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  • Rats  (2)
  • Behavior  (1)
  • Fentanyl  (1)
  • Learning  (1)
  • inhibitor  (1)
  • 1
    Electronic Resource
    Electronic Resource
    A phase II study of the 5-lipoxygenase inhibitor, CV6504, in advanced pancreatic cancer: Correlation of clinical data with pharmacokinetic and pharmacodynamic endpoints (2000)
    Springer
    Annals of oncology 11 (2000), S. 1165-1170 
    Details
    ISSN: 1569-8041
    Keywords: inhibitor ; lipoxygenase ; pancreatic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:Primary objective was to determine response rate ofpatients with advanced pancreatic cancer to a novel lipoxygenase andthromboxane A2 synthetase inhibitor (CV6504); secondary objectives includedestimation of pharmacokinetics of CV6504, target-enzyme inhibition, safety andtolerance, quality of life and survival. Patients and methods:Thirty-one patients with advanced pancreaticcancer were planned to receive CV6504, 100 mg TDS, orally for three months,at which point CT scans were performed to assess therapeutic response rates.Steady state concentrations of CV6504 and thromboxane B2 (an indirect measureof thromboxane A2 synthetase (TA2S) inhibition) were made. Of the31 patients entered into the study, 23 were considered fully evaluable forresponse. Results:The drug was well tolerated with few side effects; nopartial or complete responses were seen, but 10 patients had stable diseaseat 3 months; quality of life was maintained during therapy; mean CV6504 steadystate plasma concentrations of 14 ± 6 ng/ml resulting in 75 ±18% inhibition of TA2S were achieved; median-survival timefor all patients considered eligible for assessment of efficacy was 36.6 weeksafter the initial dose of study medication. The actuarial one-year survivalwas approximately 25%. Conclusion:CV6504 inhibits its target enzyme in vivo,maintains stable disease in 32% of evaluable patients and is welltolerated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008303715515
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Environmental modification of tolerance to morphine discriminative stimulus properties in rats (1987)
    Springer
    Psychopharmacology 93 (1987), S. 59-68 
    Details
    ISSN: 1432-2072
    Keywords: Morphine tolerance ; Drug discrimination ; Schedule-controlled behavior ; Rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The development of tolerance to the discriminative stimulus properties of morphine was examined in rats trained to discriminate saline and 3.2 mg/kg morphine under amultiple timeout 15 min, 5 min fixed-ratio 30 schedule of food delivery. Generalization gradients were generated by administering increasing doses of morphine before successive timeout periods within the experimental session. Over the course of the study, the minimal discriminable dose (MDD) of morphine under control conditions fluctuated but did not systematically increase or decrease. Acute pretreatments of 3.2–17.8 mg/kg morphine 4–24 h before a generalization test resulted in minor changes in the MDD. To examine development of tolerance, supplemental doses of morphine (17.8 mg/kg) or saline were administered twice daily while discrimination training was either suspended or continued. Tolerance was assessed by weekly generalization tests. Greater tolerance developed to the morphine stimulus when training was suspended than when training was continued. For both training conditions, response rates during generalization tests were markedly suppressed during supplemental morphine administration, and original generalization gradients were recaptured within 2 weeks after termination of supplemental morphine administration. Supplemental saline administration did not alter the discriminative or rate-altering effects of morphine under either training condition. Thus, the magnitude of tolerance to a morphine discriminative stimulus reflected an interaction of supplemental drug treatment with the training conditions imposed during that treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02439587
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Behavioral contingencies modulate tolerance to discriminative stimulus effects of morphine (1996)
    Springer
    Psychopharmacology 125 (1996), S. 220-230 
    Details
    ISSN: 1432-2072
    Keywords: Drug discrimination ; Morphine ; Drug tolerance ; Behavior ; Learning ; Rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Experiments examined how learning processes modulate tolerance to discriminative stimulus effects of morphine. Rats were trained to discriminate saline and 3.2 mg/kg morphine, and the doses of morphine required to mimic the training dose were determined before, during and after repeated treatment with saline or high doses of morphine (10 mg/kg, b.i.d.). In one set of experiments, training was either suspended or continued with saline and the original training dose during a 2-week treatment regimen. When training was suspended, high-dose morphine treatment increased the dose of morphine required for stimulus effects approximately 3-fold. Tolerance persisted 2 days after treatment ended, but disappeared within 7 days. In contrast, continued training with saline and 3.2 mg/kg morphine during high-dose treatment both attenuated development of tolerance and transferred control to lower doses. Transfer of control to lower doses appeared conditional upon recent termination of high-dose treatment, as it disappeared within 7 days. Treatment with saline did not change the doses of morphine required for stimulus effects under either training condition. A final experiment examined whether high-dose treatment could transfer control to higher doses of morphine. The treatment dose of 10 mg/kg morphine itself was used as the training dose during a 2-week treatment regimen. The dose of morphine required for stimulus effects increased 2- to 4-fold during treatment, but quickly returned to control values when treatment ended. These results extend previous findings that conditioning and pharmacodynamic processes jointly regulate development of tolerance to discriminative effects of morphine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02247332
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  • 4
    Electronic Resource
    Electronic Resource
    Tolerance and cross-tolerance to morphine-like stimulus effects of µ opioids in rats (1997)
    Springer
    Psychopharmacology 133 (1997), S. 17-28 
    Details
    ISSN: 1432-2072
    Keywords: Key words Tolerance ; Drug discrimination ; Fentanyl ; Morphine ; Nalbuphine ; Efficacy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The purpose of these experiments was to examine the relationship of agonist relative efficacy to the pattern of tolerance and cross-tolerance to the morphine-like stimulus effects of three opioid agonists. Rats were trained to discriminate 3.2 mg/kg morphine from saline under fixed-ratio 15 schedule of food reinforcement. Morphine, nalbuphine, and fentanyl produced dose-dependent increases in morphine-like stimulus effects and decreases in response rates. Repeated treatment with 20 mg/kg per day morphine increased the ED50 for stimulus control by fentanyl, morphine, or nalbuphine two-, four-, or 40-fold, respectively. Repeated treatment with 64 mg/kg per day nalbuphine increased the ED50 for stimulus control for morphine by two-fold, but lower or higher treatment doses had no significant effect. Treatment with 100 mg/kg per day nalbuphine increased the ED50 for nalbuphine by six-fold. Repeated treatment with 0.22 mg/kg per day fentanyl increased the ED50 for stimulus control by fentanyl or morphine by approximately two-fold. Comparisons among treatment conditions suggested that magnitude of tolerance to morphine-like stimulus effects did not vary as an inverse function of the relative efficacy of the agonist used for repeated treatment. Rather repeated morphine and fentanyl treatments produced comparable tolerance, whereas repeated nalbuphine treatment did not evoke substantial tolerance. Comparisons within treatment conditions, however, suggested that magnitude of tolerance may vary inversely with relative efficacy of the agonist tested for morphine-like stimulus effects. During treatment with morphine or fentanyl, greater tolerance was observed to the morphine-like stimulus effects of the lower efficacy agonist relative to the higher efficacy agonist.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050366
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    Paper (German National Licenses)
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