Cyclooxygenase (COX) – inhibition of prostaglandin E₂ (PGE₂) biosynthesis. [2]

Naproxen etemesil is a lipophilic, non-acidic, inactive prodrug of naproxen that, when absorbed, hydrolyzes to produce naproxen that is pharmacologically active. One well-known non-steroidal anti-inflammatory medication is naproxen. With IC50s of 2.2 μg/mL and 1.3 μg/mL, respectively, naproxen is a nearly equal inhibitor of COX-1 and COX-2 in intact cells [1].

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Naproxen inhibited ex vivo TXB₂ synthesis in rat blood with an IC₅₀ of 5.3 μM, an I_max fixed to 1 (assuming full inhibition), and a Hill factor of 1.35. The baseline TXB₂ concentration was 2515 ng/mL. [3]
Naproxen inhibited ex vivo LPS-induced PGE₂ synthesis in rat blood with an IC₅₀ of 13 μM, an estimated I_max of 11.4 ng/mL, and a Hill factor of 1.025. The baseline PGE₂ concentration was 12.6 ng/mL. [3]

Naproxen reduces inflammation and inhibits fibrosis in a mouse model of lung fibrosis caused by bleomycin. Additionally, naproxen inhibits the production of the Smad3/4 complex and TGF-β levels [2]. Similar potency (IC50=27, 40, 13 μM) was shown in the time course suppression of pain, fever, and PGE2 by naproxen [3].

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Airway resistance to inflation (PAO): intratracheal bleomycin caused a significant increase in PAO (+2.06±0.25 mm). naproxen alone (21 mg/kg total dose, 0.55 mg/kg/day via micro‑osmotic pump for 15 days) caused a significant reduction of bleomycin‑induced airway stiffness (−1.07±0.22 mm, P<0.01 vs. bleomycin+vehicle). The efficacy of JNJ7777120 was slightly higher but not statistically different. Combination of naproxen with JNJ7777120 showed similar results. [2]
- Lung collagen deposition (Azan‑stained optical density): bleomycin increased collagen fibers. naproxen alone significantly reduced collagen deposition (P<0.05 vs. bleomycin+vehicle). Combination with JNJ7777120 showed a trend toward increased effect. [2]
- Goblet cell hyperplasia (PAS‑positive cells): bleomycin increased goblet cell percentage (+10.09%±1.30%, P<0.001). naproxen alone significantly reduced the percentage of goblet cells (−5.74%±1.38%, P<0.05). Combination with JNJ7777120 showed a statistically significant reduction compared with naproxen alone (−4.46%±1.38%, P<0.05). [2]
- Smooth muscle layer thickness: bleomycin increased thickness (+27.38±3.35 μm, P<0.001). naproxen alone significantly reduced thickness (−18.97±3.50 μm, P<0.05). [2]
- Transforming growth factor‑β (TGF‑β) levels: bleomycin increased TGF‑β (+274.9±13.68 pg/mg protein, P<0.001). naproxen alone caused a significant reduction (−123.0±6.84 pg/mg protein, P<0.01). Combination with JNJ7777120 was more effective than naproxen alone (−87.12±5.60 pg/mg protein vs. naproxen, P<0.01). [2]
- Smad3/4 complex formation: Western blotting on immunoprecipitated Smad4 showed upregulation of Smad3 in fibrotic controls, which was prevented by naproxen alone. Combination was more effective. [2]
- Myeloperoxidase (MPO) activity: bleomycin increased MPO. naproxen alone caused a significant reduction (−9.39±0.027 mU/mg protein, P<0.001). Combination with JNJ7777120 showed an increased effect (−11.27±0.34 mU/mg protein, P<0.05 vs. naproxen alone). [2]
- Prostaglandin E₂ (PGE₂) levels: bleomycin increased PGE₂ (+52.08±2.69 pg/mg protein, P<0.001). naproxen alone caused a significant reduction (−35.30±2.36 pg/mg protein, P<0.01). Combination was more effective than naproxen alone (−9.16±2.23 pg/mg protein vs. naproxen, P<0.001). [2]
- Interleukin‑10 (IL‑10) levels: bleomycin reduced IL‑10 (−17.05±1.51 pg/mg protein, P<0.001). naproxen alone caused a statistically significant increase (P<0.01). Combination with JNJ7777120 showed a potentiated effect. [2]
- Malondialdehyde (MDA, as TBARS): bleomycin increased TBARS (+41.33±11.15 nmol/mg protein, P<0.001). naproxen alone significantly reduced TBARS (−23.50±7.32 nmol/mg protein, P<0.01). Combination was more effective than naproxen alone (−8.74±2.98 nmol/mg protein, P<0.01). [2]
- 8‑Hydroxy‑2′‑deoxyguanosine (8‑OHdG): bleomycin increased 8‑OHdG (+51.25±2.77 ng/mg protein, P<0.001). naproxen alone significantly reduced 8‑OHdG (−33.48±2.65 ng/mg protein, P<0.01). Combination showed a slight but not significant effect compared with naproxen alone. [2]

