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Journal of Medicinal Chemistry Nov 2022Severe acute respiratory syndrome-coronavirus-1/2 (SARS-CoV-1/2) macrodomain 3 (Mac3) is critical for replication and transcription of the viral genome and is therefore...
Severe acute respiratory syndrome-coronavirus-1/2 (SARS-CoV-1/2) macrodomain 3 (Mac3) is critical for replication and transcription of the viral genome and is therefore a potential therapeutic target. Here, we solved the crystal structure of SARS-CoV-2 Mac3, which reveals a small-molecule binding pocket. Two low-molecular-weight drugs, oxaprozin and meclomen, induced different patterns of nuclear magnetic resonance (NMR) chemical shift perturbations (CSPs). Meclomen binds to site I of SARS-CoV-2 Mac3 with binding pose determined by NMR CSP and transferred paramagnetic relaxation enhancement, while oxaprozin binds to site II as revealed by the crystal structure. Interestingly, oxaprozin and meclomen both perturb residues in site I of SARS-CoV Mac3. Fluorescence polarization experiments further demonstrated that oxaprozin and meclomen inhibited the binding of DNA-G4s to SARS-CoV-2 Mac3. Our work identified two adjacent ligand-binding sites of SARS-CoV-2 Mac3 that shall facilitate structure-guided fragment linking of these compounds for more potent inhibitors.
Topics: Humans; Binding Sites; Meclofenamic Acid; Oxaprozin; SARS-CoV-2; Viral Nonstructural Proteins; Coronavirus Papain-Like Proteases; COVID-19 Drug Treatment
PubMed: 36356292
DOI: 10.1021/acs.jmedchem.2c01168 -
Journal of Clinical Pharmacology Apr 1997The nonsteroidal antiinflammatory drugs (NSAIDs) oxaprozin and piroxicam have long elimination half-lives (t 1/2 approximately 55 hours), permitting once-daily dose... (Clinical Trial)
Clinical Trial Comparative Study
The nonsteroidal antiinflammatory drugs (NSAIDs) oxaprozin and piroxicam have long elimination half-lives (t 1/2 approximately 55 hours), permitting once-daily dose regimens. The protein-binding characteristics of these drugs, however, vary widely. This study examines the effect of these binding differences on the drugs' disposition kinetics at steady state. A total of 52 participants (26 young healthy volunteers, and 26 elderly osteoarthritic patients, 15 men and 37 women (2 of them poor metabolizers of debrisoquine [CYP2D6]) completed the two-period, two-treatment, randomized, single-dose and 21-day, once-daily multiple-dose, cross-over study. Doses of oxaprozin and piroxicam were 1,200 mg once daily and 20 mg once daily, respectively. Mean single-dose kinetic parameters of oxaprozin versus piroxicam did not differ more than +/-14% (t1/2, 53.0 versus 57.4 hours; apparent oral clearance adjusted for 70-kg body weight [Clpo], 0.139 versus 0.121 L/hr; apparent volume of distribution adjusted for 70-kg body weight [Vd/F]; 10.2 L versus 9.13 L). Protein binding was plasma-concentration dependent with oxaprozin (range, 10-400 mg/L) but not with piroxicam (range, 1-30 mg/ L). Steady-state conditions were established within 3 days with oxaprozin but took almost 12 days with piroxicam. Compared with the single-dose values, steady-state Clpo (Clpo,ss) and Vd/F of total drug increased with oxaprozin by almost 127% but remained within +/-10% with piroxicam. Post-steady-state apparent t 1/2 of the total and unbound drugs of approximately 62 hours were similarly prolonged with piroxicam but differed substantially with oxaprozin (50.6 hours [total drug] versus 23.8 hours [unbound drug]). Single dose Clpo (Clpo,sd) values of both NSAIDs were significantly correlated in the study populations. With both NSAIDs, Clpo in the two poor metabolizers of debrisoquine was within +/-20% of mean values for the population. Clinically important age- and gender-dependent decreases were not observed in the weight-adjusted, Clpo,sd or Vd/F values of the total drug for either NSAID. Clearances of the two NSAIDs were significantly correlated, suggesting that a common P450 isozyme (most likely CYP2C9, in that piroxicam is a known substrate of this isozyme) may be at least partly involved in the oxidative metabolism of these NSAIDs.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Body Weight; Cross-Over Studies; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Osteoarthritis; Oxaprozin; Piroxicam; Propionates; Protein Binding; Sex Factors
