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PubMed1998

Effect of clopidogrel on naproxen-induced gastrointestinal blood loss in healthy volunteers.

The effect of clopidogrel, a potent inhibitor of platelet aggregation, on naproxen-induced faecal blood loss was investigated in 30 healthy volunteers in a randomized, double-blind, placebo-controlled, two parallel treatment groups study. All subjects first received naproxen 250 mg b.i.d. during 7 days, after which they were randomly allocated to additionally receive either clopidogrel 75 mg once daily (n = 15) or matching placebo (n = 15) for 11 days. Faecal blood loss was measured by the 51Cr-labelled erythrocyte method during the last four days of each of the four study periods, i.e. baseline, treatment with naproxen alone, combined treatment and wash-out. Mean daily faecal blood loss was below 0.5 ml/day during the baseline period in both treatment groups and increased during treatment with naproxen alone to (mean +/- SD) 1.14 +/- 0.58 ml/day in the naproxen + placebo group and to 1.93 +/- 1.51 ml/day in the naproxen + clopidogrel group. Addition of clopidogrel to naproxen treatment was associated with an increase of the mean daily blood loss to 6.83 +/- 9.32 ml/day, which was statistically significantly higher than 1.75 +/- 1.40 ml/day observed during treatment with naproxen + placebo. During the wash-out period, mean daily blood loss decreased to 0.98 +/- 0.51 ml/day in the naproxen + placebo group and to 1.07 +/- 0.46 ml/day in the naproxen + clopidogrel group. Based on these results, it can be concluded that clopidogrel increases naproxen-induced gastrointestinal blood loss in healthy volunteers. Caution should therefore be called for when these drugs are coadministered.

Adult↗
PubMed1995

Effect of naproxen on gastroesophageal reflux and esophageal function: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: Gastrointestinal symptoms, particularly pyrosis, complicate nonsteroidal anti-inflammatory drug (NSAID) use. NSAIDs cause esophageal injury, and H2 blockers are often prescribed for, and successfully control, NSAID-related symptoms. To determine whether NSAIDs can induce gastroesophageal reflux, we studied the effect of a commonly used NSAID, naproxen, on reflux parameters and esophageal function. METHODS: Nine healthy volunteers (five males, four females, age 23-34 yr) were studied. After basal measurements were taken, the subjects randomly received naproxen 500 mg p.o. b.i.d. or placebo for 1 wk. On day 6, the subjects underwent esophageal manometry with a water-perfused system and Dent sleeve. Body pressures, contraction velocity, and duration of contraction were recorded in the distal 7 cm of the esophagus. The lower esophageal sphincter pressure (LESP) and number of transient relaxations (TLESRs) were monitored. This was followed by 24-h pH monitoring. The subjects then crossed over to the other drug after a minimum 14-day wash-out period. RESULTS: No subject experienced any GI symptoms during the study. One subject developed reflux-induced symptoms a few months after completing the study and was excluded from the analysis. The total fraction of time (pH < 4) was 4.9 +/- 1.0% in the basal state, 5.5 +/- 1.4% on placebo, and 5.4 +/- 1.5% on naproxen. These differences were not significant. The number of reflux episodes and the esophageal clearance time were not affected by naproxen. The LESP in the basal state was 32.1 +/- 5.6 mm Hg, 32.3 +/- 4.2 mm Hg on placebo, and 29.9 +/- 3.3 mm Hg on naproxen (p = NS). The number of TLESRs per 30 minutes in the basal state was 3.5 +/- 0.9, 4.6 +/- 1.2 on placebo, and 5.8 +/- 1.0 on naproxen (p = NS). The speed and duration of contractions were not affected by naproxen. The excluded subject had marked basal reflux (total fraction of time pH < 4 = 10.7%), low LESP (8 mm Hg), and a marked increase in reflux on naproxen (total fraction of time pH < 4 = 53%). CONCLUSIONS: Naproxen did not induce reflux in normal subjects, although reflux did increase in some subjects. Naproxen had no significant effect on motility parameters. Our data suggest that NSAIDs do not impair the anti-reflux barrier or induce reflux. Pyrosis experienced during NSAID use may not arise from the esophagus or may reflect altered esophageal sensitivity. A single subject with decreased LESP and asymptomatic increased acid exposure in the basal state had a marked increase in reflux on naproxen. This person subsequently developed symptomatic gastroesophageal reflux. The effect of NSAIDs on individuals with a propensity to reflux deserves further study.