Myeloperoxidase (MPO) activity determination: frozen lung tissue samples (about 50‑70 mg) were homogenized in a solution containing 0.5% hexadecyl trimethyl ammonium bromide dissolved in 10 mM potassium phosphate buffer, pH 7, then centrifuged for 30 minutes at 20,000g at 4°C. An aliquot of the supernatant was allowed to react with a solution of tetramethylbenzidine (1.6 mM) and 0.1 mM H₂O₂. The rate of change in absorbance was measured spectrophotometrically at 650 nm. MPO activity was defined as the quantity of enzyme degrading 1 μmol of peroxide per minute at 37°C and expressed in mU/mg of protein (protein determined by Bradford method). [2]
- Prostaglandin E₂ (PGE₂) level measurement: PGE₂ levels were measured on aliquots (100 μl) of lung homogenate supernatants using commercial enzyme‑linked immunosorbent assay kits following the protocol provided by the manufacturer. Values are expressed as ng/mg of protein. [2]
- Interleukin‑10 (IL‑10) level measurement: IL‑10 levels were measured on aliquots (100 μl) of lung homogenate supernatants using commercial enzyme‑linked immunosorbent assay kits following the protocol provided by the manufacturer. Values are expressed as pg/mg of protein. [2]
- Transforming growth factor‑β (TGF‑β) level measurement: TGF‑β levels were measured on aliquots (100 μl) of lung homogenate supernatants using a Flow Cytomix assay. A suspension of anti‑TGF‑β‑coated beads was incubated with the samples and a TGF‑β standard curve, then with biotin‑conjugated secondary antibodies and streptavidin‑phycoerythrin. Fluorescence was read with a cytofluorimeter. Values are expressed as pg/mg of protein. [2]
- Thiobarbituric acid‑reactive substance (TBARS) assay for malondialdehyde (MDA): lung tissue (~100 mg) was homogenized with 1 ml of 50 mM Tris‑HCl buffer containing 180 mM KCl and 10 mM EDTA, final pH 7.4. 0.5 ml of 1% (w/v) 2‑thiobarbituric acid in 0.05 M NaOH and 0.5 ml of 25% (w/v) HCl in water were added to 0.5 ml of sample. The mixture was heated in boiling water for 10 minutes. After cooling, the chromogen was extracted in 3 ml of 1‑butanol and the organic phase was separated by centrifugation at 2000g for 10 minutes. Absorbance was read at 532 nm. Values are expressed as nmol of TBARS (MDA equivalents) per mg of protein using a standard curve of 1,1,3,3‑tetramethoxypyropane. [2]
- 8‑Hydroxy‑2′‑deoxyguanosine (8‑OHdG) determination: lung samples were homogenized in 1 ml of 10 mM phosphate‑buffered saline, pH 7.4; sonicated on ice for 1 minute; added to 1 ml of 10 mM Tris‑HCl buffer, pH 8, containing 10 mM EDTA, 10 mM NaCl, and 0.5% SDS; and incubated for 1 hour at 37°C with 20 μg/ml of RNase 1 and overnight at 37°C under argon in the presence of 100 μg/ml of proteinase K. The mixture was extracted with chloroform/isoamyl alcohol (10:2 v/v). DNA was precipitated from the aqueous phase with 0.2 volumes of 10 mM ammonium acetate; solubilized in 200 μl of 20 mM acetate buffer, pH 5.3; and denatured at 90°C for 3 minutes. The extract was then supplemented with 10 IU of P1 nuclease in 10 μl of PBS and incubated for 1 hour at 37°C with 5 IU of alkaline phosphatase in 0.4 M phosphate buffer, pH 8.8. All procedures were performed in the dark under argon. The mixture was filtered, and 50 μl of each sample was used for 8‑OHdG determination using an enzyme immunoassay kit. Values are expressed as ng of 8‑OHdG per mg of protein. [2]
- Smad3 expression level (Western blotting): tissue samples were homogenized on ice and lysed. Total protein extract (1 mg) was precleared by Protein G for 1 hour at 4°C. After centrifugation, supernatants were collected and incubated overnight at 4°C with 4 μg of goat polyclonal anti‑Smad4 antibody. Immunocomplexes were recovered using Protein G, subjected to electrophoresis, blotted with rabbit polyclonal anti‑Smad3 (1:1000), and then reprobed with anti‑Smad4 antibody (1:1000). [2]

