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Nonsteroidal antiinflammatory drugs: effects on normal and interleukin 1 treated human articular chondrocyte metabolism in vitro.

Smith RL, Kajiyama G, Lane NE.

Orthopaedic Research Laboratory, Stanford University School of Medicine, CA, USA.

OBJECTIVE. To test the effects of nonsteroidal antiinflammatory drugs (NSAID), naproxen, ibuprofen and diclofenac, and salicylates on normal and interleukin 1 (IL-1) treated human articular chondrocyte metabolism in vitro. METHODS. Normal adult human articular chondrocytes were isolated and cultured as primary monolayers; the cells were treated with NSAID and salicylates at low and high plating density for assessing effects on proliferation and matrix synthesis and IL-1 modulated cell metabolism, respectively. RESULTS. Cell proliferation was inhibited by ibuprofen and high doses of salicylates. Glycosaminoglycan (GAG) synthesis was stimulated by ibuprofen at 10 micrograms/ml but was not changed by any other drugs at similarly low concentrations; at medium to high concentrations, only the salicylates inhibited GAG synthesis. Collagen synthesis was unaffected by any drug at the concentrations tested. IL-1 induced prostaglandin E2 release was completely inhibited by the NSAID and partially inhibited by the salicylates. IL-1 induced IL-6 release was inhibited by ibuprofen and the salicylates where as IL-1 induced APMA-activated collagenase was only inhibited by the salicylates. CONCLUSION. Normal human chondrocytes respond differentially to naproxen, ibuprofen, dicolfenac, and the salicylates; these observations suggest that each drug may exhibit unique attributes with respect to longterm efficacy on cartilage metabolism.

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Characterization of the protein binding of chiral drugs by high-performance affinity chromatography. Interactions of R- and S-ibuprofen with human serum albumin.

Hage DS, Noctor TA, Wainer IW.

Department of Chemistry, University of Nebraska, Lincoln 68588-0304.

Zonal elution and high-performance affinity chromatography were used to study the different binding characteristics of R- and S-ibuprofen with the protein human serum albumin (HSA). This was done by injecting small amounts of R- and S-ibuprofen onto an immobilized HSA column in the presence of a mobile phase that contained a known concentration of R- or S-ibuprofen as a competing agent. These studies indicated that R- and S-ibuprofen had one common binding site on the immobilized HSA column. In addition, S-ibuprofen had at least one other major binding region. The association equilibrium constant for R-ibuprofen with HSA was found to be 5.3 x 10(5) M-1 at pH 6.9 and 25 degrees C. Under the same conditions, the association constants for S-ibuprofen at its two sites were 1.1 x 10(5) M-1 and 1.2 x 10(5) M-1. The S-ibuprofen sites were present in about a 1:1 ratio and appeared to exhibit some allosteric interactions at high S-ibuprofen concentrations. The chromatographic technique used in this work is a general one which can be adapted for use in studying the interactions of other chiral compounds with either HSA or additional proteins.

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Paradoxic effect of ibuprofen on neutrophil accumulation in pulmonary and cutaneous inflammation.

Hellewell PG, Young SK, Henson PM, Worthen GS.

Department of Medicine and Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado.