PubMed: 9115051
DOI: 10.1002/j.1552-4604.1997.tb04302.x -
Expert Opinion on Pharmacotherapy May 2005Oxaprozin is a nonsteroidal anti-inflammatory drug characterised by a propionic acid-based structure. It is able to diffuse easily into inflamed synovial tissues after... (Review)
Review
Oxaprozin is a nonsteroidal anti-inflammatory drug characterised by a propionic acid-based structure. It is able to diffuse easily into inflamed synovial tissues after oral administration. Although discovered > 20 years ago, it is now under intensive investigation because of its unusual pharmacodynamic properties. Other than being a nonselective cyclooxygenase inhibitor, the drug is capable of inhibiting both anandamide hydrolase in neurons (median inhibitory concentration [IC50] = 85 micromol/l), with consequent potent analgesic activity, and NF-kappaB activation in inflammatory cells (IC50 = 50 micromol/l). Moreover, oxaprozin induces apoptosis of activated monocytes in a dose-dependent manner, with the effect being detectable at a concentration of 5 micromol/l and reaching the maximum activity at 50 micromol/l. As monocyte-macrophages and NF-kappaB pathways are crucial for synthesis of proinflammatory and histotoxic mediators in inflamed joints, oxaprozin appears to be endowed with pharmacodynamic properties exceeding those presently assumed as markers of classical nonsteroidal anti-inflammatory drug.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Drug Industry; Humans; Oxaprozin; Propionates
PubMed: 15934904
DOI: 10.1517/14656566.6.5.777 -
Advance For Nurse Practitioners Jul 1997
Review
Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Humans; Oxaprozin; Propionates
PubMed: 9459947
DOI: No ID Found -
Canadian Journal of Physiology and... Jun 2022The effect of oxaprozin (OXP) on an experimental model of seizures in rats was investigated in this study. Seizures in Wistar rats (200-250 g) were induced by...
The effect of oxaprozin (OXP) on an experimental model of seizures in rats was investigated in this study. Seizures in Wistar rats (200-250 g) were induced by pentylenetetrazole (PTZ, 60 mg/kg). The anticonvulsant effect of OXP (100, 200, and 400 mg/kg, intraperitoneally) was evaluated in a seizure model. After behavioral tests, the animals underwent deep anesthesia and were put down painlessly. Animal serum was isolated for antioxidant assays (nitric oxide (NO) and glutathione (GSH)). The animals' brains were also isolated to gauge the relative expression of genes in the oxidative stress pathway (sirtuin 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α)). Intraperitoneal injection of OXP increased the mean latency of myoclonic jerks and generalized tonic-clonic seizure (GTCS) and decreased the number of myoclonic jerks and GTCS duration compared with the PTZ group. Biochemical tests showed that pretreatment with OXP was able to restore GSH serum levels and reverse the augmented NO serum levels caused by PTZ induction to the normal level. The quantitative polymerase chain reaction results also revealed that OXP counteracts the negative effects of PTZ by affecting the expression of the and genes. Overall, this study suggests the potential neuroprotective effects of the nonsteroidal, anti-inflammatory OXP drug in a model of neural impairment caused by seizures via the mechanism of inhibition of the oxidative stress pathway.