For COX‑1 activity, bovine aortic endothelial cells were incubated with naproxen (concentration range 0.1 ng/ml to 1 mg/ml) for 30 minutes. Then arachidonic acid (30 μM) was added and the cells were incubated for another 15 minutes at 37°C. The medium was removed and the formation of 6‑keto‑PGF₁α was measured by radioimmunoassay as an indicator of COX‑1 activity. [1]
For COX‑2 activity, cultured J774.2 macrophages were treated with endotoxin (1 μg/ml) for 12 hours to induce COX‑2. The culture medium was then changed, and naproxen (concentration range 0.1 ng/ml to 1 mg/ml) was added for 30 minutes at 37°C. Arachidonic acid (30 μM) was then added, and the cells were incubated for a further 15 minutes at 37°C. The medium was removed and analyzed by radioimmunoassay for 6‑keto‑PGF₁α. The inhibitory effects were measured in at least nine separate determinations on at least three different experimental days. [1]

Dissolved in 0.9% NaCl; 2.5, 10 or 25 mg/kg; i.v. or i.p. injection Male Sprague-Dawley rats

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Male C57BL/6 mice (~2 months old, 25‑30 g) were used. Bleomycin (0.05 IU in 100 μl saline) was instilled intratracheally under anesthesia with zolazepam/tiletamine (50 μg/g in 100 μl saline i.p.). naproxen was administered via subcutaneously implanted micro‑osmotic pump (allowing release of 0.11 μl of drug per hour) for 15 days after surgery. The total dose of naproxen was 21 mg/kg body weight, corresponding to a daily dosage of 0.55 mg/kg. The naproxen dose (0.55 mg/kg per day) was selected according to previous results in the same animal model of fibrosis, where 1 mg/kg showed maximal effect; the present study investigated the efficacy of combination to reduce the toxicity of naproxen (ED50 3.7 mg/kg). [2]
- Functional assay of fibrosis (airway resistance to inflation): at day 14 after surgery, under anesthesia, a 22‑gauge cannula was inserted into the trachea and mice were ventilated with a small‑animal respirator (tidal volume 0.8 ml, rate 20 strokes/min). Changes in lung resistance to inflation (pressure at the airway opening, PAO) were registered by a pressure transducer connected to a polygraph (gain 1, chart speed 25 mm/s). Inflation pressure was measured for at least 3 minutes. PAO measurements were carried out on at least 40 consecutive tracings of respiratory strokes after breathing stabilization and then averaged. [2]
- After functional assay, animals were killed with a lethal dose of anesthetic. Left lungs were excised and fixed in 4% formaldehyde for histology. Right lungs were weighed, frozen, and stored at −80°C for biochemical assays. [2]

