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  • 1
    Electronic Resource
    Electronic Resource
    Increased CNS uptake and enhanced antinociception of morphine-6-glucuronide in rats after inhibition of P-glycoprotein (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 83 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Morphine-6-glucuronide (M6G) is a substrate of P-glycoprotein (P-gp), which forms an outward transporter at the blood–brain 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.01177.x
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  • 2
    Electronic Resource
    Electronic Resource
    Inhibition of Noxious Stimulus-Induced Spinal Prostaglandin E2 Release by Flurbiprofen Enantiomers (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 74 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E2 release at the site of inflammation and in the spinal cord. The antiinflammatory and antinociceptive effects of cyclooxygenase-inhibiting 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 R-flurbiprofen acts via inhibition of spinal PG release, concentrations of PGE2 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-1, 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 PGE2 dialysate concentrations were 100.6 ± 6.4 pg ml-1 (mean ± SEM). After formalin injection they rose about threefold with a maximum of 299.4 ± 68.4 pg ml-1 at 7.5 min. After ∼ 1 h PGE2 levels returned to baseline. Both flurbiprofen enantiomers completely prevented the formalin-induced increase of spinal PGE2 release and reduced PGE2 concentrations below basal levels. S- and R-flurbiprofen at 9 mg kg-1 produced a minimum of 15.8 ± 5.2 and 27.7 ± 14.9 pg ml-1, respectively, and 27 mg kg-1S- and R-flurbiprofen resulted in 11.7 ± 1.7 and 9.3 ± 4.7 pg ml-1, respectively. PGE2 levels remained at the minimum up to the end of the observation period at 5 h. When 27 mg kg-1R-flurbiprofen was injected intravenously without subsequent formalin challenge, baseline immunoreactive PGE2 concentrations were not affected. S-Flurbiprofen (27 mg kg-1), however, led to a moderate reduction (∼40%). The data suggest that antinociception produced by R-flurbiprofen is mediated at least in part by inhibition of stimulated spinal PGE2 release and support the current view that increased spinal PGE2 release significantly contributes to nociceptive processing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0742094.x
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  • 3
    Electronic Resource
    Electronic Resource
    Effects of selective COX-1 and -2 inhibition on formalin-evoked nociceptive behaviour and prostaglandin E2 release in the spinal cord (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 79 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 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 formalin-evoked nociceptive behaviour and spinal PGE2 release. SC560 (10 and 20 mg/kg) significantly reduced the nociceptive response and completely abolished the formalin-evoked PGE2 raise. In contrast, celecoxib (10 and 20 mg/kg) was ineffective in both regards, i.e. the flinching behaviour was largely unaltered and the formalin-induced PGE2 raise as assessed using microdialysis was only slightly, not significantly 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 efficacy 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 efficacy of celecoxib in early injury evoked pain may be less than that of unselective NSAIDs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00613.x
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  • 4
    Electronic Resource
    Electronic Resource
    Relevance of neoadjuvant and adjuvant treatment for patients with resectable liver metastases of colorectal carcinoma (1999)
    Springer
    Langenbeck's archives of surgery 384 (1999), S. 328-338 
    Details
    ISSN: 1435-2451
    Keywords: Key words Adjuvant chemotherapy ; Colorectal cancer ; Liver metastases ; Neoadjuvant chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Background: Excellent results after resection of colorectal liver metastases are associated with a high rate of recurrence. Influenced by positive results of palliative and adjuvant treatment in advanced cancer, various chemotherapy regimens were evaluated to improve long-term results. Methods: The databases Medline and Cancerlit (1982–1998) gave information about 675 patients who were treated either by means of systemic, intra-arterial, intraportal or intraperitoneal administration before or after liver resection. Results: In general, the feasibility of an adjuvant treatment was tested. Proof has been furnished for the practicability of systemic and arterial therapy and for immunotherapy after liver resection whereas, for peritoneal and portal treatment, further studies are necessary. In a few non-randomised trials, it has been possible to discern a trend towards an improvement due to adjuvant postoperative therapy using historical or matched-pair control groups. Until now, only one of five randomised studies has been published. Six months of postoperative adjuvant intra-arterial treatment using 5-fluorouracil (1000 mg/m2 for 5 days every 28 days) and folinic acid (200 mg/m2 for 5 days every 28 days) was compared with observation only. Neither in the intention-to-treat nor in the as-treated analysis was median survival time (34.5 months versus 40.8 months and 39.7 months versus 44.8 months, respectively) significantly increased. As neoadjuvant treatment was successful in primary non-resectable patients, this approach is now being tested in resectable patients. Conclusion: Despite several theoretical reasons for post- or preoperative treatment in resectable patients, every approach should be tested using of controlled studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004230050210
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