Adult↗
PubMed1992

Long-term effect of naproxen on cancellous bone in ovariectomized rats.

Previous work shows that at 42 d post-ovariectomy (OX) in aged rats, naproxen, a nonsteriodal anti-inflammatory drug (NSAID) prevents cancellous bone loss. The purpose of this study was to evaluate the effects of naproxen on cancellous bone of aged OX and sham-OX rats, at 90 days post-OX. Six-month-old Sprague-Dawley retired breeder female rats underwent either sham-OX (n = 49) or OX (n = 65). Sham-OX rats were randomized into five groups and OX rats into six groups. The first five groups of both were given ad lib access to water containing 0, 4, 10, 25, or 62.5 mg/l of naproxen sodium. The sixth group of OX rats was given water containing 156.25 mg naproxen sodium/l. After ninety days, the rats were killed following in vivo dual calcein labeling. Terminal serum naproxen was measured by HPLC. In the proximal tibial metaphysis, trabecular bone volume, trabecular thickness, trabecular number, mineralizing surface (double label), osteoclast surface, and bone formation rate were measured. Sham-OX and OX rats were compared by t-test of means. Kruskal-Wallis tests and, as necessary, Dunnett's t-tests, were applied separately to the groups of Sham-OX and OX rats. Dose-related serum levels of naproxen up to 9.4 mcg/ml were achieved in the 156.25 mg/ml group. OX rats had significantly lower bone volume, trabecular thickness, and trabecular number than Sham-OX groups (p less than .001). OX rats had significantly higher mineralizing surface, formation rate, and osteoclast surface than sham-OX rats (p less than .001). No differences related to naproxen treatment existed in sham-OX rats. Naproxen treatment producing a serum level of 9.4 mcg/ml reduced bone volume in OX rats consuming water with 156.25 mg/l (p less than .05). At 90 days post-OX, naproxen, at serum levels of 9.4 mcg/ml or less, did not diminish estrogen-depletion cancellous bone loss in rats. Naproxen lacks lasting ability to halt estrogen-depletion bone loss in aged OX rats.

Animals↗
PubMed2004

Postoperative naproxen after coronary artery bypass surgery: a double-blind randomized controlled trial.

OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) are routinely used after coronary artery bypass surgery (CABG), yet their effects have seldom been evaluated in randomized controlled settings. The aim of this study was to examine the efficacy and safety of a commonly used NSAID, naproxen. We hypothesized that naproxen would reduce postoperative pain following CABG without increasing complications. METHODS: Patients (N=98) undergoing primary CABG were randomized to receive naproxen (500 mg q12hX5 doses via suppository started 1h after operation, followed by oral 250 mg q8hX6 doses) or placebo. Standard analgesic and anti-emetic regimens were available to both patient groups. Interventions were double-blinded. Primary end-points were postoperative pain measured before and after chest physiotherapy by visual analog scale and pulmonary slow vital capacity (SVC). RESULTS: Baseline characteristics were equivalent between the two groups. Over the first 4 postoperative days, naproxen decreased pain by 47+/-17% on average before chest physiotherapy (P=0.034), and 44+/-13% after chest physiotherapy (P=0.0092). Patients who received naproxen also had better preservation of SVC over the first 4 postoperative days (mean loss of SVC from baseline: 2.1+/-0.1 vs. 2.5+/-0.1l, naproxen vs. placebo, P=0.0032). This was concomitant with a lower white blood cell count observed in naproxen patients (9.2+/-0.3 vs. 12.7+/-1.5x10(9)/l, naproxen vs. placebo, P=0.03). Patients who received naproxen had more chest tube drainage after 4h postoperatively, but there was no difference in the incidence or amount of transfusions. There was no difference in medication use, length of stay, or in the incidence of atrial fibrillation, azotemia, and other complications. CONCLUSIONS: Naproxen is an effective and low-cost adjunct for optimization of pain control and lung recovery after CABG. Its use may result in increased chest tube drainage, but no apparent increase in other complications.

