دورية أكاديمية
Limitation of the in vitro whole blood assay for predicting the COX selectivity of NSAIDs in clinical use
| العنوان: | Limitation of the in vitro whole blood assay for predicting the COX selectivity of NSAIDs in clinical use |
|---|---|
| المؤلفون: | Blain, Hubert, Boileau, Christelle, Lapicque, Françoise, Nédélec, Emmanuelle, Loeuille, Damien, Guillaume, Cécile, Gaucher, Alain, Jeandel, Claude, Netter, Patrick, Jouzeau, Jean-Yves |
| المساهمون: | Département de médecine interne et de gériatrie, Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Centre National de la Recherche Scientifique (CNRS), Centre Lillois d’Études et de Recherches Sociologiques et Économiques - UMR 8019 (CLERSÉ), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Physiopathologie, Pharmacologie et Ingénierie articulaires (PPIA), Université Henri Poincaré - Nancy 1 (UHP)-Centre National de la Recherche Scientifique (CNRS) |
| المصدر: | ISSN: 0306-5251. |
| بيانات النشر: | HAL CCSD Wiley |
| سنة النشر: | 2002 |
| المجموعة: | LillOA (HAL Lille Open Archive, Université de Lille) |
| مصطلحات موضوعية: | Adult, Blood Platelets, Chromatography, High Pressure Liquid, Cross-Over Studies, Cyclooxygenase 1, Cyclooxygenase 2, Diclofenac, Humans, Isoenzymes, Monocytes, Prostaglandin-Endoperoxide Synthases, Stereoisomerism, Thiazines, Thiazoles, Anti-Inflammatory Agents, Non-Steroidal, Ibuprofen, Male, Membrane Proteins, MESH: Adult, MESH: Anti-Inflammatory Agents, MESH: Blood Platelets, MESH: Chromatography, MESH: Cross-Over Studies, MESH: Cyclooxygenase 1, MESH: Cyclooxygenase 2, MESH: Diclofenac, MESH: Humans, MESH: Ibuprofen |
| الوصف: | International audience ; AIMS: To assess if the inhibitory potency of nonsteroidal anti-inflammatory drugs (NSAIDs) on cyclooxygenase (COX) isoenzymes, when given therapeutically in humans, can be predicted from their in vitro concentration-response curves using the whole blood assay. METHODS: Twenty-four healthy male volunteers aged 20--27 years were recruited. Inhibition of blood COX isoenzymes was determined in vitro before any drug intake and ex vivo after single and repeated intake of either 7.5 mg meloxicam once, 400 mg ibuprofen three times daily or 75 mg diclofenac SR once, taken in a randomized cross-over design. Production of thromboxane B2 (TXB2) during clotting and of prostaglandin E2 (PGE2) during endotoxin exposure served as indicators of platelet COX-1 and monocyte COX-2 activity, respectively. Drugs were determined in plasma by h.p.l.c., with a chiral separation of ibuprofen and free fractions after equilibrium dialysis. RESULTS: Intra-subject variation for COX-1 and COX-2 at baseline was at 26 +/- 18% and 18 +/- 13% respectively, and intersubject variation at 39% and 36%, respectively. The ratios of IC50s and, at best, of IC80s revealed diclofenac and meloxicam as selective COX-2 inhibitors and ibuprofen as a preferential COX-1 inhibitor in vitro. However, after oral intake, ibuprofen inhibited ex vivo COX-2 by 80% whereas diclofenac inhibited COX-1 by 70%. Meloxicam inhibited COX-1 from 30 to 55% depending on the repetition of the dose and increase in plasma concentrations. Using in vitro dose--response curves, the in vivo inhibitory potency of diclofenac was estimated adequately from its circulating concentration ([-0.18, 0.21] for COX-1 and [-0.13, -0.03] for COX-2) but this was not the case for ibuprofen on COX-2 ([-0.14, 0.27]) and meloxicam on COX-1 ([0.31, 1.05]). The limited predictability of the system was not improved through considering the unbound fraction of the drugs or the variable chiral inversion of ibuprofen. CONCLUSIONS: Assessment of COX-2 selectivity based on in vitro ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/11874389; hal-00466565; https://hal.science/hal-00466565Test; PRODINRA: 248283; PUBMED: 11874389 |
| الإتاحة: | https://hal.science/hal-00466565Test |
| رقم الانضمام: | edsbas.A5BD2922 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |