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Ibuprofen inhibits rat brain deamidation of anandamide at pharmacologically relevant concentrations. Mode of inhibition and structure-activity relationship.

Fowler CJ, Tiger G, Stenstrom A.

Department of Pharmacology, Umea University, Umea, Sweden.

The ability of rat brain (minus cerebellum) homogenates to deamidate arachidonyl ethanolamide (anandamide) was determined with a custom-synthesized substrate, arachidonyl ethanolamide-[1-3H] ([3H]anandamide). Conditions whereby initial velocities were measured were established. The homogenates deamidated anandamide with a Km value of 0.8 microM and a Vmax value of 1.73 nmol . (mg protein)-1 . min-1. The deamidation of 2 microM -3H-anandamide was inhibited by phenylmethylsulfonyl fluoride and arachidonyl trifluoromethyl ketone with IC50 values of 3.7 and 0.23 microM, respectively. Ibuprofen inhibited anandamide deamidation in a mixed fashion, with Ki and K'i values of 82 and 1420 microM. At an anandamide concentration of 2 microM, the IC50 values (in microM) of a series of compounds related in structure to ibuprofen were as follows: suprofen, 170; ibuprofen, 270; fenoprofen, 480; naproxen, 550; ketoprofen, 650; diclofenac, approximately 1000. Sulindac produced 27% inhibition at a concentration of 1000 microM, whereas isobutyric acid, hydrocinnamic acid, acetylsalicylic acid and acetaminophen were essentially inactive at concentrations </= 1 mM. We conclude that ibuprofen inhibits anandamide deamidation at pharmacologically relevant concentrations and that there is some specificity to the inhibition produced by ibuprofen and suprofen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9353392&dopt=Abstract ibuprofen Motrin



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Key role for cyclooxygenase-2 in PGE2 and PGF2alpha receptor regulation and cerebral blood flow of the newborn.

Li DY, Hardy P, Abran D, Martinez-Bermudez AK, Guerguerian AM, Bhattacharya M, Almazan G, Menezes R, Peri KG, Varma DR, Chemtob S.

Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.

Ibuprofen, a cyclooxygenase (COX) inhibitor nonselective for either COX-1 or COX-2 isoform, upregulates cerebrovascular prostaglandin E2 (PGE2) and PGF2alpha receptors in newborn pigs. COX-2 was shown to be the predominant form of COX and the main catalyst of prostaglandin synthesis in the newborn brain. We proceeded to establish direct evidence that COX-2-generated prostaglandins govern PGE2 and PGF2alpha receptor density and function in the cerebral vasculature of the newborn. Hence, we determined PGE2 and PGF2alpha receptor density and functions in brain vasculature by using newborn pigs treated with saline, ibuprofen, COX-1 inhibitor (valerylsalicylate), or COX-2 inhibitors (DUP-697 and NS-398). Newborn brain PGE2 and PGF2alpha concentrations were significantly reduced by ibuprofen, DUP-697, and NS-398 but not by valerylsalicylate. In newborn pigs treated with DUP-697, NS-398, and ibuprofen, PGE2 and PGF2alpha receptor densities in brain microvessels were increased to adult levels; there was also a significant increase in inositol 1,4,5-trisphosphate (IP3) production and cerebral vasoconstrictor effects of 17-phenyl trinor PGE2 (EP1 receptor agonist), M&B-28767 (EP3 receptor agonist), PGF2alpha, and fenprostalene (PGF2alpha analog). Treatment with ibuprofen or DUP-697 also increased the upper blood pressure limit of cerebral cortex and periventricular blood flow autoregulation from 85 to > or = 125 mmHg (uppermost blood pressure studied). However, valerylsalicylate treatment did not affect cerebrovascular PGE2 and PGF2alpha receptors, IP3 production, or vasoconstrictor effects in newborn animals. These in vivo and in vitro observations indicate that COX-2 is mainly responsible for the regulation of PGE2 and PGF2alpha receptors and their functions in the newborn cerebral vasculature.

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Ibuprofen protects alpha-crystallin against posttranslational modification by preventing protein cross-linking.

Plater ML, Goode D, Crabbe MJ.

Division of Cell and Molecular Biology, School of Animal and Microbial Sciences, University of Reading, UK.