Analysis of Variance↗
PubMed2005

Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects.

OBJECTIVES: We investigated the occurrence of pharmacodynamic interaction between low-dose aspirin and naproxen. BACKGROUND: The uncertainty of cardioprotection by naproxen has encouraged its combination with aspirin in patients with arthritis and cardiovascular disease. METHODS: The incubation of washed platelets with naproxen for 5 min before the addition of aspirin reduced the irreversible inhibition of thromboxane (TX)B(2) production by aspirin. The pharmacodynamic interaction between the two drugs was then investigated in four healthy volunteers who received aspirin (100 mg daily) for 6 days and then the combination of aspirin and naproxen for further 6 days: aspirin 2 h before naproxen (500 mg, twice-daily dosing). After 14 days of washout, naproxen was given 2 h before aspirin for further 6 days. RESULTS: The inhibition of serum TXB(2) production (index of platelet cyclooxygenase [COX]-1 activity) and platelet aggregation ex vivo and urinary 11-dehydro-TXB(2) levels (index of TXB(2) biosynthesis in vivo) by aspirin alone (99 +/- 0.2%, 95 +/- 0.6%, and 81 +/- 4%, respectively) was not significantly altered by the co-administration of naproxen, given either 2 h after aspirin or in reverse order. In a second study, the concurrent administration of a single dose of aspirin and naproxen did not affect platelet TXB(2) production and aggregation at 1 h after dosing, when aspirin alone causes maximal inhibitory effect. Moreover, the rapid recovery of platelet COX-1 activity and function supports the occurrence of a pharmacodynamic interaction between naproxen and aspirin. CONCLUSIONS: Naproxen interfered with the inhibitory effect of aspirin on platelet COX-1 activity and function. This pharmacodynamic interaction might undermine the sustained inhibition of platelet COX-1 that is necessary for aspirin's cardioprotective effects.

Adult↗
PubMed2000

Piperazinylalkyl prodrugs of naproxen improve in vitro skin permeation.

Novel morpholinyl (4a) and piperazinylalkyl (4b-e) esters were synthesized and evaluated in vitro for their properties as bioreversible topically administered dermal prodrugs of naproxen. These ionizable prodrugs exhibited various aqueous solubilities and lipophilicities, depending on the pH of medium. As indicated by octanol-buffer partition coefficients (logP(app)) at pH 7.4, all of the prodrugs were significantly more lipophilic (logP(app)=0.7-3.9) than naproxen (logP(app)=0.3). Furthermore, the most aqueous of the soluble prodrugs (4b-d) were only 2-3-fold less soluble in an aqueous buffer of pH 7.4 ( approximately 30-50 mM) than was naproxen ( approximately 100 mM). At a pH of 5.0, prodrugs showed a generally higher aqueous solubility and similar logP(app) values, compared to naproxen. The chemical and enzymatic hydrolysis of prodrugs at 37 degrees C was investigated in aqueous buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4), respectively. The prodrugs showed moderate chemical stability (t(1/2)=15-150 days at pH 5.0), and they were hydrolyzed enzymatically to naproxen, with half-lives ranging from 0.4 to 77 min. In permeation studies using post-mortem human skin in vitro, the flux of naproxen was 6.5 and 1.6 nmol/cm(2). h in a saturated aqueous buffer vehicle of pH 7.4 and 5.0, respectively. Among the prodrugs, two piperazinyl derivatives (4c and 4d) resulted in a 9- and 4-fold enhancement of permeation, respectively, when compared to naproxen itself at pH 7.4. 4c also resulted in a significantly (4-fold) better permeation than naproxen at pH 5.0. In conclusion, piperazinyl esters improved skin permeation of naproxen and are promising prodrugs of naproxen for topical drug delivery.

