Absorption and distribution of etoricoxib in plasma, CSF, and wound tissue in patients following hip surgery—a pilot study

The perioperative administration of selective cyclooxygenase-2 (COX-2)-inhibitors to avoid postoperative pain is an attractive option: they show favorable gastro-intestinal tolerability, lack inhibition of blood coagulation, and carry a low risk of asthmatic attacks. The purpose of this study was to determine the cerebrospinal fluid (CSF), plasma, and tissue pharmacokinetics of orally administered etoricoxib and to compare it with effect data, i.e., COX-2-inhibition in patients after hip surgery. The study was performed in a blinded, randomized, parallel group design. A total of 12 adult patients were included who received 120 mg etoricoxib (n = 8) or placebo (n = 4) on day 1 post-surgery. Samples from plasma, CSF, and tissue exudates were collected over a period of 24 h post-dosing and analyzed for etoricoxib and prostaglandin E2 (PGE2) using liquid chromatography-tandem mass spectrometry and immuno-assay techniques. CSF area under the curve (AUC) [AUCs(O–24h)] for etoricoxib amounted to about 5% of the total AUC in plasma (range: 2–7%). Individual CSF lag times with respect to (50%) peak plasma concentration were ≤2 h in all but one case (median: 1 h). PGE2 production in tissue was significantly blocked by the COX-2 inhibitor starting with the appearance of etoricoxib in tissue and lasting for the whole observation period of 24 h (P < 0.01). In conclusion, etoricoxib reaches the CSF and site of surgery at effective concentrations and reduces PGE2 production at the presumed site of action

Prostanoid receptor EP1 and Cox-2 in injured human nerves and a rat model of nerve injury: a time-course study

BACKGROUND: Recent studies show that inflammatory processes may contribute to neuropathic pain. Cyclooxygenase-2 (Cox-2) is an inducible enzyme responsible for production of prostanoids, which may sensitise sensory neurones via the EP1 receptor. We have recently reported that while macrophages infiltrate injured nerves within days of injury, they express increased Cox-2-immunoreactivity (Cox-2-IR) from 2 to 3 weeks after injury. We have now investigated the time course of EP1 and Cox-2 changes in injured human nerves and dorsal root ganglia (DRG), and the chronic constriction nerve injury (CCI) model in the rat. METHODS: Tissue sections were immunostained with specific antibodies to EP1, Cox-2, CD68 (human macrophage marker) or OX42 (rat microglial marker), and neurofilaments (NF), prior to image analysis, from the following: human brachial plexus nerves (21 to 196 days post-injury), painful neuromas (9 days to 12 years post-injury), avulsion injured DRG, control nerves and DRG, and rat CCI model tissues. EP1 and NF-immunoreactive nerve fibres were quantified by image analysis. RESULTS: EP1:NF ratio was significantly increased in human brachial plexus nerve fibres, both proximal and distal to injury, in comparison with uninjured nerves. Sensory neurones in injured human DRG showed a significant acute increase of EP1-IR intensity. While there was a rapid increase in EP1-fibres and CD-68 positive macrophages, Cox-2 increase was apparent later, but was persistent in human painful neuromas for years. A similar time-course of changes was found in the rat CCI model with the above markers, both in the injured nerves and ipsilateral dorsal spinal cord. CONCLUSION: Different stages of infiltration and activation of macrophages may be observed in the peripheral and central nervous system following peripheral nerve injury. EP1 receptor level increase in sensory neurones, and macrophage infiltration, appears to precede increased Cox-2 expression by macrophages. However, other methods for detecting Cox-2 levels and activity are required. EP1 antagonists may show therapeutic effects in acute and chronic neuropathic pain, in addition to inflammatory pain

Obituary. Laurence Remington Rupert (1902-1978)

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Increased susceptibility of annexin-A1 null mice to nociceptive pain is indicative of a spinal antinociceptive action of annexin-A1

Background and purpose: Annexin-A1 (ANXA1), a glucocorticoid-regulated protein, mediates several of the anti-inflammatory actions of the glucocorticoids. Previous studies demonstrated that ANXA1 is involved in pain modulation. The current study, using ANXA1 knockout mice (ANXA1(-/-)), is aimed at addressing the site and mechanism of the modulatory action of ANXA1 as well as possible involvement of ANXA1 in mediating the analgesic action of glucocorticoids.Experimental approach: The acetic acid-induced writhing response was performed in ANXA1(-/-) and wild-type (ANXA1(+/+)) mice with spinal and brain levels of prostaglandin E-2 (PGE(2)) examined in both genotypes. The effect of the ANXA1 peptomimetic Ac2-26 as well as methylprednisolone on the writhing response and on spinal cord PGE(2) of ANXA1(+/+) and ANXA1(-/-) was compared. The expression of proteins involved in PGE(2) synthesis, cytosolic phospholipase A(2) (cPLA(2)) and cyclooxygenases (COXs), in the spinal cord of ANXA1(+/+) and ANXA1(-/-) was also compared.Key results: ANXA1(-/-) mice exhibited a significantly greater writhing response and increased spinal cord levels of PGE(2) compared with ANXA1(+/+) mice. Ac2-26 produced analgesia and reduced spinal PGE(2) levels in ANXA1(+/+) and ANXA1(-/-) mice, whereas methylprednisolone reduced the writhing response and spinal PGE(2) levels in ANXA1(+/+), but not in ANXA1(-/-) mice. The expression of cPLA(2), COX-1, COX-2 and COX-3 in spinal cord tissues was upregulated in ANXA1(-/-) compared with ANXA1(+/+).Conclusions and implications: We conclude that ANXA1 protein modulates nociceptive processing at the spinal level, by reducing synthesis of PGE(2) by modulating cPLA(2) and/or COX activity. The analgesic activity of methylprednisolone is mediated by spinal ANXA1