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.

In extubated patients, continuous assessment of respiration rate with an acoustic monitor correlated well with capnometry.