Diclofenac readily penetrates the cerebrospinal fluid in children.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Diclofenac, a nonselective nonsteroidal anti-inflammatory drug,, exerts analgesic action both in the peripheral tissues and in the central nervous system by inhibiting cyclooxygenase enzymes COX-1/2, but central nervous system penetration of diclofenac has not been evaluated in humans. WHAT THIS STUDY ADDS: Diclofenac penetrates the cerebrospinal fluid rapidly, and after a single intravenous dose of 1 mg kg(-1), sufficient concentrations to inhibit COX-1/2 are sustained for up to 4 h. AIMS: The primary aim was to study the cerebrospinal fluid (CSF) penetration of intravenous diclofenac in children. The secondary aim was to evaluate the plasma diclofenac concentration at the onset of wound pain after inguinal surgery in children. METHODS: A total of 31 children (24 boys) aged 3 months to 12 years received a single intravenous injection of diclofenac 1 mg kg(-1). Paired CSF and blood samples were obtained 5 min to 22 h (median 69 min) later. In children having inguinal surgery a second blood sample was obtained at the time that the children felt wound pain for the first time after surgery. Diclofenac concentrations in CSF, plasma and protein free plasma were measured by gas chromatography with mass spectrometric detection. RESULTS: In the 28 CSF samples obtained at 5 min to 3 h 43 min after injection, diclofenac concentrations ranged between 0.5 and 4.7 microg l(-1). At 5.5 h the CSF concentration was 0.1 microg l(-1), and no diclofenac was detected in the two CSF samples obtained at 22 h. The median of plasma diclofenac concentration at the time when pain returned after inguinal surgery was 104 microg l(-1) (range 70-272 microg l(-1)). No serious or unexpected adverse effects were reported. CONCLUSIONS: Diclofenac penetrates the CSF rapidly, and a sufficient concentration to inhibit cyclooxygenase enzymes is sustained for up to 4 h.

Influence of plasma protein on the potencies of inhibitors of cyclooxygenase-1 and -2.

It is widely believed that the potencies of nonsteroid anti-inflammatory drugs (NSAIDs) as inhibitors of cyclooxygenase (COX) are influenced by protein binding in the extracellular fluid, since NSAIDs are bound to circulating albumin by well over 95%. This is an important point because the protein concentrations in synovial fluid and the central nervous system, which are sites of NSAID action, are markedly different from those in plasma. Here we have used a modified whole-blood assay to compare the potencies of aspirin, celecoxib, diclofenac, indomethacin, lumiracoxib, meloxicam, naproxen, rofecoxib, sodium salicylate, and SC560 as inhibitors of COX-1 and COX-2 in the presence of differing concentrations of protein. The potencies of diclofenac, naproxen, rofecoxib, and salicylate, but not aspirin, celecoxib, indomethacin, lumiracoxib, meloxicam, or SC560, against COX-1 (human platelets) increased as protein concentrations were reduced. Varying protein concentrations did not affect the potencies of any of the drugs against COX-2, with the exception of sodium salicylate (A549 cells). Clearly, our findings show that the selectivity of inhibitors for COX-1 and COX-2, which are taken to be linked to their efficacy and side effects, may change in different extracellular fluid conditions. In particular, selectivity in one body compartment does not demonstrate selectivity in another. Thus, whole-body safety or toxicity cannot be linked to one definitive measure of COX selectivity.

Avoiding glucocorticoid administration in a neurooncological case.

Restricting glucocorticoid (GC) use in the treatment of patients with a solid tumor may help improving outcome. Here, we report administration of celecoxib rather than dexamethasone to prevent brain edema in a patient with a cerebellar glioblastoma multiforme WHO grade IV (GBM) upon the patient's request, as well as determining cerebrospinal fluid (CSF) and serum concentrations. CSF concentration (0.04 microM) was 54 times below serum concentration (2.18 microM), or 2500 times below levels inhibiting GBM cells in vitro (100 microM), revealing a blood CSF barrier for celecoxib. The patient did not require dexamethasone for the entire treatment. GC administration hence was avoided successfully in this case. The role of COX-2 inhibitors in treatment of GBM is detailed, leading to the conclusion of a pressing need for a clinical evaluation of non-steroidal COX-2 inhibitors with the ability to penetrate into brain tumors.

Central nervous system concentrations of cyclooxygenase-2 inhibitors in humans.

BACKGROUND: Cyclooxygenase-2 (COX-2)-selective inhibitors (coxibs) are under investigation for the potential therapy, attenuation, or prevention of neuroinflammatory and neurodegenerative disorders. Coxibs are also a significant advance in pain therapy and are traditionally considered to achieve analgesia via peripheral effects. However, in animals, central nervous system (CNS) COX-2 activity and prostanoid concentrations are increased by peripheral inflammation, central sensitization has been proposed to account for long-term pain-related phenomena, and coxibs achieve significant cerebrospinal fluid (CSF) concentrations and may cause analgesia via CNS action. Nevertheless, it remains unknown whether or which coxibs reach the CNS in humans. This investigation determined whether coxibs can reach the CNS in humans, based on CSF concentrations. METHODS: Ten healthy human volunteers simultaneously received a single oral dose of celecoxib (200 mg), rofecoxib (50 mg), and valdecoxib (40 mg). Blood and CSF were serially sampled for 10 h, and plasma total and unbound and CSF coxib concentrations were quantified by mass spectrometry. RESULTS: Total plasma concentrations and time to maximum plasma concentration were similar among the three coxibs. In contrast, unbound (free) plasma concentrations differed significantly. Maximum unbound plasma concentrations were 1.4 +/- 0.5, 42 +/- 17, and 6.0 +/- 2.9 ng/ml, respectively, for celecoxib, rofecoxib, and valdecoxib. COX-2 inhibitors rapidly penetrated the CNS. Maximum CSF concentrations were 2 +/- 2, 57 +/- 25, and 10 +/- 4 ng/ml, respectively, for celecoxib, rofecoxib, and valdecoxib. CSF concentrations exceeding the median inhibitory concentration for COX-2 were achieved by rofecoxib and valdecoxib but not celecoxib. CONCLUSIONS: These results show that coxibs do reach the CNS in humans, with rapid penetration, and in concentrations apparently sufficient to inhibit COX-2 activity. There were significant differences among coxibs in CSF penetration. Unbound (free) plasma coxib concentration was the major determinant of CSF concentration. This supports the hypothesis that coxibs may act, in part, in the human CNS, provide important new information on the mechanism and treatment of pain and may guide coxib selection for therapeutic trials when CNS penetration is desirable.