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Biological & Pharmaceutical Bulletin Dec 2009A series of 4,5-diaryloxazole analogs were designed and the interaction between oxaprozin and cyclooxygenase-2 studied by the docking method to improve the biological...
A series of 4,5-diaryloxazole analogs were designed and the interaction between oxaprozin and cyclooxygenase-2 studied by the docking method to improve the biological activity and reduce the gastrointestinal side effects of oxaprozin. Finally, 3-(4-(4-fluorophenyl)-5-(4-aminosulfonyl-3-fluorophenyl)-oxazole-2-yl) propanoic acid (NC-2142), the best candidate, was selected for synthesis and bioassay based on the screening result. NC-2142 could lower the tumefaction rates of back metatarsus in rats, as well as reduce the writhing times in mice. NC-2142 produced fewer gastric lesions than oxaprozin. After the aminosulfonyl group was introduced into the benzene ring of oxaprozin, its analgesic and anti-inflammatory activities remained unchanged, and it reduced the number of gastric lesions. This provided a feasible method for further structure modification and optimization of oxaprozin.
Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Chemistry, Pharmaceutical; Cyclooxygenase 2; Edema; Female; Male; Metatarsal Bones; Mice; Mice, Inbred Strains; Oxaprozin; Pain; Propionates; Rats; Rats, Wistar; Stomach; Structure-Activity Relationship; Sulfonamides
PubMed: 19952416
DOI: 10.1248/bpb.32.1986 -
Journal of Biomedicine & Biotechnology 2009The modulation of CD40L activity might represent a promising therapeutic target to reduce monocyte inflammatory functions in chronic diseases, such as rheumatoid...
The modulation of CD40L activity might represent a promising therapeutic target to reduce monocyte inflammatory functions in chronic diseases, such as rheumatoid arthritis. In the present study, we investigated the possible influence of nonsteroidal anti-inflammatory drugs (NSAIDs) on CD40L-induced monocyte survival. Monocytes were isolated from buffy coats by using Ficoll-Percoll gradients. Monocyte apoptosis was evaluated by fluorescence microscopy on cytopreps stained with acridine orange or using flow cytometry analysis of Annexin-V and Propidium Iodide staining. Akt and NF-kappaB activation was assessed using western blot. Caspase 3 activity was determined spectrophotometrically. Among different NSAIDs, only oxaprozin dose-dependently increased apoptosis of CD40L-treated monocytes. Oxaprozin pro-apoptotic activity was associated with the inhibition of CD40L-triggered Akt and NF-kappaB phosphorylation and the activation of caspase 3. In conclusion, our data suggest that oxaprozin-induced apoptosis in CD40L-treated human monocytes is associated with previously unknown cyclooxygenase (COX)-independent pathways. These intracellular proteins might be promising pharmacological targets to increase apoptosis in CD40L-treated monocytes.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; CD40 Ligand; Caspase 3; Cyclooxygenase Inhibitors; Humans; Inflammation; Mitogen-Activated Protein Kinases; Monocytes; NF-kappa B p50 Subunit; Oxaprozin; Phosphatidylinositol 3-Kinases; Phosphorylation; Propionates; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 19672323
DOI: 10.1155/2009/478785 -
British Journal of Pharmacology May 2009Monocytes-macrophages play a key role in the initiation and persistence of inflammatory reactions. Consequently, these cells represent an attractive therapeutic target...
BACKGROUND AND PURPOSE
Monocytes-macrophages play a key role in the initiation and persistence of inflammatory reactions. Consequently, these cells represent an attractive therapeutic target for switching off overwhelming inflammatory responses. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drugs for the symptomatic treatment of rheumatic diseases. Their effects have been explained on the basis of cyclooxygenase (COX) inhibition. However, some of the actions of these drugs are not related to inhibition of prostaglandin synthesis.
