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PubMed2002

Comparison of the efficacy and safety of nonprescription doses of naproxen and naproxen sodium with ibuprofen, acetaminophen, and placebo in the treatment of primary dysmenorrhea: a pooled analysis of five studies.

BACKGROUND: Dysmenorrhea is the most common menstrual complaint in young women, with a prevalence as high as 90%. It is responsible for substantial repeated short-term absenteeism from school and work in young women. Effective treatments are available, including nonsteroidal anti-inflammatory drugs (NSAIDs). In many countries, a variety of NSAIDs have become available as over-the-counter (OTC) drugs. OBJECTIVE: The goal of this study was to compare the efficacy and safety of OTC doses of naproxen (400 mg) and naproxen/naproxen sodium (200/220 mg) with acetaminophen (1000 mg), ibuprofen (200 mg), and placebo in the treatment of primary dysmenorrhea. METHODS: A pooled analysis of 5 trials was performed. Efficacy was assessed by pain relief, relief of other dysmenorrheic symptoms, time to backup medication or remedication, and treatment preference. Tolerability was assessed by recording adverse events (AEs). RESULTS: A total of 443 women were enrolled in the combined studies. Naproxen 400 mg provided greater pain relief than acetaminophen and placebo within 30 minutes of administration (P < 0.01 and P < 0.05, respectively). Furthermore, naproxen 400 mg and 200 mg provided greater pain relief than both acetaminophen (P < 0.01 and P < 0.05, respectively) and ibuprofen (P < 0.001 and P < 0.01, respectively) at 6 hours after administration. Both doses of naproxen had higher scores than placebo for symptom relief and drug preference (all P < 0.001). The AEs and their frequency were similar among the treatment groups. No serious AEs were reported. CONCLUSION: When administered at OTC doses, naproxen was effective in the relief of pain and other symptoms of primary dysmenorrhea and had a good safety profile in the population studied.

Acetaminophen↗

PubMed1996

Displacement of valproic acid and carbamazepine from protein binding in normal and uremic sera by tolmetin, ibuprofen, and naproxen: presence of inhibitor in uremic serum that blocks valproic acid-naproxen interactions.

Displacement of valproic acid (90-95% bound to albumin) and carbamazepine (80% bound to albumin) by salicylate, leading to higher concentrations of pharmacologically active free drugs, has been reported. We studied the possibility of displacement of valproic acid and carbamazepine by other strongly albumin-bound nonsteroidal antiinflammatory drugs tolmetin, ibuprofen, and naproxen. We observed statistically significant displacement of carbamazepine from protein binding in uremic serum at higher therapeutic concentrations of all three antiinflammatory drugs we studied, whereas in normal serum, we observed statistically significant displacement only with 75 micrograms/ml of naproxen. For valproic acid, we observed significant displacement even at lower therapeutic concentrations with all three drugs when the study was conducted using a normal serum pool. In the uremic serum pool, we observed significant displacements only with tolmetin and ibuprofen, whereas we observed no significant displacement of valproic acid even with higher concentrations of naproxen. We conclude that tolmetin, naproxen, and ibuprofen can displace both carbamazepine and valproic acid from protein binding, but uremic serum contains an inhibitor that blocks valproic acid-naproxen interaction.

Binding, Competitive↗

PubMed1992

Efficacy and tolerability of enteric-coated naproxen in the treatment of osteoarthritis and rheumatoid arthritis: a double-blind comparison with standard naproxen followed by an open-label trial.

One hundred and twenty-three patients with osteoarthritis (n = 50) or rheumatoid arthritis (n = 73) were enrolled in a 6-week, double-blind, randomized, controlled, parallel trial comparing enteric-coated naproxen with standard naproxen. Ninety-eight patients subsequently entered a 20-week, open-label trial of enteric-coated naproxen. The study demonstrated that naproxen in both its standard formulation and its new enteric-coated formulation is a highly effective form of therapy for osteoarthritis and rheumatoid arthritis. The tolerability profiles of the two formulations were similar in terms of the types of complaints reported. It is concluded that enteric-coated naproxen is an efficacious and well-tolerated formulation for the treatment of osteoarthritis and rheumatoid arthritis.

