Celecoxib, a selective cyclooxygenase‐2 (COX‐2) inhibitor, has recently been approved for the symptomatic treatment of arthritis. In some clinical studies, doses of 400 and 800 mg/day provided somewhat less efficacy compared with 200 mg/day, which suggests an early ceiling effect. Using the zymosan‐induced inflammation model in rats, we show that celecoxib significantly reduces paw swelling at 50 mg/kg but completely loses its anti‐inflammatory efficacy at doses ≥100 mg/kg. To evaluate the underlying mechanisms, we used rat renal mesangial cells as a cell culture model. In these cells, celecoxib (50 μM) increased the interleukin Iβ stimulated nuclear translocation and DNA binding of NF‐κB and facilitated the degradation of I‐κB. Consequently, COX‐2 and tumor necrosis factor α (TNF‐α) expression were increased. The up‐regulation of COX‐2 and TNF‐α also occurred in the spinal cord of rats treated with celecoxib (≥100 mg/kg), indicating that in vitro mechanisms were relevant in vivo. Clinically, the overexpression of COX‐2 might be less important because celecoxib inhibits COX‐2 enzymatically. However, the up‐regulation of TNF‐α and possibly other NF‐κB regulated proinflammatory genes might worsen the pathophysiological processes underlying chronic arthritis.

Nociception evoked prostaglandin (PG) release in the spinal cord considerably contributes to the induction of hyperalgesia and allodynia. To evaluate the relative contribution of cyclooxygenase-1 (COX-1) and COX-2 in this process we assessed the effects of the selective COX-1 inhibitor SC560 and the selective COX-2 inhibitor celecoxib on formalinevoked nociceptive behaviour and spinal PGE 2 release. SC560 (10 and 20 mg/kg) signi®cantly reduced the nociceptive response and completely abolished the formalin-evoked PGE 2 raise. In contrast, celecoxib (10 and 20 mg/kg) was ineffective in both regards, i.e. the¯inching behaviour was largely unaltered and the formalin-induced PGE 2 raise as assessed using microdialysis was only slightly, not signi®-cantly reduced. This suggests that the formalin-evoked rapid PG release was primarily caused by COX-1 and was independent of COX-2. Mean free spinal cord concentrations of celecoxib during the formalin assay were 32.0^4.5 nM, thus considerably higher than the reported IC50 for COX-2 (3±7 nM). Therefore, the lack of ef®cacy of celecoxib is most likely not to be a result of poor tissue distribution. COX-2 mRNA and protein expression in the spinal cord were not affected by microdialysis alone but the mRNA rapidly increased following formalin injection and reached a maximum at 2 h. COX-2 protein was unaltered up to 4 h after formalin injection. The time course of COX-2 up-regulation suggests that the formalin-induced nociceptive response precedes COX-2 protein de novo synthesis and may therefore be unresponsive to COX-2 inhibition. Considering the results obtained with the formalin model it may be hypothesized that the ef®cacy of celecoxib in early injury evoked pain may be less than that of unselective NSAIDs.

Peripheral tissue injury and inflammation may result in a facilitated spinal nociceptive transmission and central sensitization. Particularly, nitric oxide (NO) and prostaglandins (PGs) have been shown to be key mediators involved in the induction and maintenance of this state. By means of spinal cord microdialysis we have determined interstitial glutamate, NO (NO2-/NO3-), PGE2, glycerol, glucose and lactate concentrations in the dorsal horns of the spinal cord following peripheral nociceptive stimulation to gain further insight into the link between excitatory neurotransmitters and metabolic functions in the spinal cord during nociception. Formalin and zymosan injection into one hind paw evoked a biphasic release of glutamate and NO with the glutamate peaks preceding those of NO. Moreover, zymosan induced a biphasic increase of interstitial glycerol concentrations accompanied by an increase of interstitial lactate indicating metabolic disturbances. In contrast, formalin injection led to an elevation of dialysate glucose concentrations which may be interpreted as an indication of enhanced metabolic activity. The sequential release of glutamate and NO in the dorsal horns of the spinal cord in response to peripheral nociceptive stimulation supports the theory that NO may act as a retrograde transmitter. The metabolic changes observed after formalin and zymosan injection suggest that an intense peripheral nociceptive stimulation may not only activate but also disturb metabolic activity and possibly membrane integrity in the spinal cord.