Topics: Animals; Anticonvulsants; Disease Models, Animal; Glutathione; Myoclonus; Oxaprozin; Oxidative Stress; Pentylenetetrazole; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Rats, Wistar; Seizures; Sirtuin 1
PubMed: 35395161
DOI: 10.1139/cjpp-2021-0757 -
Clinical Pharmacology and Therapeutics Apr 1982Effects of renal disease on the disposition kinetics of oxaprozin, a nonsteroidal antiinflammatory analgesic, were assessed in 15 subjects who were normal, renally...
Effects of renal disease on the disposition kinetics of oxaprozin, a nonsteroidal antiinflammatory analgesic, were assessed in 15 subjects who were normal, renally impaired, or who had been undergoing hemodialysis. Oral dose clearance (Cloral), volume of distribution at steady-state (V88d), and elimination half-life (t 1/2) did not substantially differ among the three groups. Mean fraction unbound oxaprozin in plasma (fup) increased from 0.08% in the normal group to 0.18% and 0.28% in the two azotemic groups. Consequently, unbound drug kinetic parameters, including intrinsic clearance (Clint) and V88du of unbound drug were reduced from 2.9 l/hr/kg and 193 l/kg in normal subjects to approximately 1.6 l/hr/kg and 91 l/kg in azotemic patients. The smaller volume of distribution is consistent with a decrease in oxaprozin tissue binding in azotemia. The decreased plasma and tissue binding and lower Clint suggest that, in the treatment of azotemic patients with rheumatoid arthritis, the dose of oxaprozin should begin at 600 mg once a day.
Topics: Adult; Aged; Anti-Inflammatory Agents; Blood Proteins; Humans; Kidney Diseases; Kinetics; Metabolic Clearance Rate; Middle Aged; Oxaprozin; Oxazoles; Propionates; Protein Binding
PubMed: 7060332
DOI: 10.1038/clpt.1982.68 -
The Journal of International Medical... 1988The efficacy and tolerance of 1200 mg/day oxaprozin and 100 mg/day diclofenac sodium were compared in 40 patients with ankylosing spondylitis in a 6-week open study.... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
The efficacy and tolerance of 1200 mg/day oxaprozin and 100 mg/day diclofenac sodium were compared in 40 patients with ankylosing spondylitis in a 6-week open study. Overall improvement was seen in the patients in both treatment groups. Oxaprozin-treated patients showed significant improvement in spontaneous pain of the vertebral spine and in morning stiffness after 6 weeks' treatment. There were no statistically significant differences between the treatment groups. Therapy was discontinued in 10 patients; five treated with oxaprozin (three because of intolerance and two because of worsening of symptoms) and five taking diclofenac sodium (four because of intolerance and one because of worsening of symptoms). Five (25%) oxaprozin-treated patients and six (30%) diclofenac sodium-treated patients had side-effects, with gastro-intestinal disturbances and dizziness reported most frequently. There were no statistically significant differences between the groups in the frequency of side-effects. These results indicate that oxaprozin is a promising therapeutic agent for ankylosing spondylitis.
Topics: Diclofenac; Drug Evaluation; Humans; Oxaprozin; Patient Acceptance of Health Care; Propionates; Spondylitis, Ankylosing
PubMed: 3378661
DOI: 10.1177/030006058801600210 -
Scientific Reports Jul 2022These days, many efforts have been made to increase and develop the solubility and bioavailability of novel therapeutic medicines. One of the most believable approaches...