Adult↗

PubMed2006

Nitronaproxen: AZD 3582, HCT 3012, Naproxen Nitroxybutylester, NO-Naproxen.

Nitronaproxen [AZD 3582, HCT 3012, naproxen nitroxybutylester, NO-naproxen] is a naproxen derivative with similar anti-inflammatory activity to the parent compound, but with less gastrointestinal toxicity. It is the first of a new class of analgesic and anti-inflammatory drugs known as cyclo-oxygenase-inhibiting nitric oxide donators (CINODs), which are under development by NicOx. The better gastrointestinal tolerability of nitronaproxen appears to be due to its release of nitric oxide (NO) and the consequent maintenance of tissue perfusion and integrity. Nitronaproxen is in phase III clinical development for the treatment of osteoarthritis and is available for licensing. AstraZeneca had been a worldwide licensee for nitronaproxen and other CINODs. However, the results of phase II clinical trials of nitronaproxen did not fulfill AstraZeneca's strategic commercial criteria for further investment and NicOx reacquired rights following AstraZeneca's decision to discontinue its involvement in 2003. NicOx was surprised by AstraZeneca's decision, and remained fully convinced of the potential of nitronaproxen. NicOx is seeking new partners for development of compounds of the CINOD class. Nitronaproxen is in a phase III clinical trial for the treatment of osteoarthritis (OA) of the knee. The 13-week trial completed enrolment of 820 patients from 120 clinical sites in the US in May 2006. The study is designed to confirm that nitronaproxen is superior to placebo and is as effective as naproxen in relieving signs and symptoms of OA. The study will also seek to show that nitronaproxen has no adverse effect on blood pressure. An additional trial has begun that is employing ambulatory blood pressure monitoring to provide a description of the blood pressure effect of nitronaproxen over a 24-hour period in hypertensive subjects. This US trial will enrol approximately 120 volunteers with stable essential hypertension. The volunteers will not have osteoarthritis but will be between the ages of 50 and 75 years (representative of the osteoarthritis population). Results from both trials are expected in the fourth quarter of 2006. The phase II clinical programme for nitronaproxen, which included 2709 patients in five separate clinical studies, showed that the drug is a potent, safe anti-inflammatory agent, with potential for improved cardiovascular safety over NSAIDs and COX-2 selective NSAIDs. An independent advisory board recommended further development of nitronaproxen in the treatment of osteoarthritis in 2004 based on an evaluation of the full results of the phase II clinical programme.A clinical study had begun in September 2004 at the University of Pennsylvania in patients with mild essential hypertension, in which the effects of nitronaproxen and rofecoxib on arterial blood pressure would be compared. However, rofecoxib was withdrawn worldwide on 1 October 2004. It is unclear if the trial was completed. The STAR Multinational Study Group has conducted a phase II gastrointestinal safety and efficacy study of nitronaproxen versus naproxen in 970 patients with osteoarthritis at 80 sites in the following countries: Argentina, Brazil, Hungary, Mexico, Norway, Poland, South Africa and the UK. The study was completed in November 2002. AstraZeneca conducted a randomised, phase II trial evaluating the efficacy and safety of nitronaproxen among 672 subjects with symptomatic knee osteoarthritis. Results have been presented. Certain phase II trial data from 2003 had been somewhat disappointing. However, an underpowered trial and failures and deficiencies in a trial meant that it was not possible to draw conclusions from this data.

Animals↗

PubMedDate not supplied

Cyclobenzaprine and naproxen versus naproxen alone in the treatment of acute low back pain and muscle spasm.