Evidence exists to suggest that the local accumulation of neutrophils in pulmonary inflammation occurs by a different mechanism than in other microvascular beds. In the present study, this suggestion was investigated using the nonsteroidal antiinflammatory drug ibuprofen. This drug was used because in addition to inhibiting cyclooxygenase, it prevents several aspects of neutrophil function, including adhesion. Local inflammation in the lung and skin of the same rabbits was induced by the administration of C5a, and the effect of intravenous injection of ibuprofen on the accumulation of neutrophils at these two sites was examined. In the skin, neutrophil accumulation was inhibited by ibuprofen, and this appeared to be independent of cyclooxygenase blockade. A possible mechanism was prevention of neutrophil adherence to endothelium in postcapillary venules, and in vitro experiments showed that ibuprofen could entirely prevent neutrophil adherence, in addition to suppressing azurophil granule secretion and superoxide anion generation. However, the effect on adherence appeared to be independent of expression of the CD11/CD18 adhesion complex on the neutrophil. By contrast, in the pulmonary circulation of the same rabbit, C5a-induced neutrophil accumulation was enhanced by ibuprofen treatment. This was suggested to result from the prevention of thromboxane production, which normally serves to decrease local pulmonary blood flow to diminish delivery of neutrophils to the inflammatory site. Ibuprofen had no effect on retention of neutrophils in filters (models of pulmonary capillaries), suggesting that the drug was not enhancing the retention of neutrophils in capillaries on the first pass through the lung. Thus, it was possible that enhancement in the lung was caused by an increase in neutrophil supply. Because the accumulation of neutrophils in the skin is known to be dependent on the adherence phenomena, the paradoxic effects of ibuprofen on inflammation suggest that mechanisms responsible for the accumulation of neutrophils in cutaneous and pulmonary microcirculations are different.

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Enantioselective disposition of ibuprofen in elderly persons with and without renal impairment.

Rudy AC, Knight PM, Brater DC, Hall SD.

Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.

By using stable isotope methodology, we studied the disposition of ibuprofen after the first and last dose of a 4-week regimen of 800 mg of racemic ibuprofen every 8 hr in three groups of subjects: 1) young healthy volunteers (n = 8); 2) healthy elderly volunteers (n = 14); and 3) elderly patients with creatinine clearance between 30 and 70 ml/min (n = 13). Stereoselective gas chromatography-mass spectrometry was used to quantify deuterated S- and nondeuterated R- and S-ibuprofen in serum up to 24 hr after the first and last doses. Urinary excretion of the stereoisomeric forms of carboxyibuprofen, hydroxyibuprofen and ibuprofen glucuronide were determined up to 24-hr postdose by stereoselective high-performance liquid chromatography. Stereoselective serum protein binding was determined by ultrafiltration. Both elderly groups had significantly decreased binding of S-ibuprofen compared to the young group. The S-ibuprofen pharmacokinetics were significantly different in the elderly patients with renal impairment compared to the young volunteers: the T1/2 was increased, the unbound clearance was decreased and the unbound concentration at steady state was increased. Fraction inverted was similar for all groups, but unbound clearances of glucuronidation and hydroxylation were reduced in the elderly patients with renal impairment. These results suggest that the disposition of ibuprofen enantiomers is altered in elderly persons with renal impairment; these changes may increase the risk for nonsteroidal anti-inflammatory drug-associated adverse effects in such patients.

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Antibacterial activity of the anti-inflammatory compound ibuprofen.

Elvers KT, Wright SJ.

School of Biology and Biochemistry, University of Bath, Avon, UK.

The effect of ibuprofen on growth in vitro of six bacterial species was tested. Ibuprofen inhibited growth of the Gram-positive species, but the two Gram-negative species were unaffected. Growth of Staphylococcus aureus was suppressed by ibuprofen concentrations greater than 150 micrograms ml-1 at initial pH 7. At pH 6, such concentrations prevented growth. The antibacterial activity of ibuprofen was affected by pH, being more effective at values below pH 7. Ibuprofen may have an ancillary benefit in topical application, in controlling bacteria.

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Disposition and covalent binding of ibuprofen and its acyl glucuronide in the elderly.

Castillo M, Lam YW, Dooley MA, Stahl E, Smith PC.

Department of Medicine, University of North Carolina at Chapel Hill 27599-7360, USA.

Ibuprofen is an over-the-counter nonsteroidal anti-inflammatory drug with a low incidence of severe adverse reactions. It is metabolized by oxidation to carboxyibuprofen and hydroxyibuprofen and by conjugation to an acyl glucuronide. In vitro studies have indicated that ibuprofen glucuronide is labile and reactive, forming covalent adducts with proteins. To verify the formation of ibuprofen-protein adducts in vivo, the pharmacokinetics of ibuprofen glucuronide and its covalent binding to plasma proteins were studied in five elderly patients who received long-term administration of oral doses of ibuprofen. Plasma levels of ibuprofen glucuronide were low relative to those of ibuprofen; the ratio of area under the plasma concentration versus time curve for the glucuronide relative to the parent drug was only 4%. Covalent binding of ibuprofen to plasma protein was observed in all patients, correlating well with the area under the plasma concentration versus time curve of ibuprofen glucuronide (r = 0.966). Compared with reports for other nonsteroidal anti-inflammatory drugs that form acyl glucuronides, plasma levels of ibuprofen-protein adduct are low during long-term administration. The observed lower reactivity in vivo is probably attributable to the greater stability of ibuprofen glucuronide relative to other acyl glucuronides.