EXPERIMENTAL APPROACH
We examined the effect of oxaprozin on apoptosis of immune complex-activated monocytes in comparison with drugs of the same class, and the signalling pathway that leads activated monocytes exposed to oxaprozin to apoptosis. In particular, we studied the activity of caspase-3, the involvement of IkappaB kinase (IKK)-nuclear factor kappaB (NF-kappaB) system and the activity of X-linked mammalian inhibitor of apoptosis protein (XIAP), Akt and mitogen-activated protein kinase (MAPK) in activated monocytes in the presence of oxaprozin.
KEY RESULTS
Immune complexes caused the inhibition of monocyte apoptosis. Oxaprozin reversed in a dose-dependent manner immune complex-induced survival of monocytes, without affecting the apoptosis of resting cells. Other NSAIDs are ineffective. The activity of oxaprozin was related to inhibition of Akt activation that, in turn, prevented p38 MAPK, IKK and NF-kappaB activation. Consistently, the inhibition of NF-kappaB activation reduced the production of the anti-apoptotic molecule XIAP, leading to uncontrolled activity of caspase 3.
CONCLUSIONS AND IMPLICATIONS
These results suggest that oxaprozin exerts its anti-inflammatory activity also through COX-independent pathways. It is likely that oxaprozin-mediated inhibition of the Akt/IKK/NF-kappaB pathway contributes to its anti-inflammatory properties.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antigen-Antibody Complex; Apoptosis; Caspase 3; Electrophoretic Mobility Shift Assay; Flow Cytometry; Fluorescent Antibody Technique; Humans; I-kappa B Kinase; In Vitro Techniques; Monocytes; NF-kappa B; Oxaprozin; Propionates; Proto-Oncogene Proteins c-akt
PubMed: 19338579
DOI: 10.1111/j.1476-5381.2009.00162.x -
Redox Report : Communications in Free... 2008It has long been known that singlet oxygen ((1)O2) is generated during inflammatory processes. Once formed in substantial amounts, (1)O2 may have an important role in...
It has long been known that singlet oxygen ((1)O2) is generated during inflammatory processes. Once formed in substantial amounts, (1)O2 may have an important role in mediating the destruction of infectious agents during host defense. On the other hand, (1)O2 is capable of damaging almost all biological molecules and is particularly genotoxic, which gives a special relevance to the scavenging of this ROS throughout anti-inflammatory treatments. Considering that the use of non-steroidal anti-inflammatory drugs (NSAIDs) constitutes a first approach in the treatment of persistent inflammatory processes (due to their ability to inhibit cyclooxygenase), a putative scavenging activity of NSAIDs for (1)O2 would also represent a significant component of their therapeutic effect. The aim of the present study was to evaluate the scavenging activity for (1)O2 by several chemical families of NSAIDs. The results suggested that the pyrazole derivatives (dipyrone and aminopyrine) are, by far, the most potent scavengers of (1)O2 (much more potent compared to the other tested NSAIDs), displaying IC(50)-values in the low micromolar range. There was a lack of activity for most of the arylpropionic acid derivatives tested, with only naproxen and indoprofen displaying residual activities, as for the oxazole derivative, oxaprozin. On the other hand, the pyrrole derivatives (tolmetin and ketorolac), the indolacetic acid derivatives (indomethacin, and etodolac), as well as sulindac and its metabolites (sulindac sulfide and sulindac sulfone) displayed scavenging activity in the high micromolar range. Thus, the scavenging effect observed for dipyrone and aminopyrine will almost certainly contribute to their healing effect in the treatment of prolonged or chronic inflammation, while that of the other studied NSAIDs may have a lower contribution, though these assumptions still require further in vivo validation.
Topics: Aminopyrine; Anti-Inflammatory Agents, Non-Steroidal; Dipyrone; Dose-Response Relationship, Drug; Etodolac; Free Radical Scavengers; Indoprofen; Ketorolac; Molecular Structure; Naproxen; Oxaprozin; Propionates; Singlet Oxygen; Tolmetin
PubMed: 18647485
DOI: 10.1179/135100008X308876 -
Analytical and Bioanalytical Chemistry Aug 2008A selective molecularly imprinted solid-phase extraction (MISPE) for indomethacin (IDM) from water samples was developed. Using IDM as template molecule, acrylamide (AM)...
