrugs that are partially un-ionized under neutral and slightly acidic conditions, and thus, a desirable combination is achieved in terms of aqueous solubility and lipophilicity. Moreover, the resulting combination of biphasic solubility and fast enzymatic hydrolysis of the methylpiperazinylacyloxyalkyl derivatives gave improved topical delivery of naproxen.

Administration, Topical↗

PubMed1996

Second-derivative synchronous fluorescence spectroscopy for the simultaneous determination of naproxen and salicylic acid in human serum.

Second-derivative synchronous fluorescence spectrometry was used to develop a simple, rapid and sensitive spectrofluorimetric method for the simultaneous determination of naproxen and salicylic acid in human serum. The method is based on the intrinsic fluorescence of naproxen and salicylic acid in chloroform-1% acetic acid solution. A delta gamma of 130 nm was used for the direct measurement of salicylic acid in the binary mixture, whereas naproxen was determined from direct measurements at delta gamma = 60 nm and by means of a correction equation which incorporates the concentration of salicylic acid. The range of application is 0-14 mg l-1 for naproxen and 0-13 mg l-1 for salicylic acid. The detection limits for naproxen and salicylic acid are 0.003 and 0.01 mg l-1, respectively. Serum samples are extracted into chloroform-1% acetic acid solution prior to instrumental measurement. Analytical recoveries range from 97 to 105% (mean 102%) for naproxen and from 97 to 112% (mean 103%) for salicylic acid. The within-run precision (RSD) for the method for four naproxen-salicylic acid mixtures varied from 1.2 to 6.7% and the day-to-day precision for mixtures varied from 2.1 to 5.0%.

Humans↗

PubMed1996

Gastric mucosal injury and adaptation to oral and rectal administration of naproxen.

INTRODUCTION: Oral nonsteroidal anti-inflammatory drugs (NSAIDs) cause acute gastric mucosal injury but the relative importance of systemic and topical effect of NSAIDs to overall gastric damage remains uncertain. METHODS: Twenty-four healthy volunteers were allocated either oral or rectal naproxen 500 mg b.d. and gastroscoped before and during days 1, 7 and 28 of dosing. Macroscopic gastric damage was assessed using a modified Lanza score, mucosal blood flow recorded using laser Doppler flowmetry and prostaglandin E2 (PGE2) measured in antral mucosal biopsies. RESULTS: Maximal gastric damage occurred during the first 24 h in the oral naproxen group and was associated with a fall in antral mucosal blood flow (mean +/- S.E.M.) from 58.2 +/- 3.3 to 46.6 +/- 4.1 arbitrary units (a.u.) (P < 0.05). With continued administration of oral naproxen, gastric damage resolved and antral mucosal blood flow returned to baseline (54.2 +/- 3.7 a.u.). No macroscopic damage or significant changes in mucosal blood flow were observed during rectal administration. There was no significant difference between mucosal PGE2 concentrations in those receiving oral or rectal naproxen, falling from an initial level of 335 +/- 29 to 155 +/- 49 pg/mg at day 1 (P = 0.06) in those receiving oral naproxen and from 235 +/- 55 to 107 +/- 31 pg/mg at day 1 (P = 0.1) in those receiving rectal naproxen, and remaining suppressed throughout the study in both groups. CONCLUSIONS: These observations suggest that acute mucosal damage and changes in mucosal blood flow are caused by the topical rather than systemic actions of naproxen.

Administration, Oral↗

PubMed1985

Naproxen sodium in the treatment of migraine.