Posttranslational modification of bovine alpha-crystallin by D-erythrose-4-phosphate, fructose-6-phosphate, D-ribose-5-phosphate and carbamylation using potassium cyanate induced the loss of chaperone-like activity, as assessed by gamma-crystallin aggregation. The presence of high-molecular-weight aggregates indicated that erythrosylated, fructosylated and carbamylated alpha-crystallins were modified by non-reducible cross-linking. In contrast, ribosylation of alpha-crystallin induced the formation of reducible cross-links. Analysis of ribosylated, erythrosylated and carbamylated alpha-crystallin using non-denaturing acrylamide gels showed that the cross-linking did not sterically inhibit the normal aggregate formation or alter the oligomerisation of the aggregate. Co-incubation of ibuprofen in the presence of alpha-crystallin and the modifying agents protected the chaperone-like activity of alpha-crystallin, enabling the inhibition of gamma-crystallin aggregation. In addition, ibuprofen inhibited the formation of both reducible and non-reducible cross-linked high-molecular-weight alpha-crystallin aggregates. We show in this paper that ibuprofen can inhibit in vitro cross-linking events responsible for the loss of chaperone-like activity of alpha-crystallin and suggest that the protective effect of ibuprofen may be exerted by the binding of ibuprofen breakdown products to alpha-crystallin lysine groups, preventing posttranslational modification responsible for the loss of chaperone-like activity.

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Stereospecific analysis of the major metabolites of ibuprofen in urine by sequential achiral-chiral high-performance liquid chromatography.

Tan SC, Jackson SH, Swift CG, Hutt AJ.

Department of Pharmacy, King's College London, UK.

A sequential achiral-chiral HPLC method has been developed for the stereospecific analysis of the two major urinary metabolites of ibuprofen, namely hydroxyibuprofen and carboxyibuprofen. Achiral analysis was carried out using a Partisil column (250x4.6 mm, 5 microm) and a mobile phase of hexane:ethanol (98.2:1.8, v/v) containing trifluoroacetic acid (TFA; 0.05%, v/v) at a flow-rate of 2.0 ml/min. The HPLC eluate containing the two metabolites was separately collected, evaporated under nitrogen and the residue dissolved in the mobile phase used for chiral chromatography. Chiral-phase analysis was carried out using a Chiralpak AD CSP (250x4.6 mm, 10 microm) with a mobile phase of hexane:ethanol (92:8, v/v) containing TFA (0.05%, v/v) at a flow-rate of 1.0 ml/min. In both assays the analytes were quantified by ultraviolet detection at a wavelength of 220 nm. Modification of the mobile-phase composition allowed the resolution of all six analytes in a single chromatographic run but with an increase in run time and consequent band broadening. The analytical method described allows the direct quantitation of the stereoisomers of both metabolites of ibuprofen in urine following the administration of therapeutic doses of the racemic drug to man.

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Determination of selected pharmaceuticals and caffeine in sewage and seawater from Tromso/Norway with emphasis on ibuprofen and its metabolites.

Weigel S, Berger U, Jensen E, Kallenborn R, Thoresen H, Huhnerfuss H.

Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.

Selected pharmaceuticals, among them analgesics, ss-blockers and anti-depressants as well as caffeine, the anti-bacterial triclosan and the insect repellent N,N-diethyl-3-toluamide (DEET) were determined in different sewage samples (sewage treatment plants, hospital effluents) from Tromso/Norway and in seawater from Tromso-Sound, into which the sewage is discharged. While caffeine, triclosan, ibuprofen and its major metabolites hydroxy- and carboxy-ibuprofen were present in all sewage samples, additional pharmaceuticals were observed in sewage containing hospital effluents. Concentrations were in the range of 20-293 microg/l (caffeine), 0.2-2.4 microg/l (triclosan) and 0.1-20 microg/l (sum ibuprofen + metabolites). In seawater, only caffeine (7-87 ng/l), DEET (0.4-13 ng/l) and ibuprofen + metabolites (sum concentration < LOQ-7.7 ng/l) were detected. Ibuprofen and its metabolites hydroxy- and carboxy-ibuprofen were quantified individually by use of the respective reference compounds. Relative amounts of the three compounds were determined in different types of water showing characteristic patterns, with hydroxy-ibuprofen being the major component in sewage whereas carboxy-ibuprofen was dominant in seawater samples. The patterns which were compared to those observed in similar samples from Germany indicated different transformation behaviour under limnic and marine conditions.

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Measurement of plasma ibuprofen by gas chromatography-mass spectrometry.

Way BA, Wilhite TR, Smith CH, Landt M.

Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.

A gas-chromatography-mass spectrometry (GC-MS) method for the determination of plasma ibuprofen was developed. Plasma samples from cystic fibrosis (CF) patients receiving high-dose ibuprofen therapy were analyzed by GC-MS and the result compared to analysis by high-performance liquid chromatography (reference method). Analysis of ibuprofen was sensitive to at least 5 mg/L, and the method was linear to 200 mg/L. Within-run variations of plasma samples were 4.6% (131.7 +/- 6.0 mg/L) and 5.4% (44.4 +/- 2.4 mg/L), respectively. The between-run variation was 9.3% (45.4 +/- 4.2 mg/L) and 7.4% (88.0 +/- 6.5 mg/L). This method is suited for routine clinical use for the monitoring of plasma ibuprofen levels in treatment of CF. It may be particularly applicable in pediatric laboratories, which are likely to possess GC-MS capability.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9406052&dopt=Abstract ibuprofen Motrin