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Bioorganic & Medicinal Chemistry Letters Jun 2006The peroxyl-radical-scavenging mechanism of some nonsteroidal anti-inflammatory drugs (NSAIDs), namely tolmetin, ketorolac, indomethacin, acemetacin, and oxaprozin, is...
The peroxyl-radical-scavenging mechanism of some nonsteroidal anti-inflammatory drugs (NSAIDs), namely tolmetin, ketorolac, indomethacin, acemetacin, and oxaprozin, is clarified by combined density functional theory (DFT) calculations. It is revealed that H-atom-abstraction rather than electron transfer reaction is involved in the radical-scavenging process of these NSAIDs in polar aqueous solution. This seems contrary to the common viewpoint that the latter is predominant in polar media. The calculated results also show that H-atom at C(beta) or C(gamma) position is readily to be abstracted, and the lowest C-H bond dissociation enthalpy (BDE) can qualitatively account for the activity difference for the five NSAIDs.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Molecular Structure; Peroxides; Structure-Activity Relationship
PubMed: 16600595
DOI: 10.1016/j.bmcl.2006.03.054 -
The Journal of Pharmacy and Pharmacology Jan 2006Our purpose was to explore the use of Transcutol P (Trans) in an ocular drug delivery system. The effect of Trans on the corneal permeability of drugs was investigated...
Our purpose was to explore the use of Transcutol P (Trans) in an ocular drug delivery system. The effect of Trans on the corneal permeability of drugs was investigated in-vitro, using isolated rabbit corneas. The ocular irritation of Trans was also tested in rabbits in-vivo. In the presence of Trans, at a concentration of 0.005-0.03%, the maximum increase in the apparent permeability coefficient (P(app)) was 1.5, 1.5, 3.0 and 3.3 fold for ribavirin, gatifloxacin, levofloxacin hydrochloride and enoxacin, respectively. However, the P(app) value of oxaprozin was reduced in the presence of Trans. The maximum reduction was found to be 2.8 fold at a concentration of 0.03% Trans. The results of the ocular irritation studies showed that Trans was non-irritant at the concentrations studied (0.005-0.03%), while it produced slight irritation at a concentration of 0.05%. It was also found that Trans did not cause any visible ocular damage or abnormal clinical signs involving the cornea, iris or conjunctivae at all concentrations. We concluded that Trans may have potential clinical benefits in improving the ocular drug delivery of hydrophilic compounds.
Topics: 1-Octanol; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Cornea; Drug Carriers; Enoxacin; Ethylene Glycols; Eye; Fluoroquinolones; Gatifloxacin; In Vitro Techniques; Irritants; Levofloxacin; Ofloxacin; Oxaprozin; Permeability; Propionates; Rabbits; Ribavirin; Water
PubMed: 16393463
DOI: 10.1211/jpp.58.1.0006 -
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 -
Therapeutic Drug Monitoring Jun 2005Phenytoin is an anticonvulsant that requires therapeutic drug monitoring. Recently, Bayer HealthCare, Diagnostics Division released a turbidimetric immunoassay of...
Phenytoin is an anticonvulsant that requires therapeutic drug monitoring. Recently, Bayer HealthCare, Diagnostics Division released a turbidimetric immunoassay of phenytoin on the ADVIA 1650 analyzer. We evaluated the analytic performance of this assay by comparing values obtained in 52 patients receiving Phenytoin using this new assay with the values obtained by using a widely used fluorescence polarization immunoassay (FPIA). The new turbidimetric immunoassay for phenytoin showed the following imprecision with the low, medium, and high controls: total CV of 5.2% (mean 4.81 microg/mL), 3.7% (mean 16.24 microg/mL), and 4.1% (mean 22.65 microg/mL), respectively. The detection limit of the assay was 0.79 microg/mL, and the assay was linear up to a phenytoin concentration of 46.1 microg/mL. The assay showed excellent dilution recovery and recovery of spiked samples (mean recovery 101.4% and 94.4%, respectively). We observed an excellent correlation between the values obtained by the FPIA (x-axis) assay and the new turbidimetric (y-axis) assay (y=1.06 x-0.61, r=0.98, n=52). We also determined the cross-reactivity of 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), a major metabolite of phenytoin, and of oxaprozine, an analogue with a similar chemical structure to phenytoin, in both phenytoin assays. Both assays showed almost no cross-reactivity to oxaprozine and only small (5%-8%) cross-reactivity to HPPH. We also found that the turbidimetric assay was free from interference at least up to 1200 mg/dL of hemolysis, 30 mg/dL of free bilirubin, 34.5 mg/dL of conjugated bilirubin, and 750 mg/dL of triglyceride (Intralipid). When a drug-free serum was followed by a serum sample containing 38.5 microg/mL of phenytoin, no sample probe carryover effect was observed. We conclude that the new turbidimetric assay can be used for routine monitoring of phenytoin in clinical laboratories.
Topics: Bilirubin; Cross Reactions; Fluorescence Polarization Immunoassay; Hemolysis; Humans; Nephelometry and Turbidimetry; Oxaprozin; Phenytoin; Propionates
PubMed: 15905800
DOI: 10.1097/01.ftd.0000164315.13825.dd -
Life Sciences Apr 2005Hydrogen peroxide (H2O2) has been shown to be formed during inflammatory processes and is implicated in its pathophysiology. Thus, a putative scavenging activity against... (Comparative Study)
Comparative Study
Hydrogen peroxide (H2O2) has been shown to be formed during inflammatory processes and is implicated in its pathophysiology. Thus, a putative scavenging activity against this reactive oxygen species (ROS) by anti-inflammatory drugs may be of great therapeutical value. The present study was undertaken to evaluate the scavenging activity for H2O2 by several non-steroidal anti-inflammatory drugs (NSAIDs), namely indomethacin, acemetacin, etodolac, tolmetin, ketorolac, oxaprozin, sulindac and its metabolites sulindac sulfide and sulindac sulfone. The H2O2 scavenging assay was performed by measuring H2O2-elicited lucigenin chemiluminescence using a microplate reader. The specificity of the method was confirmed by the use of catalase, which completely prevented the H2O2-induced lucigenin chemiluminescence. The endogenous antioxidants melatonin and reduced glutathione (GSH) were used as positive controls. The obtained results demonstrated that all the studied NSAIDs display H2O2 scavenging activity, although in different extents. The ranking order of potency found was sulindac sulfone > sulindac sulfide > GSH > sulindac > indomethacin > acemetacin > etodolac > oxaprozin > ketorolac approximately melatonin > tolmetin.
Topics: Acridines; Anti-Inflammatory Agents, Non-Steroidal; Catalase; Free Radical Scavengers; Hydrogen Peroxide; Luminescent Measurements; Reactive Oxygen Species
PubMed: 15808884
DOI: 10.1016/j.lfs.2004.10.052 -
American Journal of Health-system... Apr 2005
Comparative Study
Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Butanones; Celecoxib; Cyclooxygenase Inhibitors; Drug Prescriptions; Drug Utilization; Female; Humans; Lactones; Male; Middle Aged; Nabumetone; Outpatients; Oxaprozin; Practice Patterns, Physicians'; Propionates; Pyrazoles; Sulfonamides; Sulfones
PubMed: 15790802
DOI: 10.1093/ajhp/62.7.739 -
Free Radical Biology & Medicine Dec 2004This study was undertaken to evaluate the scavenging activity for reactive oxygen species (ROS) and reactive nitrogen species (RNS) by several nonsteroidal...