Administration, Cutaneous↗
PubMedDate not supplied

Response surface methodology to obtain naproxen controlled release tablets from its microspheres with Eudragit L100-55.

PURPOSE: Naproxen CR tablets have been obtained from its microspheres prepared by coprecipitation with Eudragit L100-55. The purpose of this work was to evaluate the main and interaction effects of deaggregating agent concentration (X1), compression pressure (X2) and amount of precipitating water (X3) on naproxen release. A secondary purpose was to obtain an optimized naproxen controlled release solid oral dosage form with a predictable 12 h drug release. METHOD: Eudragit L100-55 (10 g) was dissolved in 100 ml of ethyl alcohol, and 30g of naproxen was dispersed in it with stirring. Purified water (100mL, cooled to 4 degrees C) containing calcium chloride as a deaggregating agent was added to an alcoholic solution and homogenized. The mixture was filtered to obtain microspheres. Drug content analysis was performed spectrophotometrically at 332 nm. Tablets were prepared by compressing microspheres containing 500mg of naproxen after adding 1% magnesium stearate. Dissolution was performed by the USP specifications of naproxen tablets. A 3-factor 3-level Box-Behnken design was employed to get 15 experimental runs. The independent variables used were X1, X2 and X3. The dependent variables were dissolution at different time points with constraints on yield value and angle of repose of the microspheres, and hardness and thickness of the tablets. The dissolution constraints were placed such that the naproxen is released for 12 h by Higuchi's square root of time kinetics. RESULTS: The mathematical relationship obtained between X1, X2, X3 and the cumulative per cent of naproxen dissolved in 12 h with various constraints (Y5) was Y5 = 92.39 - 1.13X1 - 4.84X2 - 2.12X3 - 2.26X1X2 - 0.5X1X3 - 0.4X2X3 + 2.4X(1)(2) - 0.4X(2)(2) (R2 = 0.9). The equation shows that X1, X2 and X3 affected the release inversely, and the most significant interaction was between X1 and X2. Y5 has been maximized for optimization of naproxen release. CONCLUSIONS: Controlled release tablets of naproxen with predictable drug release characteristics were obtained by compressing its microspheres with Eudragit L100-55.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

Analgesic efficacy and safety of nonprescription doses of naproxen sodium compared with acetaminophen in the treatment of osteoarthritis of the knee.

Nonprescription doses of naproxen sodium, acetaminophen, and placebo were compared to determine their efficacy and safety in osteoarthritis of the knee. In two identical multicenter, randomized, double-blind, placebo-controlled, multidose, parallel-design studies, patients with osteoarthritis aged (mean +/- SD) 60.6 +/- 12.8 years were randomized to daily doses of 660 mg naproxen sodium (440 mg naproxen sodium in patients >or=65 years), 4000 mg acetaminophen, or placebo for 7 days. Naproxen sodium (440/660 mg) provided significantly greater improvements in pain at rest, on passive motion, on weight-bearing, stiffness after rest (morning), day and night pain compared with placebo, and significantly greater relief from resting pain than acetaminophen (P < 0.05). Acetaminophen provided significantly greater improvements in day pain compared with placebo. Daily evaluations showed naproxen sodium (440/660 mg) provided superior pain relief to acetaminophen and was significantly better than acetaminophen at reducing difficulties experienced in walking several blocks and difficulties in bending, lifting, and stooping. Naproxen sodium (440/660 mg) and acetaminophen (4000 mg) were significantly more effective than placebo in improving mobility level, household tasks, and walking and bending. Patient and investigator evaluation scores were significantly higher in naproxen sodium and acetaminophen groups compared with placebo; no differences were observed between active treatments. Naproxen sodium and acetaminophen had similar safety profiles to placebo. Nonprescription doses of naproxen sodium (440/660 mg) effectively relieve pain and other symptoms of osteoarthritis. Naproxen sodium is an alternative in the initial treatment of osteoarthritis and may be preferred to acetaminophen as first-line therapy in patients with moderate or severe pain.