Absorption, Distribution and Excretion
Naproxen exists in both free acid and sodium salt forms. At the same dose (500 mg naproxen = 550 mg naproxen sodium), the absorption rates differ slightly, but otherwise, their therapeutic and pharmacological effects are equivalent. Naproxen sodium reaches peak plasma concentration after 1 hour, while naproxen (free acid) reaches peak plasma concentration after 2 hours. Pharmacokinetics are similar after absorption in both forms. In the treatment of acute pain, the difference in initial absorption should be considered, as naproxen sodium may have a faster onset of action. The mean Cmax values of various naproxen formulations (immediate-release, enteric-coated, controlled-release, etc.) are comparable, ranging from 94 mcg/mL to 97.4 mcg/mL. In a pharmacokinetic study, the mean time to peak concentration (Tmax) was 3 hours for a 500 mg naproxen (immediate-release formulation) taken every 12 hours for 5 days; and 5 hours for a 1000 mg naproxen (extended-release formulation) taken every 24 hours for 5 days. In the same study, the AUC 0-24hr for immediate-release naproxen was 1446 μg/h/mL, and the AUC 0-12hr for extended-release formulation was 1448 μg/h/mL. Another study comparing the pharmacokinetics of naproxen tablets and enteric-coated naproxen observed the following values: the Tmax and AUC 0-12hr for enteric-coated naproxen were 4 hours and 845 μg/h/mL, respectively, while the Tmax and AUC 0-12hr for naproxen tablets were 1.9 hours and 767 μg/h/mL, respectively. When used in combination with sumatriptan, naproxen's peak plasma concentration (Cmax) was approximately 36% lower than that of naproxen sodium 550 mg tablets, with a median time to peak concentration (Tmax) of 5 hours. Based on naproxen's area under the curve (AUC) and peak plasma concentration (Cmax), vemovor (naproxen/esomeprazole combination) and enteric-coated naproxen can be considered bioequivalent. Overall, naproxen is rapidly and completely absorbed after both oral and rectal administration. Food may delay the absorption of oral naproxen but does not affect its absorption rate. After oral administration, approximately 95% of naproxen and its metabolites are excreted in the urine, of which 66-92% are excreted as conjugated metabolites, and less than 1% are excreted as naproxen or desmethylnaproxen. Less than 5% of naproxen is excreted in the feces. The volume of distribution of naproxen is 0.16 L/kg.
The clearance rate of naproxen is 0.13 mL/min/kg.
Oral absorption of naproxen in dogs is rapid, with peak plasma concentrations reached within 0.5–3 hours. The elimination half-life in dogs has been reported to be 34–72 hours. Naproxen is highly bound to plasma proteins (>99.0%). In dogs, naproxen is primarily excreted via bile, while in other species, the primary route of excretion is the kidneys. The long half-life of naproxen in dogs appears to be due to its extensive enterohepatic circulation.
After therapeutic doses, naproxen binds to plasma proteins exceeding 99%. When the binding sites of naproxen become saturated (500 mg or more twice daily), the plasma concentration of free drug increases, potentially leading to increased urinary clearance. Therefore, plasma naproxen concentrations tend to stabilize when the dose exceeds 500 mg twice daily. A study in patients with severe renal failure found that naproxen had decreased binding to serum proteins compared to healthy adults; this decreased binding may be due to increased drug metabolism and apparent volume of distribution in these patients. In patients with chronic alcoholic liver disease, total plasma concentrations of naproxen were decreased, while free drug concentrations were increased. This study investigated the pharmacokinetics of naproxen, its metabolite 6-hydroxy-α-methyl-2-naphthylacetic acid (O-demethylnaphthen), and its acyl glucuronide after oral administration of 500 mg naproxen to 10 subjects (aged 20–50 years). The mean half-life of naproxen was 24.7 hours in 9 subjects. The half-life in the 10th subject was 7.4 hours, considered an abnormal case. Naproxen acylglucuronide accounted for 50.8% of the administered dose, its isomerized conjugate isoglucuronide accounted for 6.5%, O-demethylnaproxen acylglucuronide accounted for 14.3%, and its isoglucuronide accounted for 5.5%. The excretion of naproxen and O-demethylnaproxen was negligible. The plasma protein binding rates of naproxen were 98%, O-demethylnaproxen for 100%, naproxen acylglucuronide for 92%, naproxen isoglucuronide for 66%, O-demethylnaproxen acylglucuronide for 72%, and O-demethylnaproxen isoglucuronide for 42%. Therefore, it can be concluded that after O-demethylation, both the parent drug and metabolites of naproxen are bound to acylglucuronide. This study investigated the effect of disease activity on the pharmacokinetics of naproxen, a nonsteroidal anti-inflammatory drug with high albumin binding, in 6 patients with long-term rheumatoid arthritis receiving treatment. Pharmacokinetics were compared in these patients during disease activity and remission. Hypoalbuminemia was common during active disease (30 ± 4 g/L), compared to 41 ± 2 g/L during disease improvement (mean ± standard deviation). Total naproxen concentration was significantly reduced during active disease, while apparent volume of distribution (10.6 ± 1.8 L vs. 8.4 ± 1.3 L; P < 0.05) and systemic clearance (0.79 ± 1.8 L/hr vs. 0.59 ± 0.14 L/hr; P < 0.001) increased. Peak free naproxen concentration decreased by 29% ± 19% during disease improvement (P < 0.05). Free naproxen clearance was also reduced during active disease compared to when disease improved (488 ± 343 L/hr) (390 ± 277 L/hr; P < 0.05). This article explores the clinical significance of altered naproxen pharmacokinetics caused by polyarthritis in patients with rheumatoid arthritis. For more complete data on the absorption, distribution, and excretion of naproxen (15 species), please visit the HSDB record page.