This study was undertaken to evaluate the scavenging activity for reactive oxygen species (ROS) and reactive nitrogen species (RNS) by several nonsteroidal anti-inflammatory drugs (NSAIDs), namely indole derivatives (indomethacin, acemetacin, etodolac), pyrrole derivatives (tolmetin and ketorolac), and an oxazole derivative (oxaprozin). The inhibition of prostaglandin synthesis constitutes the primary mechanism of the anti-inflammatory action of these drugs. Nevertheless, it has been suggested that the anti-inflammatory activity of NSAIDs may be also partly due to their ability to scavenge ROS and RNS and to inhibit the respiratory burst of neutrophils triggered by various activator agents. Thus, the scavenging activity of these NSAIDs was evaluated against an array of ROS (O(2)(-), HO, HOCl, and ROO) and RNS (NO and ONOO(-)) using noncellular in vitro systems. The results obtained demonstrated that tolmetin, ketorolac, and oxaprozin were not active against O(2)(-), while acemetacin, indomethacin, and etodolac exhibited concentration-dependent effects. Oxaprozin was also the least active scavenger for HO, among all the tested NSAIDs shown to be active. The scavenging effect for HOCl was not observed for any of the tested NSAIDs. The ROO was effectively scavenged by etodolac, with the other tested NSAIDs being much less active. NO and ONOO(-) were scavenged by all the tested NSAIDs. These effects may strongly contribute to the anti-inflammatory therapy benefits that may be attained with some of the studied NSAIDs.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Chemistry Techniques, Analytical; Free Radical Scavengers; Indoles; Oxazoles; Pyrroles; Reactive Nitrogen Species; Reactive Oxygen Species
PubMed: 15528048
DOI: 10.1016/j.freeradbiomed.2004.09.001 -
Current Medical Research and Opinion Aug 2004To evaluate the efficacy and safety of oxaprozin in comparison with diclofenac in patients with periarthritis pain of the shoulder previously unsuccessfully treated with... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
OBJECTIVE
To evaluate the efficacy and safety of oxaprozin in comparison with diclofenac in patients with periarthritis pain of the shoulder previously unsuccessfully treated with nonsteroidal anti-inflammatory drugs other than diclofenac and oxaprozin.
METHODS
In this open, multicentre, randomised, controlled study, eligible patients with periarthritis of the shoulder were randomised to receive either oxaprozin 1200 mg once daily (n = 49) or diclofenac 50 mg three times daily (n = 47). The treatment period was 15 +/- 1 days. The study was planned on a hypothesis of equivalence between the two study drugs. The primary study endpoint was the change from baseline at day 15 in the patient-assessed shoulder pain score. Secondary efficacy variables included investigator-assessed shoulder function, patient-assessed quality of life on the Short-Form-36 (SF-36) Acute Health Survey and both patients' and investigators' overall assessment of efficacy.
RESULTS
At day 15, the mean changes in shoulder pain score from baseline in the oxaprozin and diclofenac groups were -5.85 +/- SD 4.62 and -5.54 +/- SD 4.41, respectively. The difference between the two groups was not statistically significant, confirming the hypothesis of the study that oxaprozin is as effective as diclofenac. Investigator-assessed shoulder function improved in both groups but more so in the oxaprozin group (p = 0.028 at day 15). Quality of life as measured by SF-36 total score was also improved in both treatment groups, with a trend toward greater improvement in the oxaprozin group. Furthermore, a significantly more favourable effect on the SF-36 'mental health' item was observed in oxaprozin compared with diclofenac-treated patients at day 15 (p = 0.0202). As assessed by investigators, the overall efficacy of oxaprozin was superior to that for diclofenac at visit 3 (8 +/- 1 days) (p = 0.0067). Patients also assessed the overall efficacy of oxaprozin as superior to that of diclofenac at visits 3 (8 +/- 1 days) (p = 0.0235) and 4 (15 +/- 1 days) (p = 0.0272). Only six adverse events, all of which were mild or moderate in intensity and occurred in four diclofenac recipients, were observed in the study.
