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81.
Dupuis DS Schrøder RL Jespersen T Christensen JK Christophersen P Jensen BS Olesen SP 《European journal of pharmacology》2002,437(3):129-137
The novel anti-ischemic compound, BMS-204352 ((3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one)), strongly activates the voltage-gated K+ channel KCNQ5 in a concentration-dependent manner with an EC50 of 2.4 microM. At 10 microM, BMS-204352 increased the steady state current at -30 mV by 12-fold, in contrast to the 2-fold increase observed for the other KCNQ channels [Schr?der et al., 2001]. Retigabine ((D-23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) induced a smaller, yet qualitatively similar effect on KCNQ5. Furthermore, BMS-204352 (10 microM) did not significantly shift the KCNQ5 activation curves (threshold and potential for half-activation, V1/2), as observed for the other KCNQ channels. In the presence of BMS-204352, the activation and deactivation kinetics of the KCNQ5 currents were slowed as the slow activation time constant increased up to 10-fold. The M-current blockers, linopirdine (DuP 996; 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one) and XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone), inhibited the activation of the KCNQ5 channel induced by the BMS-204352. Thus, BMS-204352 appears to be an efficacious KCNQ channels activator, and the pharmacological properties of the compound on the KCNQ5 channel seems to be different from what has been obtained on the other KCNQ channels. 相似文献
82.
Mortensen M Frølund B Jørgensen AT Liljefors T Krogsgaard-Larsen P Ebert B 《European journal of pharmacology》2002,451(2):125-132
A series of novel 5-(4-piperidyl)-3-isoxazolol (4-PIOL) analogues where the 4-position of the 3-isoxazolol ring was substituted with groups of different size, flexibility, and lipophilicity have been characterised. Their activity as agonists and/or antagonists on human alpha(1)beta(2)gamma(2S) GABA(A) receptors expressed in Xenopus oocytes was studied using two-electrode voltage clamp electrophysiology. Methyl- and ethyl-substituted 4-PIOL analogues were characterised as partial agonists since weak agonist responses could be potentiated with lorazepam and inhibited by the competitive antagonist 2-(3-carboxypropyl)-3-amino-6-methoxyphenyl-pyradizinum bromide (SR95531). All larger substituents in the 4-position of the 3-isoxazolol ring of 4-PIOL converted the compounds into pure competitive antagonists. Additionally, for GABA, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), piperidine-4-sulphonic acid (P4S), and 5-(4-piperidyl)-3-isothiazolol (thio-4-PIOL), a negative linear correlation was found between the agonist efficacy of the compound and the ability of lorazepam to potentiate EC(95) responses. Furthermore, a positive linear correlation between the lipophilicity of the substituents in the 4-position of the 3-isoxazolol ring of 4-PIOL and the antagonist affinity was found. These data suggest that the GABA(A) receptor contains a hydrophobic binding pocket at the GABA recognition site and that the binding of the 4-PIOL analogues is largely determined by the transfer from the aqueous phase to the hydrophobic pocket. 相似文献
83.
Nizatidine and omeprazole enhance the effect of metronidazole on Helicobacter pylori in vitro 总被引:1,自引:0,他引:1
Chen M Jensen B Zhai L Colding H Kharazmi A Kristiansen JE Andersen LP 《International journal of antimicrobial agents》2002,19(3):195-200
Treatment failures are common in patients infected with metronidazole-resistant Helicobacter pylori in the gastric mucosa when triple therapy including metronidazole is used. In patients with treatment failure and metronidazole-resistant H. pylori, a higher eradication rate for H. pylori was found after secondary treatment with bismuth/ranitidine in combination with antibiotics including metronidazole, compared with the same antibiotics combined with a standard dose of omeprazole. This agrees with our previous finding that bismuth was able to reduce the susceptibility of H. pylori to metronidazole. In this study, we have found that nizatidine, an H(2)-receptor antagonist, is also able to reduce the susceptibility of H. pylori to metronidazole in vitro, despite having no direct inhibitory effect on the growth of H. pylori. This agrees with earlier findings that compounds having the ability to reverse antibiotic resistance do not necessarily have an antibiotic or chemotherapeutic effect in the sense of growth inhibition. Therefore, it was decided to investigate the effect of nizatidine and omeprazole on the oxidative respiratory chain, as it is known that metronidazole is able to inhibit the activity of fumarate reductase of H. pylori. This enzyme is a key enzyme in the alternative respiratory chain under anaerobic conditions. Nizatidine was, in these preliminary experiments, found to inhibit fumarate reductase in a dose-dependent way, like metronidazole, whereas omeprazole had almost no effect on fumarate reductase. No other significant effects on the enzymes of the respiratory chain were found. The synergistic effect of nizatidine on metronidazole resistant H. pylori strains could be explained by the effect on fumarate reductase, whereas the effect of omeprazole is different and could be an inhibition of a proton pump in H. pylori. Reversal of antimicrobial resistance with the help of different non-antibiotics seems to be possible by using quite different compounds, and is therefore to be explained by different molecular mechanisms. 相似文献
84.