These days, many efforts have been made to increase and develop the solubility and bioavailability of novel therapeutic medicines. One of the most believable approaches is the operation of supercritical carbon dioxide fluid (SC-CO). This operation has been used as a unique method in pharmacology due to the brilliant positive points such as colorless nature, cost-effectives, and environmentally friendly. This research project is aimed to mathematically calculate the solubility of Oxaprozin in SC-CO through artificial intelligence. Oxaprozin is a nonsteroidal anti-inflammatory drug which is useful in arthritis disease to improve swelling and pain. Oxaprozin is a type of BCS class II (Biopharmaceutical Classification) drug with low solubility and bioavailability. Here in order to optimize and improve the solubility of Oxaprozin, three ensemble decision tree-based models including random forest (RF), Extremely random trees (ET), and gradient boosting (GB) are considered. 32 data vectors are used for this modeling, moreover, temperature and pressure as inputs, and drug solubility as output. Using the MSE metric, ET, RF, and GB illustrated error rates of 6.29E-09, 9.71E-09, and 3.78E-11. Then, using the R-squared metric, they demonstrated results including 0.999, 0.984, and 0.999, respectively. GB is selected as the best fitted model with the optimal values including 33.15 (K) for the temperature, 380.4 (bar) for the pressure and 0.001242 (mole fraction) as optimized value for the solubility.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Artificial Intelligence; Carbon Dioxide; Oxaprozin; Propionates; Solubility
PubMed: 35907929
DOI: 10.1038/s41598-022-17350-5 -
European Journal of Clinical... 1986Twelve healthy male volunteers participated in a single-dose four-way crossover study to evaluate potential drug interactions with oxaprozin, a nonsteroidal...
Twelve healthy male volunteers participated in a single-dose four-way crossover study to evaluate potential drug interactions with oxaprozin, a nonsteroidal antiinflammatory agent of the propionic class. The four modes of administration were: a. oxaprozin, 1200 mg alone; b. oxaprozin during concurrent acetaminophen, 500 mg 4 times daily; c. oxaprozin with cimetidine, 300 mg 4 times daily; d. oxaprozin with ranitidine, 150 mg every 12 hours. Acetaminophen, cimetidine, or ranitidine were begun 24 hours prior to oxaprozin dosage and continued for the 10-day duration of each trial. No significant differences existed among the four treatment conditions in peak plasma oxaprozin concentration (86 micrograms/ml), volume of distribution (0.23 l/kg), time of peak concentration (3.7 h after dosage), or elimination half-life (54 h). Oxaprozin oral clearance was significantly lower (by 20%) during both the cimetidine and ranitidine trials versus control (0.047 vs 0.047 vs 0.059 ml/min/kg), but clearance during acetaminophen was not significantly different from control. Thus acetaminophen, cimetidine or ranitidine has only a small influence on the pharmacokinetics of a single oral dose of oxaprozin. The reduction in oxaprozin clearance due to cimetidine or ranitidine is statistically significant but small in magnitude.
Topics: Acetaminophen; Administration, Oral; Adult; Analysis of Variance; Anti-Inflammatory Agents, Non-Steroidal; Cimetidine; Drug Interactions; Drug Therapy, Combination; Humans; Kinetics; Male; Middle Aged; Oxaprozin; Propionates; Ranitidine; Regression Analysis
PubMed: 3792438
DOI: 10.1007/BF00981141 -
Agents and Actions Jun 1989Oxaprozin (Wy-21743) is a novel and unique compound among NSAIDs: it bears an aliphatic propionic acid function as a side chain in contrast to the large group of acetic...
Oxaprozin (Wy-21743) is a novel and unique compound among NSAIDs: it bears an aliphatic propionic acid function as a side chain in contrast to the large group of acetic acids and profens. The transsynovial distribution was studied in 18 RA-patients, who required articular surgery. Following a wash-out period of 7 days they were treated with 2 x 600 mg of oxaprozin. The patients were assigned to four different groups representing different treatment duration (2, 3, 4 and 5 days). 12 hours after the last dose during surgery synovial fluid and synovial tissue specimen were removed. Blood samples were taken simultaneously and analysed for oxaprozin employing HPLC. In the synovial tissue samples concentrations of 27 micrograms/g were detected. The concentrations were considerably higher than blood (10-17 micrograms/ml) or synovial fluid (4.9-7.6 micrograms/ml) levels. Oxaprozin shows a different pattern of transsynovial distribution and tissue affinity as compared to other NSAIDs.
Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Female; Humans; Male; Middle Aged; Oxaprozin; Propionates; Synovial Fluid; Synovial Membrane
PubMed: 2801338
DOI: 10.1007/BF01972852