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Metabolism/Metabolites
Naproxen is primarily metabolized in the liver, undergoing phase I and phase II metabolism. The first step involves demethylation of naproxen via CYP1A2, 2C8, and 2C9. Both naproxen and demethylated naproxen can enter phase II metabolism; however, demethylated naproxen yields both acyl and phenolic glucuronide products, while naproxen yields only acyl glucuronide. Acyl glucuronidation involves UGT 1A1, 1A3, 1A6, 1A7, 1A9, 1A10, and 2B7, while phenolic glucuronidation is catalyzed by UGT 1A1, 1A7, 1A9, and 1A10. Desmethylnaproxen also undergoes sulfation, a process mediated by SULT 1A1, 1B1, and 1E1. Naproxen is extensively metabolized in the liver to 6-desmethylnaproxen. Approximately 95% of the drug is excreted in the urine as unchanged naproxen (less than 1%) and 6-desmethylnaproxen (less than 1%), as well as their glucuronides or other conjugates (66-92%). Some data suggest that renal excretion of unchanged naproxen may be negligible or nonexistent; previously reported unchanged drug concentrations may reflect rapid hydrolysis of conjugates during urine sample collection, storage, and processing. The half-life of naproxen metabolites and conjugates is less than 12 hours. Naproxen metabolites may accumulate in patients with renal impairment. Naproxen clearance is reduced in patients with severe renal impairment. A small amount (less than 5%) of the drug is excreted in the feces. This study investigated the pharmacokinetics of naproxen, its metabolite 6-hydroxy-α-methyl-2-naphthylacetic acid (O-demethylnaproxen), and its acyl glucuronide in 10 subjects (aged 20-50 years) after oral administration of 500 mg. The mean half-life of naproxen in 9 subjects was 24.7 hours. The half-life in the 10th subject was 7.4 hours, which was considered an outlier. Naproxen acyl glucuronide accounted for 50.8% of the dose, its isomerized conjugate isoglucuronide accounted for 6.5%, O-demethylnaproxen acyl glucuronide accounted for 14.3%, and its isoglucuronide accounted for 5.5%. The excretion of naproxen and O-demethylnaproxen was negligible. The plasma protein binding rate of naproxen is 98%, O-demethylnaproxen is 100%, naproxen acyl glucuronide is 92%, naproxen isoglucuronide is 66%, O-demethylnaproxen acyl glucuronide is 72%, and O-demethylnaproxen isoglucuronide is 42%. The study concluded that after O-demethylation, both the parent drug and metabolites of naproxen are bound to acyl glucuronide. Known metabolites of naproxen include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[(2S)-2-(6-methoxynaphthyl-2-yl)propionyl]oxaoxane-2-carboxylic acid and O-demethylnaproxen. Biological half-life: The elimination half-life of naproxen has been reported to be 12-17 hours. The elimination half-life in dogs has been reported to be 34-72 hours. The plasma half-life of naproxen in healthy adults is reported to be 10-20 hours. The manufacturer claims a plasma half-life of approximately 13 hours. The plasma half-life and elimination profile of the drug appear to be similar in children and adults. This study investigated the pharmacokinetics of naproxen, its metabolite 6-hydroxy-α-methyl-2-naphthylacetic acid (O-demethylnaphthen), and its acyl glucuronide after oral administration of 500 mg naproxen to 10 subjects (aged 20-50 years). The mean half-life of naproxen in 9 subjects was 24.7 hours. The half-life in the 10th subject was 7.4 hours and was considered an outlier.