Seventy patients with classical or common migraine were treated during their attacks with either naproxen sodium or placebo in a randomised, double-blind parallel group study. The initial dose of naproxen sodium was 825 mg followed one hour later by a further 550 mg, if symptoms were the same or had improved. If the migraine symptoms had worsened, patients were offered an escape analgesic combination of 1000 mg paracetamol and 10 mg metoclopramide. Patients were assessed at monthly intervals for changes in the severity and duration of headache, premonitory symptoms (mainly visual disturbances) and photophobia, nausea and vomiting associated with migraine attacks that had occurred since the previous visit. Patients were studied for a maximum of ten attacks and significant improvement was observed in the severity and duration of headache when the patients were on naproxen sodium. Also the premonitory symptoms and photophobia improved significantly on naproxen sodium and significantly less rescue analgesics were required. Patients suffering from common migraine had less severe headaches and photophobia when taking naproxen sodium than when taking placebo and the headaches were shorter in duration and patients took less rescue analgesic. No significant difference was observed between the treatment groups in patients with classical migraine. Ten patients in the placebo group and six in the naproxen sodium group reported side-effects but these were possibly related to the use of rescue medication. Naproxen sodium proved safe and effective in common migraine attacks, but in this study efficacy was not established for classical migraine.

Adolescent↗

PubMed1985

Acute migraine attack therapy: comparison of naproxen sodium and an ergotamine tartrate compound.

The efficacy of safety of naproxen sodium and ergotamine tartrate were compared for the treatment of acute migraine attack in a randomized, parallel trial with 114 participating patients. At the start of symptoms, patients took either three tablets of naproxen sodium (275 mg each) or one of an ergotamine combination (containing 2 mg ergotamine tartrate, 91.5 mg caffeine, and 50 mg cyclizine chlorhydrate). Patients were followed for three months or until six attacks were monitored, whichever came first. Both medications substantially shortened the duration of migraine attacks and reduced the severity of symptoms. When the test medications were taken within 2 h of onset of attack, naproxen sodium was statistically significantly more effective than the ergotamine combination in reducing the severity of headache pain, nausea, and lightheadedness. The ergotamine combination was associated with significantly more vomiting, need for rescue medication, and side effects than was naproxen sodium. Four patients required discontinuation of the ergotamine combination and one of naproxen sodium. Both patients and investigators rated tolerance for naproxen sodium as superior to tolerance for the ergotamine combination. Naproxen sodium seems to be an effective and safe treatment for migraine attacks.

Acute Disease↗

PubMed2006

Dose-effect comparisons of the CINOD AZD3582 and naproxen on upper gastrointestinal tract mucosal injury in healthy subjects.

OBJECTIVE: The objective of this endoscopic study was to compare the effects on the gastroduodenal mucosa of healthy volunteers of different doses and dosing regimens of AZD3582, a cyclooxygenase-inhibiting nitric oxide donator (CINOD), with equimolar doses of naproxen. MATERIAL AND METHODS: Healthy volunteers were enrolled in a single-centre, randomized, double-blind, crossover trial consisting of two 12-day treatment periods and employing six sequences. The groups were: AZD3582 750 mg daily versus 375 mg twice daily (n=25), AZD3582 375 mg twice daily versus 750 mg twice daily (n=25) and naproxen 250 mg twice daily versus 500 mg twice daily (n=25). RESULTS: Gastroduodenal tract damage was similar with AZD3582 375 mg twice daily and 750 mg twice daily (mean number of erosions and ulcers+/-SD: 2.88+/-3.95 versus 3.08+/-2.80, respectively; p=0.824; 1 ulcer counted as 10 erosions). There was an indication of decreased gastroduodenal toxicity with AZD3582 750 mg daily compared with 375 mg twice daily (0.92+/-2.08 versus 2.71+/-4.75, respectively; p=0.068). Gastroduodenal toxicity was significantly lower with AZD3582 375 mg twice daily than with naproxen 250 mg twice daily (2.88+/-3.95 versus 6.16+/-9.36; p<0.05), and with AZD3582 750 mg twice daily versus naproxen 500 mg twice daily (3.08+/-2.80 versus 6.68+/-6.97; p<0.05). Equimolar twice-daily doses of AZD3582 and naproxen resulted in similar naproxen plasma levels and serum thromboxane B(2) inhibition. CONCLUSIONS: AZD3582 has an improved gastroduodenal safety profile compared with equimolar doses of naproxen. The gastroduodenal effects of AZD3582 375 mg and AZD3582 750 mg twice daily are similar. A once-daily regimen of AZD3582 might be less gastrotoxic than a twice-daily regimen.