A selective molecularly imprinted solid-phase extraction (MISPE) for indomethacin (IDM) from water samples was developed. Using IDM as template molecule, acrylamide (AM) or methacrylic acid (MAA) as functional monomer, ethylene dimethacrylate (EDMA) as crosslinker, and bulk or suspension polymerization as the synthetic method, three molecularly imprinted polymers (MIPs) were synthesized and characterized with a rebinding experiment. It was found that the MIP of AM-EDMA produced by bulk polymerization showed the highest binding capacity for IDM, and so it was chosen for subsequent experiments, such as those testing the selectivity and recognition binding sites. Scatchard analysis revealed that at least two kinds of binding sites formed in the MIP, with the dissociation constants of 7.8 micromol L(-1) and 127.2 micromol L(-1), respectively. Besides IDM, three structurally related compounds--acemetacin, oxaprozin and ibuprofen--were employed for selectivity tests. It was observed that the MIP exhibited the highest selective rebinding to IDM. Accordingly, the MIP was used as a solid-phase extraction sorbent for the extraction and enrichment of IDM in water samples. The extraction conditions of the MISPE column for IDM were optimized to be: chloroform or water as loading solvent, chloroform with 20% acetonitrile as washing solution, and methanol as eluting solvent. Water samples with or without spiking were extracted by the MISPE column and analyzed by HPLC. No detectable IDM was observed in tap water and the content of IDM in a river water sample was found to be 1.8 ng mL(-1). The extraction efficiencies of the MISPE column for IDM in spiked tap and river water were acceptable (87.2% and 83.5%, respectively), demonstrating the feasibility of the prepared MIP for IDM extraction.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Chloroform; Chromatography, High Pressure Liquid; Feasibility Studies; Indomethacin; Molecular Imprinting; Molecular Structure; Polymers; Rivers; Solid Phase Extraction; Solutions; Spectrophotometry; Water; Water Pollutants, Chemical
PubMed: 18575852
DOI: 10.1007/s00216-008-2218-2 -
Clinical Pharmacokinetics 2008The question of whether metabolic drug clearance is decreased in elderly people has been the subject of considerable debate and is very important because clearance is a... (Review)
Review
The question of whether metabolic drug clearance is decreased in elderly people has been the subject of considerable debate and is very important because clearance is a determinant of dosing. Drug clearance has been shown to be consistently impaired for flow-limited (high-clearance) drugs, but there have been conflicting results for capacity-limited (low-clearance) drugs. A limitation of the studies of capacity-limited drugs is that most have estimated clearance based on total drug concentrations (protein-bound plus free). Total drug clearance reflects both the intrinsic clearance of free drug and the extent of protein binding. Total clearance is a valid measure for capacity-limited drugs with low protein binding and appears to be consistently impaired in elderly subjects. For phenazone [antipyrine] (fraction unbound [f(u)] >0.9), seven studies have demonstrated statistical reductions in clearance of 20-52%. For theophylline (f(u) 0.6), five studies have demonstrated reductions in clearance of 22-35%. For paracetamol [acetaminophen] (f(u) 0.8), the clearance of which has been quoted as unchanged, four studies have demonstrated reductions in clearance of 19-35%. For highly protein-bound drugs, total clearance is not the appropriate parameter. Free drug clearance is more appropriate since it is independent of changes in protein binding. The literature was reviewed to test the hypothesis that in elderly people, capacity-limited drugs with high protein binding will show decreased free clearance even in the absence of a decrease in total clearance. For these drugs, data for free drug clearance based on measurement of actual free drug concentrations are limited, but suggest that the intrinsic metabolic clearance is impaired in elderly subjects. Four studies of naproxen (f(u) <0.01) have shown reduced free drug clearance of 50% or more. Two studies of valproic acid (f(u) 0.1-0.2) have shown reduced free clearance of 39% and 65%. Two studies of ibuprofen (f(u) <0.01) have shown reduced free clearance of S-ibuprofen of 21% and 28%. There is some indirect evidence for reduced clearance of the highly protein-bound drugs oxaprozin, temazepam, lorazepam, diazepam, phenytoin and warfarin, although studies measuring free concentrations are lacking. Together, the above studies support the hypothesis that the intrinsic metabolic drug clearance is impaired in elderly subjects, in the order of 20-60%, and that this effect is masked if highly protein-bound drugs are assessed using total drug clearance. If the findings are confirmed in future well-designed studies of free drug clearance, there are profound and beneficial implications for dosing of drugs in elderly people. Lower doses are likely to achieve appropriate concentrations, allowing full efficacy but decreased dose-related adverse effects.