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Morphine-6-glucuronide (M6G) is a substrate of P-glycoprotein (P-gp), which forms an outward transporter at the bloodbrain barrier. Inhibition of P-gp may therefore be expected to cause increased CNS uptake of M6G. We directly assessed the spinal concentrations of M6G and its antinociceptive effects in rats following pharmacological inhibition of P-gp. Spinal cord tissue concentrations of M6G were assessed by microdialysis with probes transversally implanted through the dorsal horns of the spinal cord at level L4. Ten rats received M6G intravenously (0.018 mg/kg loading dose plus 0.00115 mg/kg/min for an 8-h infusion), five of them together with PSC833 to inhibit P-gp (32-h infusion, starting 24 h before the addition of M6G). Antinociceptive effects were explored by means of formalin tests. After having obtained evidence for enhanced CNS uptake and antinociception of M6G in the presence of PSC833, additional behavioural experiments were performed in another 32 rats to assess the dose dependency of the antinociceptive effects of M6G either with or without PSC833 in comparison with both PSC833 alone and placebo. Inhibition of P-gp increased the M6G concentrations in the spinal cord approximately three-fold whereas the plasma concentrations were increased only by a factor of 1.4, which resulted in a more than doubled spinal cord/plasma concentration ratio (from 0.08 ± 0.03 for M6G alone to 0.17 ± 0.08 for M6G plus PSC833). Antinociceptive effects of M6G were significantly enhanced by inhibition of P-gp. Inhibition of P-gp alters the transport of M6G across the blood-brain barrier, resulting in enhanced spinal cord uptake and enhanced antinociception.

In women with threatened preterm birth, quantitative fibronectin testing alone performs equal to the combination of cervical length and qualitative fibronectin. Possibly, the combination of quantitative fibronectin testing and cervical length increases this predictive capacity. Cost-effectiveness analysis and the availability of these tests in a local setting should determine the final choice.

Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E 2 release at the site of inflammation and in the spinal cord. The antiinflammatory and antinociceptive effects of cyclooxygenaseinhibiting drugs are thought to depend on the inhibition of PG synthesis. R-Flurbiprofen, however, does not inhibit cyclooxygenase activity in vitro but still produces antinociceptive effects. To find out whether Rflurbiprofen acts via inhibition of spinal PG release, concentrations of PGE 2 and flurbiprofen in spinal cord tissue were assessed by microdialysis. The catheter was transversally implanted through the dorsal horns of the spinal cord at level L4. R-and S-flurbiprofen (9 and 27 mg kg Ϫ1 , respectively) were administered intravenously 10 -15 min before subcutaneous injection of formalin into the dorsal surface of one hindpaw. Flurbiprofen was rapidly distributed into the spinal cord with maximal concentrations after 30 -45 min. Baseline PGE 2 dialysate concentrations were 100.6 Ϯ 6.4 pg ml Ϫ1 (mean Ϯ SEM). After formalin injection they rose about threefold with a maximum of 299.4 Ϯ 68.4 pg ml Ϫ1 at 7.5 min. After ϳ1 h PGE 2 levels returned to baseline. Both flurbiprofen enantiomers completely prevented the formalin-induced increase of spinal PGE 2 release and reduced PGE 2 concentrations below basal levels. S-and R-flurbiprofen at 9 mg kg Ϫ1 produced a minimum of 15.8 Ϯ 5.2 and 27.7 Ϯ 14.9 pg ml Ϫ1 , respectively, and 27 mg kg Ϫ1 S-and R-flurbiprofen resulted in 11.7 Ϯ 1.7 and 9.3 Ϯ 4.7 pg ml Ϫ1 , respectively. PGE 2 levels remained at the minimum up to the end of the observation period at 5 h. When 27 mg kg Ϫ1 R-flurbiprofen was injected intravenously without subsequent formalin challenge, baseline immunoreactive PGE 2 concentrations were not affected. S-Flurbiprofen (27 mg kg Ϫ1 ), however, led to a moderate reduction (ϳ40%). The data suggest that antinociception produced by R-flurbiprofen is mediated at least in part by inhibition of stimulated spinal PGE 2 release and support the current view that increased spinal PGE 2 release significantly contributes to nociceptive processing.

In numerous tumors, metastasis can be limited to the liver. In non-resectable patients, regional treatment modalities, especially arterial cytostatic infusion, are favored in contrast to systemic chemotherapy, whereas intraportal or intraperitoneal application is not successful. Improved results with high response rates have been reported after development of intra-arterial (i.a.) long-term regimens with FUdR in patients with colorectal liver metastases using implantable pumps and ports. However, a survival benefit could only be demonstrated in comparison with a control group only treated symptomatically. Because of several reports on major local toxicity of i.a. FUdR treatment (i.e. chemical hepatitis and biliary sclerosis) several other effective i.a. 5-FU regimens have been developed. A randomized study has demonstrated superiority of i.a. 5-FU versus i.a. FUdR. In comparison with systemic treatment, superiority has only been demonstrated in patients with an intrahepatic tumor burden of < 25%. Publications about regional treatment of patients with breast, gastric cancer or carcinoid liver metastases are rare. Despite the high response rates reported, the benefit of arterial chemotherapy remains questionable. Overall, local long-term chemotherapy cannot be recommended outside of studies as a primary treatment. However, extensive experience and new drugs support the idea of conducting further regional studies.