Adult↗

PubMed1993

Additive effect of combined naproxen and paracetamol in rheumatoid arthritis.

The clinical effect and plasma naproxen levels were studied in 20 patients with RA receiving three doses of naproxen and two naproxen doses combined with paracetamol (acetaminophen) in a randomized, double-blind, comparison in five 2-wk treatment periods. A significant dose-concentration effect relationship was found for the three naproxen doses (500, 1000 and 1500 mg daily). The following variables were measured: global clinical effect, joint index, morning stiffness, activity of daily living (ADL), pain during movement and at rest. The naproxen dose-concentration effect relationship curve was moved to the left by the addition of 4 g paracetamol daily. No major side effects were observed, but complaints concerning the gastrointestinal tract were fewer on lower naproxen doses and these were not increased by concomitant paracetamol treatment. The results show that the clinical effect of naproxen in RA may be significantly increased by concomitant paracetamol administration.

Acetaminophen↗

PubMed1998

A randomized controlled trial of the effect of naproxen on delayed onset muscle soreness and muscle strength.

OBJECTIVE: To determine the effect of naproxen in attenuating the symptoms (muscle soreness level) and signs (plasma creatine kinase [CK] activity and muscular strength decrement) of delayed onset muscle soreness (DOMS) induced by repeated bouts of eccentric exercise. DESIGN: The design was a randomized, double-blind, placebo-controlled, crossover trial with two testing phases of 8 days' duration that were separated by a "washout" period of 7 days. SETTING: University-based sports science center. PARTICIPANTS: Twenty healthy male volunteers who responded to a notice in the university's athletic complex. INTERVENTIONS: Eccentric single-leg exercises were performed on days 1, 3, and 4 to induce DOMS in the quadriceps muscles. Naproxen or placebo tablets (500 mg) were taken orally twice per day beginning on day 2 and continuing until the end of the testing phase. MAIN OUTCOME MEASURES: Perception of muscle soreness and knee extensor torque were evaluated daily throughout each phase. Plasma CK levels were evaluated on days 1, 3, 6, and 8 of each phase. RESULTS: After the eccentric exercise, plasma CK levels were similarly elevated in both naproxen and placebo conditions (F=1.42; p=0.25). After DOMS developed, naproxen reduced the perception of soreness on day 3, when muscle soreness was highest (F=2.20; p=0.04). After treatments with naproxen, peak quadriceps torque during leg extension at 60 degrees/s was higher than that after treatment with the placebo (F=4.77; p=0.04). There were no significant differences between the naproxen and placebo conditions for leg extension at 180 degrees/s (F= 1.66; p=0.21) and 300 degrees/s (F=0.71; p=0.41). CONCLUSION: The data indicate that therapeutic doses of naproxen do not prevent CK release into the plasma but decrease the perception of muscle soreness and positively influence quadriceps peak torque.

Adult↗

PubMed2004

Efficacy of celecoxib, a COX-2-specific inhibitor, and naproxen in the management of acute ankle sprain: results of a double-blind, randomized controlled trial.