Acetaminophen↗
PubMed1993

The pharmacokinetics of naproxen, its metabolite O-desmethylnaproxen, and their acyl glucuronides in humans. Effect of cimetidine.

1. The pharmacokinetics of 500 mg naproxen given orally were described in 10 subjects using a direct h.p.l.c. analysis of the acyl glucuronide conjugates of naproxen and its metabolite O-desmethylnaproxen. 2. The mean elimination half-life of naproxen was 24.7 +/- 6.4 h (range 7 to 36 h). 3. Naproxen acyl glucuronide accounted for 50.8 +/- 7.3% of the dose recovered in the urine, its isomerised conjugate isoglucuronide for 6.5 +/- 2.0%, O-desmethylnaproxen acyl glucuronide for 14.3 +/- 3.4%, and its isoglucuronide for 5.5 +/- 1.3%. Naproxen and O-desmethylnaproxen were excreted in negligible amounts (< 1%). 4. Even though the urine pH of the subjects was kept acid in order to stabilize the acyl glucuronides, isomerisation took place in blood. 5. The extents of plasma binding of the unconjugated compounds were 98% (naproxen) and 100% (O-desmethylnaproxen), while naproxen acyl glucuronide binding was 92%; that of its isomer isoglucuronide 66%. O-desmethylnaproxen acyl glucuronide was 72% bound and its isoglucuronide was 42% bound. 6. Cimetidine (400 mg twice daily) decreased the t1/2 of naproxen by 39-60% (mean 47.3 +/- 11.5%; P = 0.0014) from 24.7 +/- 6.4 h to 13.2 +/- 1.0 h. It increased (10%) the urinary recovery of naproxen acyl glucuronide (P = 0.0492). The urinary recoveries of naproxen isoglucuronide and O-desmethylnaproxen acyl glucuronide remained unchanged.

Adult↗
PubMed1979

Naproxen up to date: a review of its pharmacological properties and therapeutic efficacy and use in rheumatic diseases and pain states.

Naproxen is a propionic acid derivative with analgesic and anti-inflammatory activity which has been widely used in the treatment of rheumatic diseases. Naproxen has been well studied in rheumatoid arthritis and is as effective as aspirin but better tolerated, thus enabling more patients to continue with treatment. For this reason some clinicians now prefer to try propionic acid derivatives, such as naproxen, before aspirin in arthritic patients. In comparative studies with other non-steroidal anti-inflammatory drugs, such as indomethacin, ibuprofen, fenoprofen and others, all drugs were usually of similar overall efficacy although naproxen was sometimes preferred: but as with other non-steroidal anti-inflammatory agents, not all patients will respond to naproxen and in such cases other agents should also be tried until the most satisfactory drug is found for each patient. Naproxen is also effective in degenerative joint diseases of the hip and knee, although further well designed studies are needed to more clearly define its relative place compared with newer drugs such as diclofenac or diflunisal. Results of other comparative studies have shown that naproxen is a suitable alternative to phenylbutazone or indomethacin in ankylosing spondylitis and to aspirin in juvenile rheumatoid arthritis. Naproxen appears to be effective in reducing pain and swelling in acute gout and is an effective analgesic in patients with pain following surgery or trauma and in pain of dysmenorrhoea. Naproxen has generally been better tolerated than aspirin or indomethacin at the dosages used. Because of its relatively long plasma half-life, naproxen can with convenieice be given twice daily, and there is some evidence that once daily dosage is as effective in rheumatoid arthritis.