Two groups of 20 patients each, with mild to moderate acute low back pain with associated muscle spasm of ten days' duration or less, were treated with a combination of cyclobenzaprine and naproxen or naproxen alone in a randomized, 14-day open-label trial. Cyclobenzaprine was added to the naproxen regimen as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful, musculoskeletal conditions. The clinical characteristics of each study group, including the number of worker's compensation patients, were comparable. Combination therapy was associated with less objective muscle spasm and tenderness and greater motion of the lumbosacral spine (P less than 0.05). There were trends toward faster resolution of functional deficits and pain with combined therapy. Combination therapy was associated with more side effects, due primarily to drowsiness from the cyclobenzaprine. The results of this study demonstrated that patients with muscle spasm associated with acute low back strain benefited from the use of combination therapy consisting of a nonsteroidal anti-inflammatory agent (naproxen) and a muscle relaxant (cyclobenzaprine).

Adult↗

PubMed1997

Surfactant effect on enhancing (S)-naproxen prodrug production from racemic naproxen by lipase.

In the enantioselective esterification of racemic naproxen with 4-(2-hydroxyethyl) morpholine by Lipase MY in organic solvents, a productivity improvement of the desired (S)-naproxen ester from 0.42 to 0.72 mM at the reaction time of 130 h was observed, when the surfactant bis (2-ethylhexyl) sodium sulfosuccinate (AOT) was added in the reaction mixture. The presence of a small amount of exogenously added water dramatically activated the enzyme in AOT/cyclohexane-reversed micelles. Desorption of the surfactant molecule from the enzyme mass and solubilization of the enzyme into reversed micelles were used to elucidate an existing maximum of the initial rate of (S)-naproxen synthesis with the water content. Moreover, the effects of alcohol and surfactant concentration on the enzyme activity are reported.

Dioctyl Sulfosuccinic Acid↗

PubMed2000

Isolation of (S)-(+)-naproxene from Musa acuminata. Inhibitory effect of naproxene and its 7-methoxy isomer on constitutive COX-1 and inducible COX-2.

The isolation and characterisation of (S)-(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid, a well known synthetic non-steroidal anti-inflammatory drug (naproxene), from a natural source is described for the first time. We evaluated the ability of naproxene and its 7-methoxy isomer to abrogate constitutive COX-1 and inducible COX-2 activity in human A549 cells. Naproxene inhibited COX-1 (IC50 = 3.42 microM) and COX-2 (IC50 = 1.53 microM), whereas the 7-methoxy isomer had no appreciable effect on COX-1 (IC50 >> 100 microM) but also abrogated the activity of COX-2 enzyme (IC50 = 14.42 microM).

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Structure and hydration properties of hydroxypropyl methylcellulose matrices containing naproxen and naproxen sodium.

The present study was conducted to obtain a deeper insight into the mechanism of drug release from HPMC matrices. The microstructure, mobility, internal pH and the state of water within the gel layer of hydrated HPMC matrices (having different molecular weights) containing naproxen sodium (NS) and naproxen (N) were studied using Electron Paramagnetic Resonance (EPR), Nuclear Magnetic Resonance (NMR) and Differential Scanning Calorimetry (DSC) techniques. The study show that matrices composed of various viscosity grades of HPMC are characterized by similar microviscosity values in spite of the difference in their molecular weight. The NMR and DSC results led to the conclusion that higher molecular weights of HPMC are characterized by higher water absorption capacity and higher swelling. Analysis of non-freezable water in HPMC(K4M)-NS system revealed that addition of NS to solution increased the fraction of water bound to K4M+NS compared with the equivalent solutions without NS. The results suggest that the drug is participating in the crystallization of water and leads to the formation of a three dimensional network structure that decreases the freedom of water in K4M+NS samples. Calculation of the number of hydration shells showed that up to 2.2 layers are involved in HPMC-NS hydration compared to 1.5 layers for HPMC gel without NS. This was explained based on the different water ordering in the gel induced by NS as results of its absorption to polymer surface. Microviscosity values measured by EPR for K4M/N and K4M/NS hydrated matrices were found to be higher for K4M/N matrices, especially at initial stage of hydration. Mobile compartment calculations showed lower values for K4M/N compared with K4M/NS matrices. pH measurements by EPR revealed that incorporation of N to HPMC matrix led to lower internal pH value inside the hydrated tablet compared with NS. This behavior led to lower solubility of N which dictates its surface erosion mechanism, compared with NS matrix that was characterized by higher internal pH value and higher drug solubility. These properties of HPMC/NS increased chain hydration and stability, and led to drug release by the diffusion mechanism.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2002

Chemical reactivity of the naproxen acyl glucuronide and the naproxen coenzyme A thioester towards bionucleophiles.

