These data demonstrated that adipokines serum levels are not predictive values for SF determination. The joint cavity is a special space where each adipokine undergoes specific regulatory pathways, strengthening the hypothesis that adipokines may have local effects in the joint and may account for the high prevalence of OA in women.

Since the antipyretic and probably the analgesic effects of paracetamol are, at least in part, centrally mediated, its plasma and cerebrospinal fluid (CSF) concentrations were measured in 43 patients with nerve-root compression pain. Each subject was given a short i.v. infusion of 2 g propacetamol, a prodrug which is hydrolysed to paracetamol within 7 min. Single blood and CSF samples were drawn concomitantly in each patient at intervals between 20 min and 12 h. Maximum CSF drug concentrations were observed at the 4th hour, subsequent concentrations exceeding those in plasma. The elimination half-life of paracetamol calculated from pooled data was shorter in plasma (2.4 h) than in CSF (3.2 h). The time-course of paracetamol in CSF may parallel that of analgesic effect.

Aims To assess if the inhibitory potency of nonsteroidal anti-in¯ammatory 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 B 2 (TXB 2 ) during clotting and of prostaglandin E 2 (PGE 2 ) 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 26t18% and 18t13% respectively, and intersubject variation at 39% and 36%, respectively. The ratios of IC 50 s and, at best, of IC 80 s 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 ([x0.18, 0.21] for x0.03] for COX-2) but this was not the case for ibuprofen on COX-2 ([x0.14, 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 studies and pharmacological modelling has a limited clinical relevance. There is a need to investigate COX selectivity at therapeutic plasma concentrations of NSAIDs using the ex vivo whole blood assay.

Human serum albumin is known to have two major and selective drug binding sites, termed sites I and II. The fluorescent probes, dansylamide and dansylsarcosine selectively interact with sites I and II, respectively. However, the binding site of the fluorescent probe dansylglycine on human serum albumin is not clear from the literature. This study investigated whether dansylglycine interacts tightly with site I or II. Spectrofluorimetric titrations (quenching and complex) and circular dichroism measurements were performed to determine the binding characteristics of dansylglycine to human serum albumin. Modification in probe fluorescence was described by fluorescence titrations to be a result of competitive displacement by ligands. The pattern of displacement of this probe by several ligands whose primary binding sites are exactly known, enabled the identification of its specific binding site. The fluorescence of dansylglycine is only extensively changed when ligands of site II are added, suggesting that it strongly interacts with the benzodiazepine/indole binding site on human serum albumin.

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Since both (R)‐ and (S)‐enantiomers of ibuprofen may act on the central nervous system, we investigated their plasma and cerebrospinal fluid (CSF) concentrations in 46 patients with nerve‐root compression pain requiring a lumbar puncture. Each patient received an oral dose of 800 mg rac‐ibuprofen. A single blood and CSF sample was drawn concomitantly from each patient at intervals between 30 min and 8 h after dosing. Both isomers peaked later in the CSF (3 h) than in the plasma (1.5 h). Their CSF concentrations became higher than their concurrent free plasma concentrations after 90 min. The estimated elimination half‐ lives of (R)‐ and (S)‐ibuprofen were 1.7 h and 2.5 h in plasma and 3.9 h and 7.9 h in CSF, respectively. The AUCCSF/AUCplasma ratios (0, 8 h) were 0.009 and 0.015 for the (R)‐ and (S)‐forms, respectively.

Stereoselective binding of nonsteroidal anti-inflammatory drugs (NSAIDs) can be studied using various techniques. Thus the results obtained by different investigators may be poorly consistent and even contradictory. NSAIDs are bound stereoselectively to serum albumin to different degrees depending on the drug investigated (ibuprofen, indoprofen, carprofen, etodolac, ketoprofen and flurbiprofen). For other drugs, both enantiomers are bound to a similar extent (pirprofen, fenoprofen). This stereoselectivity could vary with experimental conditions, in particular with protein concentration (ketoprofen, etodolac), leading to individual differences. Finally, the stereoselectivity of protein binding and of pharmacokinetics can be compared: differences in binding between enantiomers can explain their differences in pharmacokinetics, once metabolic properties such as inversion have been taken into account.

Plasma and cerebrospinal fluid (CSF) concentrations of indomethacin have been determined in 52 patients hospitalized for nerve-root compression pain. Samples of blood and CSF were collected at the same time in each subject, 0.5 to 12 h after a single intramuscular injection of 50 mg indomethacin. Analgesic effect was assessed by the absolute and percentage variation in Huskisson's visual analogue scale between dosing and sampling. According to its high lipid solubility, indomethacin rapidly crossed the blood-brain barrier, being detected in CSF 0.5 h after administration. After attainment of equilibrium within 2 h, the CSF level exceeded the free plasma level. Since the drug was extensively bound to serum albumin (99.7 +/- 0.1%), this phenomenon may represent a slight degree of binding of indomethacin in CSF. The analgesic activity was not related to either the plasma or CSF concentration of indomethacin.