Animals↗
PubMed2004

Comparison of the analgesic efficacy and safety of nonprescription doses of naproxen sodium and Ibuprofen in the treatment of osteoarthritis of the knee.

OBJECTIVE: To compare the analgesic efficacy and safety of nonprescription doses of naproxen sodium, ibuprofen, and placebo in patients with osteoarthritis (OA) of the knee. METHODS: In 2 identical multicenter, randomized, double-blind, placebo-controlled, multidose, parallel-design studies, patients aged > or = 25 years with OA were randomized to daily doses of naproxen sodium 660 mg, naproxen sodium 440 mg (patients > or = 65 years), ibuprofen 1200 mg, or placebo, for 7 days. RESULTS: For investigator and patient assessment of knee joint pain, naproxen sodium (440/660 mg) and ibuprofen were clinically effective at relieving pain compared with placebo (n = 444); both treatments reduced the mean symptom score by 30-45%, compared with a 20-25% reduction with placebo. Naproxen sodium (440/660 mg) significantly improved all 7 symptoms from baseline compared with placebo, while ibuprofen significantly improved 5 of the symptoms. For the subgroup of patients aged > or = 65 years (n = 183), naproxen sodium 440 mg was significantly superior to placebo in all symptoms except pain on weight-bearing; ibuprofen only significantly reduced day pain. For daily diary evaluations, naproxen sodium and ibuprofen were effective in reducing all 6 symptoms; there was a trend toward higher efficacy for night-time pain with naproxen sodium 440/660 mg compared with ibuprofen. There were no significant differences in adverse event reporting between groups. CONCLUSION: Over-the-counter doses of naproxen sodium (440/660 mg) and ibuprofen (1200 mg) effectively relieve pain in patients with mild to moderate OA of the knee. Naproxen sodium provided more effective pain relief for most variables compared with placebo, and for night pain compared with ibuprofen. Efficacy was combined with good safety and tolerability.

Aged↗
PubMed1997

Pharmacokinetic and local tissue disposition studies of naproxen-following topical and systemic administration in dogs and rats.

The pharmacokinetic profiles of naproxen in blood and synovial fluid (SF) following topical and i.v. bolus administration in dogs, and the local tissue disposition of the drug following topical and oral administration in rats, were investigated to assess the feasibility of topical delivery of naproxen for local and systemic effects. The naproxen gel in poloxamer 407 (PF-127) was applied on the stifle joint of dogs, and serum and synovial fluid samples were collected. For local tissue disposition studies, the naproxen gel was applied on the dorsal skin in rats, and blood, skin, and muscle samples were taken at 3, 6, and 12 h postdose after removing the residual gel from the skin. Steady state serum concentrations occurred at approximately 20 h after topical doses and lasted for the next approximately 30 h in dogs. Similar SF-serum concentration ratios of naproxen were found between i.v. (0.61 +/- 0.16) and topical (0.55 +/- 0.14) routes of administration. Following the i.v. dose, the half-life of naproxen in SF (approximately 60 h) was significantly longer than that in serum (approximately 40 h). The bioavailability of naproxen in the topical gel was approximately 2% of the applied dose in dogs. A large accumulation of drug in the epidermis, dermis, and muscle tissue beneath the gel application site was found in rats. Isopropyl myristate (IPM) significantly increased the systemic absorption as well as the concentrations of naproxen in the underlying dermis and muscle tissues, but exerted little effect on the disposition of naproxen in the epidermis.

Administration, Oral↗
PubMed1989

Effect of R and S enantiomers of naproxen on aggregation and thromboxane production in human platelets.