OBJECTIVE: To assess the efficacy and safety of celecoxib and naproxen in the treatment of acute ankle sprain. DESIGN: Double-blind, parallel-group, randomized trial. SETTING: Multicenter outpatient. PATIENTS: Adult patients (n = 397) with acute first-degree or second-degree ankle sprain. INTERVENTIONS: Patients randomized to celecoxib 200 mg b.i.d. (n = 198) or naproxen 500 mg b.i.d. (n = 198) for 7 days. MAIN OUTCOME MEASURES: Primary measures of efficacy were Patient's Assessment of Ankle Pain Visual Analogue Scale (VAS) and Patient's Global Assessment of Ankle Injury. Secondary efficacy measures included Physician's Global Assessment of Ankle Injury, Patient's Return to Normal Function/Activity, and Patients' and Physicians' Satisfaction Assessments. Adverse events (AEs) were reported by investigators during the study. RESULTS: For the primary endpoints at day 4, the mean pain VAS scores were 31.9 mm +/- 1.96 for celecoxib and 29.0 mm +/- 1.91 for naproxen, and the responder rate for Patient's Global Assessment of Ankle Injury was 71% in the celecoxib group and 72% in the naproxen group, differences that were not statistically significant. In addition, noninferiority analysis demonstrated treatment differences that were within prespecified minimal clinical important differences. Gastrointestinal AEs were the most common AE, accounting for 14% in the celecoxib group and 21% in the naproxen group. The incidence of dyspepsia was 3% for celecoxib compared with 12% for naproxen (P = 0.032). CONCLUSIONS: Celecoxib is as effective as naproxen in treating acute first-degree or second-degree ankle sprains but causes significantly less dyspepsia.

Acute Disease↗

PubMed2004

Anesthetic effect of intrauterine lidocaine plus naproxen sodium in endometrial biopsy.

OBJECTIVE: To compare the efficacy of intrauterine lidocaine with oral naproxen sodium on pain perception of the patients during endometrial biopsy using the Pipelle instrument and to investigate their effects when used in combination. METHODS: One-hundred twenty women were randomly assigned to receive either 5 mL of intrauterine 2% lidocaine or saline and either 550 mg of naproxen sodium or a similar-appearing placebo tablet. Subsequently, each woman completed a 10-cm visual analog scale for subjective pain experience and a physician scored visible signs of the women's distress during the procedure using a 3-point observer scale. RESULTS: There was no statistically significant difference between the 4 groups in age, vaginal parity, history of chronic pelvic pain, menopausal status, tenaculum use, previous endometrial biopsy, or difficulty in passing the cervical os. The mean pain scores of the women in the naproxen only (5.8 +/- 2.2) and lidocaine only (5.9 +/- 2.2) groups were not significantly different compared with placebo group (7.1 +/- 2.0). However, the mean pain score in the lidocaine plus naproxen group (4.6 +/- 1.8) compared with the placebo group showed significant reduction in pain (P <.05). Pain rated by the physician was significantly lower in the lidocaine plus naproxen group compared with other groups, and a significant correlation was noted between the visual analog pain score and the patients' distress recorded by the physician (r =.791, P <.001). One patient in the naproxen-only group had vasovagal syncope after the procedure. CONCLUSION: Intrauterine lidocaine instillation significantly decreases pain associated with Pipelle endometrial biopsy when used in combination with oral naproxen sodium. LEVEL OF EVIDENCE: I

Administration, Oral↗

PubMed1995

Gastric mucosal adaptation to etodolac and naproxen.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) frequently cause damage to the gastroduodenal mucosa, principally by suppressing mucosal prostaglandin synthesis. However, such acute mucosal injury usually resolves, despite continued NSAID administration, by a process known as adaptation. Newer NSAIDs, such as etodolac, have been developed to minimize effects on prostaglandin synthesis. AIM: To determine whether etodolac causes less acute damage than naproxen, and whether the damage produced resolves with continued NSAID administration. METHODS: Twenty-four healthy volunteers were given a 28-day course of either etodolac 300 mg b.d. or naproxen 500 mg b.d. Gastroduodenal damage was assessed using a modified Lanza scoring system and mucosal blood flow with laser doppler flowmetry at endoscopy before NSAID administration and during days 1, 7 and 28 of continued intake. RESULTS: Maximum gastric damage (median grade and interquartile range, IQR) occurred during the first 24 h of administration, being greater with naproxen (2.0, IQR 1.0-3.0) than etodolac (1.0, IQR 1.0-1.5; P = 0.03). Such damage was associated with a fall in antral blood flow in the naproxen group (mean +/- S.E.M.) from 54.5 +/- 3.4 to 43.8 +/- 3.4 arbitrary units (P = 0.07) and a slight increase in mucosal blood flow in the etodolac group from 43.5 +/- 2.24 to 49.5 +/- 3.6 arbitrary units. With continued intake this damage resolved in all subjects taking etodolac and in eight of 14 subjects on naproxen. Resolution in the naproxen group was associated with a return to normal of antral blood flow. CONCLUSIONS: These observations suggest that etodolac causes less mucosal damage than naproxen and that adaptation occurs to both.

Adolescent↗

PubMed2004

Naproxen reduces excitotoxic neurodegeneration in vivo with an extended therapeutic window.

The purpose of this study was to examine the optimal dose and therapeutic window of opportunity of the nonsteroidal anti-inflammatory drug naproxen in an animal model of excitotoxic neuronal injury. Injection of N-methyl-D-aspartate (NMDA; 18-20 nmol) into the CA1 region of the left hippocampus resulted in significant brain edema as measured by the percentage of total forebrain water content that occurred 24 h after intrahippocampal microinjection of NMDA with approximately 50% loss of CA1 neurons assessed 72 h later. Naproxen pretreatment (20 mg/kg) resulted in significantly less brain edema. Ten, 15, or 20 mg/kg naproxen, administered systemically 1 day (b.i.d.) before and for 3 days after (b.i.d.) NMDA injection, attenuated the neuronal damage by 27.2 +/- 7.8, 39.6 +/- 11.1, and 57.0 +/- 5.2%, respectively. By comparison, a single dose of MK-801 (2 mg/kg i.p.) given 20 min before NMDA injection inhibited subsequent hippocampal injury by 65.6 +/- 8.8%. Most importantly, neuroprotection was still evident when naproxen treatment (20 mg/kg i.p.) was initiated 6 h after NMDA microinjection. Protection was lost if administration of naproxen was delayed for 20 h. These findings demonstrate that naproxen can prevent excitotoxic neuronal injury in vivo, that it is nearly as effective as direct NMDA receptor antagonism, and that it has an extended therapeutic time window. As such, naproxen may be a particularly promising pharmaceutical for the treatment of neurological diseases associated with overactivation of NMDA receptors.

Animals↗

PubMed2004

A randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritis.

OBJECTIVE: To evaluate the gastrointestinal safety and efficacy of the COX inhibiting nitric oxide donator AZD3582 in patients with hip or knee osteoarthritis. METHODS: 970 patients were randomised (7:7:2) to AZD3582 750 mg twice daily, naproxen 500 mg twice daily, or placebo twice daily in a double blind study. The primary end point was the six week incidence of endoscopic gastroduodenal ulcers (diameter > or =3 mm). Overall damage measured on the Lanza scale was a secondary end point. Safety and tolerability assessments included endoscopic upper gastrointestinal erosions and the gastrointestinal symptom rating scale (GSRS). Efficacy was primarily assessed by WOMAC. RESULTS: The incidence of ulcers with AZD3582 was 9.7% and with naproxen 13.7% (p = 0.07, NS), v 0% on placebo. The incidence of Lanza scores >2 was higher with naproxen (43.7%) than with AZD3582 (32.2%) (p<0.001). Compared with baseline, significantly fewer ulcers and erosions developed in stomach and stomach/duodenum combined, and fewer erosions developed in stomach, duodenum, and both combined on AZD3582 than on naproxen. GSRS reflux and abdominal pain subscale scores were lower for AZD3582 than for naproxen but there was no difference for indigestion, constipation, and diarrhoea. AZD3582 was as effective as naproxen at improving WOMAC scores. Both agents were well tolerated, with no significant effects on blood pressure. CONCLUSIONS: At doses with similar efficacy in relieving osteoarthritis symptoms, the primary end point of six week endoscopic gastroduodenal ulcer incidence was not significantly different between AZD3582 and naproxen. Most secondary endoscopic gastrointestinal end points favoured AZD3582.

Adult↗