European journal of pharmacology
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Combinations of analgesics with different mechanisms of action offer the possibility of efficient analgesia with a decrease in side effects as a result of reduced dosages of one or both compounds. Based on a clinical observation of synergism between nefopam, a centrally acting non-opioid that inhibits monoamines reuptake, and ketoprofen, a non-steroidal anti-inflammatory drug, the objective of this study was to further explore this antinociceptive synergy in four distinct animal models of pain (both drugs were administered subcutaneously). Strong antinociceptive properties were observed in the mouse writhing abdominal test with ED50 values of 2.56+/-0.38 and 1.41+/-0.41 mg/kg for nefopam and ketoprofen, respectively. ⋯ Combination of low analgesic doses of nefopam (10 or 30 mg/kg) with low analgesic doses of ketoprofen (30 or 100 mg/kg) significantly reduced or reversed allodynia, with a more pronounced anti-allodynic effect and a longer duration efficacy. In a rat model of postoperative thermal hyperalgesia induced by incision, co-administration of nefopam at a low analgesic dose (10 mg/kg) with ketoprofen at non-analgesic doses (30 or 100 mg/kg) showed the appearance of a strong anti-hyperalgesic effect, maintained during at least 3 h. In conclusion, co-administration of nefopam with ketoprofen is synergistic, and should allow either to increase their analgesic efficacy and/or to reduce their side effects.
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In the rat, selective suppression of conditioned avoidance response has been widely reported as a test with high predictive validity for antipsychotic efficacy. Recent studies have shown that the relationship between dopamine D2 receptor occupancy and the suppression of conditioned avoidance response behaviour correlates well with the relationship between human dopamine D2 receptor occupancy and clinical effect. The aim of the present study was to evaluate how pharmacokinetic/pharmacodynamic (PK/PD) predictions of therapeutic effective steady-state plasma levels by means of conditioned avoidance response behaviour in rodents, correlate with clinically relevant plasma exposure for the classical antipsychotic drug haloperidol and four second generation antipsychotics: sertindole, clozapine, risperidone and olanzapine, including selected metabolites. ⋯ Overall, a good agreement was observed between the rat dopamine D2 receptor occupancy levels providing 50% response in the conditioned avoidance response test and the dopamine D2 receptor occupancy levels reported from responding schizophrenic patients treated with antipsychotics. Predictions of therapeutically effective steady-state levels for sertindole (+dehydrosertindole) and olanzapine were 3-4-fold too high whereas for haloperidol, clozapine and risperidone the predicted steady-state EC50 in conditioned avoidance responding rats correlated well with the therapeutically effective plasma levels observed in patients. Accordingly, the proposed PK/PD model may act as a guide for determining effective plasma concentrations of potential antipsychotics in the clinical setting and thereby accelerating the overall drug development process.
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The present study evaluated the possible role of nicotinic acetylcholine receptors of the dorsal hippocampus on morphine-induced amnesia and morphine state-dependent memory in adult male Wistar rats. The animals were bilaterally implanted with chronic cannulas in the CA1 regions of the dorsal hippocampi, trained in a step-through type passive avoidance task, and tested 24 h after training to measure step-through latency. Results indicate that post-training subcutaneous (s.c.) administration of morphine (2.5-7.5 mg/kg) dose-dependently reduced the step-through latency, showing an amnestic response. ⋯ Pre-test injection of mecamylamine (0.5-2 microg/rat) prevented the restoration of memory by pre-test morphine. It is important to note that post-training or pre-test intra-CA1 administration of the same doses of nicotine or mecamylamine, alone did not affect memory retrieval. These results suggest that nicotinic acetylcholine receptors of the hippocampal CA1 regions may play an important role in morphine-induced amnesia and morphine state-dependent memory.
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Analgesics such as morphine cause many side effects including addiction, but kappa-opioid receptor agonist can produce antinociception without morphine-like side effects. With the aim of developing new and potent analgesics with lower abuse potential, we studied the antinociceptive and physical dependent properties of a derivate of ICI-199441, an analogue of (-)U50,488H, named (2-(3,4-dichloro)-phenyl)-N-methyl-N-[(1S)-1-(2-isopropyl)-2-(1-(3-pyrrolinyl))ethyl] acetamides (LPK-26). LPK-26 showed a high affinity to kappa-opioid receptor with the Ki value of 0.64 nM and the low affinities to micro-opioid receptor and delta-opioid receptor with the Ki values of 1170 nM and >10,000 nM, respectively. ⋯ Moreover, LPK-26 failed to induce physical dependence, but it could suppress naloxone-precipitated jumping in mice when given simultaneously with morphine. Taken together, our results show that LPK-26 is a novel selective kappa-opioid receptor agonist with highly potent antinociception effects and low physical dependence potential. It may be valuable for the development of analgesic and drug that can be used to reduce morphine-induced physical dependence.
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Benzotriazole derivatives have been shown to be able to induce growth inhibition in cancer cells. In the present study, we synthesized bioactive compound, 3-(1H-benzo [d] [1,2,3] triazol-1-yl)-1-(4-methoxyphenyl)-1-oxopropan-2-yl benzoate (BmOB), which is a novel benzotriazole derivative. BmOB displayed anti-proliferative effects on several human tumor cell lines. ⋯ BmOB induced cytotoxicity could be prevented by antioxidant vitamin C and mitochondrial permeability transition inhibitor cyclosporine A. cyclosporine A could also protect the BmOB induced collapse of DeltaPsim in BEL7402 cells, while vitamin C did not show similar effects. The results suggest that BmOB could inhibit BEL-7402 cell proliferation, and the cell death may occur through the modulation of mitochondrial functions regulated by reactive oxygen species. It appears that collapse of DeltaPsim prior to intracellular reactive oxygen species arose during the cytotoxic process in our experimental system.