The effects of R and S enantiomers of naproxen [(+)-6-methoxy-alpha-methyl- 2-naphthaleneacetic acid] were studied on platelet aggregation and on the production of thromboxane B2 from collagen-stimulated human platelets in order to determine the effect of each enantiomer in terms of cyclooxygenase inhibition. S-Naproxen caused inhibition of platelet aggregation in platelet-rich plasma and washed human platelets in a concentration-related fashion in the range 1-80 micrograms/L. A similar concentration-related suppression was noted for R-naproxen, but this inhibition was significantly less than that induced by S-naproxen for all concentrations except 1 micrograms/L. Similarly, both R- and S-naproxen (1-80 micrograms/L) caused a concentration-dependent suppression of thromboxane B2 production from platelet-rich plasma. These values were significant at all concentrations of drug (10-80 micrograms/L) except at 1 micrograms/L. Significant differences in thromboxane B2 production from washed human platelets were noted at concentrations of 10 and 25 micrograms/L. The findings support previous studies reported in the literature that S-naproxen is more active than R-naproxen. Our findings that S-naproxen is more active than R-naproxen on collagen-stimulated platelet aggregation and prostaglandin production suggest that the findings of greater activity of S isomer over the R isomer in animal models of inflammation may be a direct expression of the differential action on prostaglandin synthesis.

Collagen↗
PubMed1980

Pharmacokinetics of naproxen in subjects with normal and impaired renal function.

The pharmacokinetics of naproxen after a single oral dose of 250 mg has been studied in 8 subjects with normal renal function and 16 patients with varying degrees of chronic renal insufficiency. Unchanged naproxen and its main unconjugated metabolite, 6-0-desmethylnaproxen, were determined fluorometrically in serum. In healthy subjects the elimination half-life of naproxen was 17.7 +/- 3.0 h (mean +/- SD) and it was not significantly prolonged in patients with renal failure (18.1 +/- 5.3) h. No accumulation of naproxen in serum occurred in uraemic patients. On the contrary, serum drug levels were slightly but significantly lower in patients with severe renal failure. The total body clearance and apparent volume of distribution of naproxen were significantly increased in this group of patients. Decreased binding of naproxen to serum proteins was observed in patients with renal failure. The apparent half-life of desmethylnaproxen was of the same order of magnitude as that of naproxen (18.6 +/- 4.4 h), and was also independent of renal function. A good correlation was found between the area under the curve (AUC), the peak concentration of the metabolite and the serum creatinine concentration. These observations suggest increased metabolism and an increased apparent volume of distribution of naproxen in severe renal failure, probably caused by decreased serum protein binding of the drug. However, it is proposed that in naproxen therapy no adjustment of the dosage regimen is necessary in patients with impaired renal function.

Adult↗
PubMed1987

Effects of concurrent sucralfate administration on pharmacokinetics of naproxen.

Sucralfate has been reported to protect the gastroduodenal mucosa against a variety of agents and is known to adsorb bile salts. Since gastrointestinal side effects can seriously compromise the efficacy of nonsteroidal anti-inflammatory drug therapy, and since it seems reasonable to assume that sucralfate may adsorb nonsteroidal anti-inflammatory drugs, the influence of sucralfate on the pharmacokinetic parameters of naproxen was assessed in 12 healthy volunteers. To do so, the pharmacokinetic profile of naproxen, administered alone or with sucralfate, singly or repeatedly (twice daily for five days), was compared. No significant difference was observed with any pharmacokinetic parameter between the single administration of naproxen alone or with sucralfate. However, a significantly lower maximum plasma concentration was attained with the repeated administration of naproxen in combination with sucralfate, compared with the repeated administration of naproxen alone. When single- and multiple-dose administration were compared, significant differences were observed in the maximum plasma concentration and the cumulative area under the curve. These results suggest an accumulation of naproxen after five days' administration. This accumulation, however, is not altered by the administration of sucralfate. The results of this study suggest that when naproxen is administered with sucralfate, only a delay in naproxen's absorption may occur, confirmed by a lower maximum plasma concentration, a longer time to reach the maximum plasma concentration, a similar elimination half-life, and equivalence in bioavailability. The clinical importance of such a delay has yet to be proved; however, it is unlikely that the clinical efficacy of naproxen will be altered, since the amount of drug absorbed remains the same.