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The time-course of naproxen plasma concentrations in rats was best described by a two-compartment model with first-order absorption. The estimated population parameters were: apparent clearance (CL/F) without fever = 0.0318 L/h/kg; CL/F with fever = 0.0244 L/h/kg (24% reduction); absorption rate constant (Kα) = 0.542 /h; apparent volume of central compartment (V1/F) = 0.016 L/kg; inter-compartmental distribution (Q) = 0.153 L/h/kg; apparent volume of peripheral compartment (V2/F) = 0.16 L/kg. The residual variability was 41%. Brewer's yeast-induced fever reduced naproxen clearance by 24%. The half-life was reported to be 3.5 hours. [3]

Interactions
Methotrexate is a cornerstone drug for the treatment of juvenile idiopathic arthritis (JI). Although methotrexate can cause many minor adverse reactions, its short-term and long-term safety profile in the treatment of JI is good. While many children with JI treated with methotrexate develop abnormal liver enzymes, there have been no reported cases of irreversible liver damage or severe non-infectious hepatitis with Reye's features in non-systemic JI. One case reported by researchers involved a 2-year-old girl with juvenile arthritis whose liver enzymes were elevated to more than 45 times the upper limit of normal. She developed hypoglycemia and hyperammonemia after 10 months of treatment with methotrexate and naproxen. Infection and metabolic tests for other etiologies were normal. She fully recovered after treatment with leucovorin; methotrexate and naproxen were not re-initiated. Although very rare in JI, the synergistic effect of methotrexate and naproxen can induce severe hepatotoxicity, therefore screening children for abnormal liver enzymes is crucial. Because naproxen is highly protein-bound, it could theoretically be displaced from its binding site by other protein-binding drugs (such as oral anticoagulants, phenytoins, salicylates, sulfonamides, and sulfonylureas), or conversely, naproxen could displace other protein-binding drugs from its binding site. Although no clinically significant drug interactions have been reported, patients taking naproxen in combination with any of these drugs should be closely monitored for adverse reactions. Concomitant use of naproxen with warfarin may result in a slight increase in serum free warfarin levels, but it does not affect warfarin's prothrombin-lowering effect. Because naproxen may cause gastrointestinal bleeding and inhibit platelet aggregation, it should be used with caution in patients receiving any anticoagulants or thrombolytic agents (such as streptokinase). A study in diabetic patients showed that naproxen did not interfere with the effect of tolbutamide on plasma glucose concentrations. For more complete data on naproxen interactions (18 in total), please visit the HSDB record page.

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Non-human toxicity values
Mice intravenous LD50: 435 mg/kg
Mice oral LD50: 1234 mg/kg
Mice intraperitoneal LD50: 500 mg/kg
Mice subcutaneous LD50: 475 mg/kg
For more complete data on non-human toxicity values of naproxen (9 values in total), please visit the HSDB record page.

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The combination of naproxen with JNJ7777120 was used in order to reduce the toxicity of naproxen. The ED50 of naproxen is reported as 3.7 mg/kg. [2]

[1]. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11693-7.

