Molecular characteristics of the inhibition of human neutrophil elastase by nonsteroidal antiinflammatory drugs
Kooil KangSung Jun BaeWoo Mi KimDae-Heui LeeUnsuck ChoMyung Huck LeeMu-Sang LeeSang-il NamKlaus E. KuettnerDavid E. Schwartz
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Abstract:
Nonsteroidal antiinflammatory drugs(NSAIDs) are known as clinically effective agents for treatment of inflammatory diseases. Inhibition of cyclooxygenase has been thought to be a major facet of the pharmacological mechanism of NSAIDs. However, it is difficult to ascribe the antiinflammatory effects of NSAIDs solely to the inhibition of prostaglandin synthesis. Human neutrophil elastase (HNElastase; HNE, EC 3.4.21.37) has been known as a causative factor in inflammatory diseases. To investigate the specific relationship between HNElastase inhibition and specificity of molecular structure of several NSAIDs, HNElastase was purified by Ultrogel AcA54 gel filtration, CM-Sephadex ion exchange, and HPLC (with TSK 250 column) chromatography. HNElastase was inhibited by aspirin and salicylate in a competitive manner and by naproxen, ketoprofen, phenylbutazone, and oxyphenbutazone in a partial competative manner, but not by ibuprofen and tolmetin. HNElastase-phenylbutazone-complex showed strong Raman shifts at 200, 440, 1124, 1194, 1384, 1506, and 1768 cm(-1). The Raman bands 1194, 1384, and 1768 cm(-1) may represent evidences of the conformational change at -N=N-Φ radical, pyrazol ring, and -C=O radical of the elastase-drug complex, respectively. Phenylbutazone might be bound to HNElastase by ionic and hydrophobic interaction, and masked the active site. Inhibition of HNElastase could be another mechanism of action of NSAIDs besides cyclooxygenase inhibition in the treatment of inflammatory diseases. Different inhibition characteristics of HNE-lastase by NSAIDs such as aspirin, phenylbutazone-like drugs and ineffective drugs could be important points for drawing the criteria for appropriate drugs in clinical application.Keywords:
Flurbiprofen
Ketoprofen
Oxyphenbutazone
Ibuprofen
Anti-inflammatory
Sulindac
Mechanism of Action
Acetaminophen
The possibility that the major non-steroidal anti-inflammatory drugs may inhibit the complement system and thus ameliorate the acute pathological changes induced by immune complexes was investigated. Treatment of fresh human serum with indomethacin (IDM), sulindac (Su), phenylbutazone (Ph) and oxyphenbutazone (OPh) inhibited both the classical and alternative complement (C) pathway activities in a dose-dependent fashion with a 50% inhibition dose of 4.65, 1.0, 1.65 and 1.3 mg/ml respectively. Aspirin, on the other hand, had a comparatively weak anti-complementary activity. Su, Ph and OPh were shown to form complexes with C5, thereby inhibiting the interaction between C3b and C5 and the cleavage of the latter into phlogistic fragments.
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The plasma half-life of phenylbutazone in horses was not increased after pretreatment with chloramphenicol or quinidine, but was increased after oxyphenbutazone. This increased plasma half-life after oxyphenbutazone is consistent with observations in other species and suggests that oxyphenbutazone inhibits the metabolism of phenylbutazone in horses. Lack of inhibition of phenylbutazone metabolism in the horse by chloramphenicol and quinidine is inconsistent with results obtained in other species.
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Abstract Fourth derivative-difference (ΔD4.) spectrophoto metry is presented for the simultaneous assay of phenylbutazone and oxyphenbutazone as metabolites of bumadizone either in laboratory made mixtures or in human plasma. Phenylbutazone and oxyphenbutazone are determined through the measurement of ΔD4 signals at 293 and 282 nm, respectively. The linear relationship of these values versus concentration of both compoundsin the range 1–5 μg/ml for phenylbutazone and 3–8 μg/ml for oxyphenbutazone permits their determination with high accuracy and good reproducibility. The relative standard deviation is less than 1.35% The proposed method could be used for monitoring bumadizone metabolites. Key Words: Phenylbutazoneoxyphenbutazonebumadizonederivative spectrophotometry
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In the literature there is only one report of a fixed drug eruption due to oxyphenbutazone. We are reporting a patient whose fixed drug eruption was caused by oxyphenbutazone and who showed cross-sensitivity to phenylbutazone. There was no history of phenylbutazone having been administered to this patient earlier than the challenging test dose.
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In healthy subjects plasma concentrations of 2-benzenesulfonylamino-4-(beta-methoxy-ethoxy)pyrimidine (glymidine) are considerably elevated during ingestion of 600 mg oxyphenbutazone additionally to 500 mg glymidine per day. In contrast phenylbutazone has only a slight and not significant effect on the glymidine plasma concentrations. In vitro equilibrium dialysis experiments show a decrease of serum protein binding of glymidine after the addition of phenylbutazone and oxyphenbutazone. The increase of the glymidine plasma concentrations together with the decrease of serum protein binding is predestined to lead to an increased pharmacodynamic effect of the drug.
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