Absorption↗
PubMed2006

Naproxen-induced oxidative stress in the isolated perfused rat liver.

We previously showed that naproxen induced the oxidative stress in the liver microsomes and the isolated hepatocytes of rats. In this study, the in situ effect of naproxen on the rat liver tissue was investigated, using the isolated perfused liver from the view-point of the naproxen-induced hepatotoxicity. The leakage of glutamic-oxaloacetic transaminase (GOT) from the perfused liver and appearance of thiobarbituric acid reactive substances (TBARS) in the perfusate increased with the progress of perfusion after a lag time of about 1h. The naproxen-perfusion of the liver decreased the biliary excretion of glutathione (GSH) and oxidized glutathione, glutathione disulfide (GSSG) prior to TBARS production and GOT leakage. GSSG content in the naproxen-perfused liver was significantly higher than in the control. TBARS appeared in the perfusate of the naproxen-perfused liver for 30 min, but not in the control. The biliary excretion clearance (CL(bile)) of indocyanine green (ICG), a reagent for testing the liver function, in the liver perfused with naproxen decreased to a half of that in the liver perfused without naproxen. Thus, the naproxen-induced oxidative stress in the liver was shown to affect the physiological function of liver through the impairment of biliary excretion, which is recognized as a detoxification system.

Animals↗
PubMed2003

Zinc-naproxen complex: synthesis, physicochemical and biological evaluation.

Naproxen has a propensity to cause ulcers whereas zinc ions are known to possess an anti-ulcer and anti-inflammatory activity. Therefore, zinc complex of naproxen was prepared by adding zinc sulfate to an aqueous solution of sodium naproxen and its structure was characterized by IR, 1H NMR and 13C NMR, UV, DSC, atomic absorption spectroscopy, and elemental analysis. Anti-inflammatory studies, using the carrageenan-induced hind paw oedema showed that there was a significant difference (P<0.05, ANOVA plotted by Dunnet's test) in the anti-inflammatory activity of naproxen, its zinc complex, and the physical mixture of naproxen and zinc sulfate. In addition, zinc complex of naproxen showed a significant reduction in ulcers (lesion index (LI)) as compared to that of naproxen and physical mixture of naproxen and zinc sulfate. Thus, the use of the complex may be preferable to naproxen alone.

Animals↗
PubMed1999

Synthesis and in vitro evaluation of aminoacyloxyalkyl esters of 2-(6-methoxy-2-naphthyl)propionic acid as novel naproxen prodrugs for dermal drug delivery.

PURPOSE: To synthesize and evaluate various novel aminoacyloxyalkyl esters of naproxen (3a-i) and naproxenoxyalkyl diesters of glutamic and aspartic acids (3j-m) as potential dermal prodrugs of naproxen. METHODS: The prodrugs 3a-m were synthesized, and their aqueous solubilities, lipophilicities and hydrolysis rates were determined in a buffered solution and in human serum. The permeation of selected prodrugs across excised postmortem human skin was studied in vitro. RESULTS: The aminoacyloxyalkyl prodrugs showed higher aqueous solubilities and similar lipid solubilities, in terms of octanol-buffer partition coefficients (log Papp) at pH 5.0, when compared with naproxen. At pH 7.4 the prodrugs were significantly more lipophilic than naproxen. Prodrugs 3a-i showed moderate chemical stability in aqueous solutions at pH 5.0 and were rapidly converted to naproxen in human serum (t1/2 = 4-19 min). The selected aminoacyloxyalkyl prodrugs possessed a higher flux across the skin than naproxen, with a maximum enhancement of 3-fold compared to naproxen. Prodrugs 3j-m showed poor aqueous solubility and permeation across the skin. CONCLUSIONS: Combinations of adequate aqueous solubility and lipophilicity of naproxen aminoacyloxyalkyl prodrugs having fast rates of enzymatic hydrolysis resulted in improved dermal delivery of naproxen.

Anti-Inflammatory Agents, Non-Steroidal↗