Topics: Aged; Animals; Humans; Pharmaceutical Preparations; Protein Binding
PubMed: 18399712
DOI: 10.2165/00003088-200847050-00002 -
Cancer Research Apr 2007Epidemiologic studies show that patients chronically consuming nonsteroidal anti-inflammatory drugs (NSAID) for arthritis exhibit a reduced incidence of prostate cancer....
Epidemiologic studies show that patients chronically consuming nonsteroidal anti-inflammatory drugs (NSAID) for arthritis exhibit a reduced incidence of prostate cancer. In addition, some NSAIDs show anticancer activity in vitro. NSAIDs exert their anti-inflammatory effects by inhibiting cyclooxygenase (COX) activity; however, evidence suggests that COX-independent mechanisms mediate decreased prostate cancer cell survival. Hence, we examined the effect of selected aryl propionic acid NSAIDs and structurally related compounds on the decreased survival of prostate cancer cell lines PC-3, DU-145, and LNCaP by induction of the p75(NTR) protein. p75(NTR) has been shown to function as a tumor suppressor in the prostate by virtue of its intracellular death domain that can initiate apoptosis and inhibit growth. The most efficacious compounds for induction of p75(NTR) and decreased survival, in rank-order, were R-flurbiprofen, ibuprofen, oxaprozin, fenoprofen, naproxen, and ketoprofen. Because R-flurbiprofen and ibuprofen exhibited the greatest efficacy, we examined their dose-dependent specificity of induction for p75(NTR) relative to other members of the death receptor family. Whereas treatment with R-flurbiprofen or ibuprofen resulted in a massive induction of p75(NTR) protein levels, the expression of Fas, p55(TNFR), DR3, DR4, DR5, and DR6 remained largely unchanged. Moreover, transfection of either cell line before R-flurbiprofen or ibuprofen treatment with a dominant negative form of p75(NTR) to antagonize p75(NTR) activity or p75(NTR) small interfering RNA to prevent p75(NTR) protein expression rescued both cell lines from decreased survival. Hence, R-flurbiprofen and ibuprofen selectively induce p75(NTR)-dependent decreased survival of prostate cancer cells independently of COX inhibition.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Cell Survival; Dose-Response Relationship, Drug; Flurbiprofen; Humans; Ibuprofen; Male; Nerve Tissue Proteins; Prostatic Neoplasms; RNA, Small Interfering; Receptors, Nerve Growth Factor; Transfection; Up-Regulation
PubMed: 17409433
DOI: 10.1158/0008-5472.CAN-06-3657 -
Biological & Pharmaceutical Bulletin Nov 2006The model penetrants oxaprozin, nimesulide, gliclazide, and ribavirin, because of their different lipophilicities, were selected to assess the enhancing activity of...