CONCLUSIONS
As expected, once-daily oxaprozin proved to be as effective as diclofenac three times daily in reducing the primary efficacy variable of patient-assessed shoulder pain score in patients with periarthritis of the shoulder refractory to previous treatments with other NSAIDs. Oxaprozin was shown to be superior to diclofenac in improving shoulder function and was considered by investigators and patients to have greater overall efficacy than diclofenac. In addition, oxaprozin showed a trend toward superior results in improving patients' quality of life compared with diclofenac. A trend towards better tolerability results for oxaprozin compared with diclofenac was also noted.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Female; Humans; Male; Middle Aged; Oxaprozin; Pain Measurement; Periarthritis; Propionates; Quality of Life; Self-Assessment; Shoulder Joint; Shoulder Pain; Treatment Outcome
PubMed: 15324531
DOI: 10.1185/030079904125004411 -
Current Medical Research and Opinion Aug 2004Oxaprozin (4,5-diphenyl-2-oxazolepropionic acid) is a non-steroidal anti-inflammatory drug (NSAID) which is effective in models of inflammation, pain and pyrexia. It is...
Oxaprozin (4,5-diphenyl-2-oxazolepropionic acid) is a non-steroidal anti-inflammatory drug (NSAID) which is effective in models of inflammation, pain and pyrexia. It is effective and well tolerated in the clinical management of adult rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis, soft tissue disorders and post operative dental pain. Oxaprozin has a high oral bioavailability (95%), with peak plasma concentrations at 3 to 5 hours after dosing. It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes. Oxaprozin's strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder, since it exhibits actions such as inhibition of COX-1 and COX-2 isoenzymes, inhibition of nuclear translocation of NF-kappaB and of metalloproteases, and modulates the endogenous cannabinoid system. This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain, in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period. Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain. Oxaprozin and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF-36 quality of life component. The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti-rheumatic agents such as aspirin, diclofenac, ibuprofen, indomethacin etc. in several different painful musculoskeletal conditions.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Diclofenac; Humans; Oxaprozin; Periarthritis; Propionates; Shoulder Joint; Shoulder Pain; Treatment Outcome
PubMed: 15324530
DOI: 10.1185/030079904125004420 -
Drugs & Aging 2004Data on file with the US FDA, and other published studies, suggest that the selective cyclo-oxygenase (COX)-2 inhibitor NSAID rofecoxib has a greater hypertensive...
BACKGROUND AND OBJECTIVE
Data on file with the US FDA, and other published studies, suggest that the selective cyclo-oxygenase (COX)-2 inhibitor NSAID rofecoxib has a greater hypertensive adverse effect than other NSAIDs, including celecoxib. In this study we describe a pharmacoepidemiologic analysis of spontaneous adverse event reports of acute, clinically serious hypertension (as defined by hospitalisation) reported in association with rofecoxib, celecoxib, nabumetone and oxaprozin. The objective of this analysis is to assess whether postmarketing data are consistent with results of clinical trials. We also collapse cases into series for the identification of possible risk factors for clinically severe, NSAID-associated hypertension.
METHODS
Domestic (US) cases of apparently unconfounded, acute hypertension leading to hospitalisation were collected and reviewed from the spontaneous adverse events database of the FDA for rofecoxib, celecoxib, nabumetone and oxaprozin for the initial 3 years of marketing. Drug use data for the same intervals enabled calculation of reporting rates.
RESULTS
In an analysis of reporting rates, hospitalisation for acute blood pressure (BP) elevation was reported more frequently (3.8-fold) for rofecoxib compared with celecoxib. A total of 34 cases are collapsed into case series. No cases were identified for either nabumetone or oxaprozin. Inspection of reviewed cases for celecoxib and rofecoxib suggest that these patients (average age 72 years) were potentially high-risk candidates for NSAID therapy.
DISCUSSION AND CONCLUSION
During early marketing, hospitalisation for acute BP elevation appears to have been reported more frequently for rofecoxib compared with celecoxib. This is consistent with clinical trial data on file with the FDA, and other published studies that found rofecoxib to have a greater effect on BP than other NSAIDs, including celecoxib. This finding may be particularly relevant in older patients given the prevalence of hypertension and cardiovascular disease in this age group.
Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Butanones; Celecoxib; Clinical Trials as Topic; Cyclooxygenase 2; Female; Hospitalization; Humans; Hypertension; Isoenzymes; Lactones; Male; Membrane Proteins; Middle Aged; Nabumetone; Oxaprozin; Propionates; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides; Sulfones
PubMed: 15132714
DOI: 10.2165/00002512-200421070-00005