[2]. Prevention of bleomycin-induced lung inflammation and fibrosis in mice by naproxen and JNJ7777120 treatment. J Pharmacol Exp Ther. 2014 Nov;351(2):308-16.

[3]. Pharmacokinetic-pharmacodynamic modeling of the inhibitory effects of naproxen on the time-courses of inflammatory pain, fever, and the ex vivo synthesis of TXB2 and PGE2 in rats.

Therapeutic Uses
Nonsteroidal anti-inflammatory drugs; cyclooxygenase inhibitors; gout suppressants. Naproxen and its salts are used to relieve postoperative pain (including dental surgery-related pain), postpartum pain, primary dysmenorrhea, pain after IUD insertion, orthopedic pain, headaches (including migraines), and cancer-related visceral pain. Naproxen sodium can also be used for self-medication to temporarily relieve mild pain such as the common cold, headache, toothache, muscle aches, and back pain. /Included on US product label/ Naproxen has been used to treat osteitis deformans (Paget's bone disease) and Barthel syndrome. /This use is not currently included on the US FDA-approved label/ When used to treat rheumatoid arthritis or juvenile rheumatoid arthritis, naproxen relieves pain and stiffness, reduces swelling, and improves mobility and grip strength. When used to treat osteoarthritis, naproxen relieves pain and stiffness and improves knee function. Naproxen appears to only relieve symptoms of these conditions and has not been shown to permanently stop or reverse the underlying disease progression. Naproxen sodium can also be used for self-medication to temporarily relieve mild pain associated with arthritis. /Included in US product label/
For more complete data on the therapeutic uses of naproxen (of 9 types), please visit the HSDB record page.

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Drug Warnings
Pseudomyrosis is characterized by fragile skin, blisters and scarring in sun-exposed areas, but with normal porphyrin metabolism. Phenylpropionic acid nonsteroidal anti-inflammatory drugs, especially naproxen, are known to cause pseudoporphyrosis. Naproxen is currently one of the most commonly used medications for treating juvenile idiopathic arthritis. A 9-year retrospective study of children with juvenile idiopathic arthritis and related conditions determined the prevalence of pseudoporphyrosis. In addition, researchers conducted a prospective study of 196 patients (127 girls and 69 boys) with juvenile idiopathic arthritis and related diseases who received naproxen treatment between July 2001 and March 2002 to observe the incidence of pseudoporphyria. …Researchers compared these data with matched control groups of juvenile idiopathic arthritis and related diseases who did not receive naproxen treatment to identify risk factors for pseudoporphyria. The incidence of pseudoporphyria in the naproxen-treated group was 11.4%. Pseudoporphyria was particularly common in children with early-onset oligoarticular juvenile idiopathic arthritis (mean age 4.5 years). Pseudoporphyria was associated with signs of disease activity, such as decreased hemoglobin (<11.75 g/dL), increased white blood cell count (>10,400/μL), and increased erythrocyte sedimentation rate (>26 mm/hour). Concomitant medication, especially chloroquine, appeared to be an additional risk factor. The average duration of naproxen treatment prior to the onset of pseudoporphyria was 18.1 months, and most children with pseudoporphyria developed skin lesions within the first two years of naproxen treatment. Disease activity in juvenile idiopathic arthritis appears to be a confounding factor for pseudoporphyria. In particular, patients with early-onset oligoarticular juvenile idiopathic arthritis, especially those with significant inflammation, appear more likely to develop pseudoporphyria after naproxen treatment. Short-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) to relieve acute pain, especially at low doses, does not appear to increase the risk of serious cardiovascular events (except for immediate use after coronary artery bypass grafting (CABG)). Therefore, in early 2005, the U.S. Food and Drug Administration (FDA) concluded that currently available over-the-counter NSAID formulations (including naproxen) have a good benefit-risk ratio when used as directed, and decided that these formulations should continue to be available over-the-counter despite the addition of a black box warning on the professional labels of prescription formulations.
Except for the sodium content-related precautions for naproxen sodium, the precautions for using naproxen sodium are the same as for naproxen. Each 275 mg or 550 mg naproxen sodium tablet contains approximately 1 mEq and 2 mEq of sodium, respectively, while each milliliter of commercially available naproxen suspension contains approximately 0.34 mEq of sodium; this should be considered for patients who need to restrict their sodium intake. /Naproxen Sodium/
Patients should be informed that naproxen, like other nonsteroidal anti-inflammatory drugs (NSAIDs), is not without potential adverse reactions, including some that may cause discomfort, and in rare cases, more serious adverse reactions (such as gastrointestinal bleeding), which may require hospitalization and may even be life-threatening. Patients should also be informed that while NSAIDs are commonly used to treat some less serious conditions, for certain conditions (such as rheumatoid arthritis), NSAID treatment is generally considered essential, and these drugs play an important role in pain management. Clinicians may need to discuss the potential risks and benefits of NSAID treatment with patients, especially when considering these drugs for milder conditions where treatment regimens without NSAIDs may be acceptable alternatives for both the patient and the clinician. For more complete data on drug warnings for naproxen (40 total), please visit the HSDB records page. Pharmacodynamics: Naproxen is a marketed, non-selective NSAID used as an analgesic, anti-inflammatory, and antipyretic. Similar to other NSAIDs, naproxen's pharmacological activity can be attributed to its inhibition of cyclooxygenase, thereby reducing prostaglandin synthesis in various tissues and fluids, including synovial fluid, gastric mucosa, and blood. Although naproxen is an effective analgesic, it can also produce unexpected adverse effects on patients. For example, naproxen may have an adverse effect on blood pressure control. One study found that taking naproxen caused an increase in blood pressure, although the increase was not as significant as taking ibuprofen. Furthermore, the study found that patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) had an average risk of upper gastrointestinal bleeding that was four times higher. Other factors that increase the risk of upper gastrointestinal bleeding include concurrent use of corticosteroids or anticoagulants, and a history of peptic ulcer disease.