The model penetrants oxaprozin, nimesulide, gliclazide, and ribavirin, because of their different lipophilicities, were selected to assess the enhancing activity of pre-treatment solutions consisting of isopropyl palmitate (IP) in ethanol (5%, 10%, 15%and 20%, w/w, respectively) across excised rat skin using Franz diffusion cells and HPLC detection. All pre-treatment solutions produced a significant increase in the flux and permeation of all four penetrants (p<0.001) and a relationship between penetrant lipophilicity and enhancement effect was observed. The general order of IP effectiveness at concentration was 20%>15%>10%>5% (w/w). The lag-time of drugs did not significantly change except for ribavirin.
Topics: Abdomen; Administration, Cutaneous; Animals; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Fatty Acids; Gliclazide; In Vitro Techniques; Lipids; Male; Oxaprozin; Palmitates; Permeability; Pharmaceutical Preparations; Propionates; Rats; Rats, Wistar; Ribavirin; Skin; Skin Absorption; Solubility; Sulfonamides
PubMed: 17077540
DOI: 10.1248/bpb.29.2324 -
Pharmacoepidemiology and Drug Safety Dec 2006The objective of this study was to quantify the associations between NSAIDs and COX-2 inhibitors and risk for initiating antihypertensive therapy.
PURPOSE
The objective of this study was to quantify the associations between NSAIDs and COX-2 inhibitors and risk for initiating antihypertensive therapy.
METHODS
We conducted a population-based case-control study in a large, integrated health system in the Midwestern United States. Cases (N = 23 562) were new users of antihypertensive therapy from 1, July 1997, through 31, January 2003. Controls (N = 23 562) were randomly selected and matched to cases on age, copay, medical care utilization, sex, and index date. The main outcome measures were exposure to NSAIDs and COX-2 inhibitors.
RESULTS
Recent prescription NSAID use was associated with an increased risk for initiation of antihypertensive therapy (odds ratio (OR) = 1.6, 95%CI 1.5, 1.7) as were selective COX-2 inhibitors (OR = 1.8, 95%CI 1.6, 2.1). After adjusting for age, sex, co-payment, race, and exposure to other NSAIDs/COX-2, each non-selective NSAID (diclofenac, ibuprofen, indomethacin, naproxen, oxaprozin) was associated with an increased risk of antihypertensive therapy initiation, with ORs ranging from 1.4 to 1.8. Recent users of COX-2 inhibitors had an increased risk of initiating antihypertensive therapy, regardless of specific drug (celecoxib adjusted OR = 1.7 (95%CI 1.3, 2.1); rofecoxib adjusted OR = 1.7 (95%CI 1.4, 1.9)).
CONCLUSIONS
A consistent increased risk of initiation of antihypertensive therapy was observed among recent users of NSAIDs and COX-2 inhibitors. Unlike previous studies, the results indicate that the effects of rofecoxib and celecoxib are equivalent.
Topics: Drug-Related Side Effects and Adverse Reactions; Health Planning; Product Surveillance, Postmarketing; Risk Management
PubMed: 17024689
DOI: 10.1002/pds.1327 -
International Journal of Biological... Nov 2006The interaction between Oxaprozin-E and bovine serum albumin (BSA) was studied by spectroscopic methods including fluorescence and UV-vis absorption spectroscopy. The...
The interaction between Oxaprozin-E and bovine serum albumin (BSA) was studied by spectroscopic methods including fluorescence and UV-vis absorption spectroscopy. The quenching mechanism of fluorescence of BSA by Oxaprozin-E was discussed to be a dynamic quenching procedure. The number of binding sites n and apparent binding constant K was measured by fluorescence quenching method. The thermodynamics parameter DeltaH, DeltaG, DeltaS were calculated. The results indicate the binding reaction was mainly entropy-driven and hydrophobic forces played major role in the binding reaction. The distance r between donor (BSA) and acceptor (Oxaprozin-E) was obtained according to Förster theory of non-radioactive energy transfer.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cattle; Oxaprozin; Propionates; Serum Albumin, Bovine; Spectrometry, Fluorescence; Spectrophotometry; Spectrophotometry, Ultraviolet; Thermodynamics
PubMed: 16828154
DOI: 10.1016/j.ijbiomac.2006.03.020