Drugs may be metabolised to reactive electrophilic species that spontaneously react with proteins. The presence of such drug-protein adducts has been associated with drug toxicity. In this study, the reactivity of the major metabolite of naproxen--the 1-beta-O-glucuronide (Nap-GlcU)--was compared to the corresponding naproxen coenzyme A (Nap-CoA) thioester. The reactivity of the two metabolites was assessed in vitro in a phosphate buffer (pH 7.4; 0.1 M) at 37 degrees C towards the model bionucleophiles glutathione and human serum albumin (HSA). The reaction between the electrophilic species (Nap-GlcU and Nap-CoA) and glutathione forming the Nap-glutathione conjugate was monitored using LC-MS-MS and LC-UV, respectively. It was shown that Nap-CoA resulted in an approximate 100-fold higher formation of Nap-glutathione conjugate than Nap-GlcU. The presence of Nap-CoA also resulted in acylated HSA with a rate and a yield that was significantly higher than reported for Nap-GlcU. In summary, the data suggest that CoA metabolites may be more reactive species than acyl glucuronides that previously have been associated with severe drug related side effects in vivo.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2002

Kinetics of the radicals induced in gamma-irradiated naproxen sodium and apranax. Applicability of ESR technique to monitor radiosterilization of naproxen sodium-containing drugs.

In the present work the spectroscopic and kinetic features of the radicals induced in gamma-irradiated naproxen sodium (NS) and apranax (AP) tablet are investigated at room and different temperatures in the dose range of 2.5-25 kGy by electron spin resonance technique (ESR). Radiation produces two different radicals (I, II) in NS quite stable at room temperature but relatively unstable above room temperature, giving rise to a broad singlet centered at g = 2.0057. Dose-response and decay curves associated with the broad singlet were found to follow bi-exponentials. Information concerning the saturation decay rates and activation energies were obtained through the characteristics of these exponentials. Similar calculations were also performed for AP, which contains 550 mg NS as active ingredient, and the applicability of ESR technique for monitoring radiosterilization of AP was discussed.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2001

Disposition of naproxen, naproxen acyl glucuronide and its rearrangement isomers in the isolated perfused rat liver.

1. An isolated perfused rat liver (IPRL) preparation was used to investigate separately the disposition of the non-steroidal anti-inflammatory drug (NSAID) naproxen (NAP), its reactive acyl glucuronide metabolite (NAG) and a mixture of NAG rearrangement isomers (isoNAG), each at 30 microg NAP equivalents ml perfusate (n = 4 each group). 2. Following administration to the IPRL, NAP was eliminated slowly in a log-linear manner with an apparent elimination half-life (t 1/2) of 13.4 +/- 4.4h. No metabolites were detected in perfusate, while NAG was the only metablolite present in bile in measurable amounts (3.9 +/- 0.8% of the dose). Following their administration to the IPRL, both NAG and isoNAG were rapidly hydrolysed (t 1/2 in perfusate = 57 +/- 3 and 75 +/- 14 min respectively). NAG also rearranged to isoNAG in the perfusate. Both NAG and isoNAG were excreted intact in bile (24.6 and 14.8% of the NAG and isoNAG doses, respectively). 3. Covalent NAP-protein adducts in the liver increased as the dose changed from NAP to NAG to isoNAG (0.20 to 0.34 to 0.48% of the doses, respectively). Similarly, formation of covalent NAP-protein adducts in perfusate were greater in isoNAG-dosed perfusions. The comparative results suggest that isoNAG is a better substrate for adduct formation with liver proteins than NAG.

Acylation↗

PubMedDate not supplied