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naproxen is a classical nonsteroidal anti‑inflammatory drug (NSAID) that inhibits cyclooxygenase and prostanoid biosynthesis. In this bleomycin‑induced mouse model of pulmonary fibrosis, naproxen alone reduced lung inflammation, oxidative stress, collagen deposition, goblet cell hyperplasia, smooth muscle thickening, TGF‑β levels, and Smad3/4 complex formation. The combination with the H₄ receptor antagonist JNJ7777120 produced additive or synergistic effects on most parameters, suggesting that combined therapy with an H₄R antagonist and an NSAID could be an effective therapeutic strategy for pulmonary fibrosis. [2]
- The authors note that prostaglandin inhibition may have beneficial effects during the inflammatory phase but not when fibrosis is already established. The combination strategy overcomes the safety limitations of existing anti‑inflammatory drugs in the treatment of pulmonary fibrosis. [2]

C14H14O3

230.2592

230.094

C, 73.03; H, 6.13; O, 20.85

22204-53-1

(±)-Naproxen;23981-80-8;Naproxen sodium;26159-34-2

156391

White to off-white solid powder

1.2±0.1 g/cm3

403.9±20.0 °C at 760 mmHg

152-154 °C(lit.)

154.5±15.3 °C

0.0±1.0 mmHg at 25°C

1.609

3

1

3

3

17

277

1

O(C([H])([H])[H])C1C([H])=C([H])C2C([H])=C(C([H])=C([H])C=2C=1[H])[C@@]([H])(C(=O)O[H])C([H])([H])[H]

CMWTZPSULFXXJA-VIFPVBQESA-N

InChI=1S/C14H14O3/c1-9(14(15)16)10-3-4-12-8-13(17-2)6-5-11(12)7-10/h3-9H,1-2H3,(H,15,16)/t9-/m0/s1

(S)-2-(6-methoxynaphthalen-2-yl)propanoic acid

CG 3117 CG3117 CG-3117 Naproxen Naposin Napratec

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~434.29 mM)
H2O : ~75 mg/mL (~325.72 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.86 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.86 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.86 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 2 mg/mL (8.69 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)