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Inhibition of cerebral vasospasm by intracranial delivery of ibuprofen from a controlled-release polymer in a rabbit model of subarachnoid hemorrhage.

Frazier JL, Pradilla G, Wang PP, Tamargo RJ.

Department of Neurological Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-7713, USA.

OBJECT: Leukocyte-endothelial cell interactions may play a role in the development of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) because the extravasation of circulating leukocytes into the periadventitial space within 24 hours after the hemorrhage appears to be a critical event in this process. Ibuprofen is an antiinflammatory agent that inhibits the expression of specific cell adhesion molecules and, consequently, disrupts leukocyte-endothelial cell interactions. The authors investigated the efficacy of ibuprofen delivered locally from controlled-release polymers in the rabbit basilar artery (BA) model of cerebral vasospasm. METHODS: Ibuprofen was incorporated into controlled-release ethylene-vinyl acetate copolymer (EVAc) constituting 45% of the resulting polymer by weight. Fifty-four New Zealand White rabbits were randomized to 10 groups: sham operation (seven animals); SAH only (seven animals); and SAH plus either empty EVAc or ibuprofen-EVAc polymer at 30 minutes or 6, 12, or 24 hours (five animals per group; 40 total). The rabbits were killed 72 hours after induction of SAH, at the time of maximal vasospasm. The efficacy of ibuprofen in preventing vasospasm was assessed by measuring lumen patency of the rabbit's BAs. The intracranial controlled release of ibuprofen resulted in a significant inhibition of vasospasm when treatment was initiated at 30 minutes (patency 92.3 +/- 5.1% compared with 52.1 +/- 5.1% in animals given empty EVAc; p < 0.001) and 6 hours (patency 69.5 +/- 3.5% compared with 47.2 +/- 1.5% in animals given empty EVAc; p < 0.03) after blood deposition compared with treatment with empty EVAc. No effect was observed when treatment was begun at either 12 or 24 hours. CONCLUSIONS: Local intracranial delivery of ibuprofen accomplished using controlled-release polymers prevents vasospasm in the rabbit BA model of vasospasm when administered within 6 hours after blood exposure.

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Enantiospecific determination of ibuprofen in rat plasma using chiral fluorescence derivatization reagent, (-)-2-[4-(1-aminoethyl)phenyl]-6- methoxybenzoxazole.

Kondo J, Suzuki N, Naganuma H, Imaoka T, Kawasaki T, Nakanishi A, Kawahara Y.

Product Development Laboratories, Sankyo Co. Ltd., Tokyo, Japan.

A highly sensitive and reversed-phase high-performance liquid chromatographic method for the determination of the enantiomeric composition of ibuprofen in rat plasma is described. The method is based on the resolution of the diastereomeric amides formed on reaction of the ibuprofen enantiomers with (-)-2-[4-(1-aminoethyl)phenyl]-6-methoxybenzoxazole ((-)-APMB) in the presence of 2,2'-dipyridyl disulphide (DPDS) and triphenylphosphine (TPP) in dichloromethane. The reaction mixture was allowed to stand at room temperature for 5 min, and the reaction was completed by evaporation with a stream of nitrogen at 40 degrees C. The minimum quantifiable concentrations were 0.2 microgram/mL and 0.4 microgram/mL for S-ibuprofen and R-ibuprofen, respectively, in a 10 microL injection volume. The method was applied to the determination of enantiomeric ibuprofen in plasma after oral administration to rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7812120&dopt=Abstract ibuprofen Motrin