Tardive dyskinesia (TD) is a serious motor side effect of long-term neuroleptic treatment that may persist after drug withdrawal. Alterations in striatal enkephalinergic neurons due to excessive glutamatergic activity is a possible pathogenetic mechanism. We studied the effect of the NMDA antagonist memantine in a rat model of TD, in which vacuous chewing movements (VCM) were induced by 20 weeks of haloperidol administration. The striatal density of preproenkephalin mRNA was measured and the number of neurons estimated. Haloperidol induced persistent VCM that was associated with increased striatal expression of preproenkephalin mRNA. Memantine inhibited the development of haloperidol-induced persistent VCM and attenuated the increase in preproenkephalin mRNA expression. This suggests that glutamate-mediated up-regulation of striatal enkephalin plays a role in the development of haloperidol-induced persistent oral dyskinesias. 相似文献
85.
Dynamics of microglia in the developing rat brain 总被引:4,自引:0,他引:4
Dalmau I Vela JM González B Finsen B Castellano B 《The Journal of comparative neurology》2003,458(2):144-157
Entrance of mesodermal precursors into the developing CNS is the most well-accepted origin of microglia. However, the contribution of proliferation and death of recruited microglial precursors to the final microglial cell population remains to be elucidated. To investigate microglial proliferation and apoptosis during development, we combined proliferating cell nuclear antigen (PCNA) immunohistochemistry, in situ detection of nuclear DNA fragmentation (TUNEL), and caspase-3 immunohistochemistry with tomato lectin histochemistry, a selective microglial marker. The study was carried out in Wistar rats from embryonic day (E) 16 to postnatal day (P) 18 in cerebral cortex, subcortical white matter, and hippocampus. Proliferating microglial cells were found at all ages in the three brain regions and represented a significant fraction of the total microglial cell population. The percentage of microglia expressing PCNA progressively increased from the embryonic period (25-51% at E16) to a maximum at P9, when the great majority of microglia expressed PCNA (92-99%) in all the brain regions analyzed. In spite of the remarkable proliferation and expansion of the microglial population with time, the density of microglia remained quite constant in most brain regions because of the considerable growth of the brain during late prenatal and early postnatal periods. In contrast, apoptosis of microglia was detected only at certain times and was restricted to some ameboid cells in white matter and primitive ramified cells in gray matter, representing a small fraction of the microglial population. Therefore, our results point to proliferation of microglial precursors in the developing brain as a physiological mechanism contributing to the acquisition of the adult microglial cell population. In contrast, microglial apoptosis occurs only locally at certain developmental stages and thus seems less crucial for the establishment of the final density of microglia. 相似文献
86.
It has been suggested that the dysfunction of the prefrontal cortex in schizophrenics is due to dysfunctional connections between the prefrontal cortex and more posterior structures. The present study uses a recent stereological method that allows quantitation of the myelinated nerve fibers in the brain white matter. As especially the prefrontal region is of interest in schizophrenics, the prefrontal white matter was quantitated separately. The total length of nerve fibers in post-mortem brains was estimated from eight male chronic schizophrenics and nine male controls (age-range: 40–81 years). Samples were taken systematically and randomly from both the entire white matter and selectively from the prefrontal white matter. The biopsies were rotated randomly before sectioning to avoid bias due to the anisotropic nature of nerve fibers. The fibers were counted at light microscopic level at about 10,000× magnification and the fiber diameter of each counted fiber was measured to get the size distribution of the fibers. The schizophrenics had a total of 129,000 km myelinated fibers in the white matter and 25,700 km in the prefrontal white matter, which was non-significantly different from a total of 137,000 km in the entire white matter and 27,600 km in the prefrontal white matter in controls. The size distribution of the fibers in schizophrenics was within normal limits compared to controls. Our results do not show a larger loss of nerve fibers in neither the white matter globally or in the prefrontal white matter of schizophrenics. 相似文献
87.
Baelum V Machiulskiene V Nyvad B Richards A Vaeth M 《Community dentistry and oral epidemiology》2003,31(4):252-260
OBJECTIVE: To demonstrate the usefulness of a survival-time regression model for the analysis of data from two 3-year trials of the caries-preventive effect of sugar-substituted chewing gums and fluoride toothpaste, carried out among 892 Lithuanian children. METHODS: A caries onset was defined as a transition from sound to carious and a caries recovery was defined as a transition from carious to sound. The time at risk for each type of transition was calculated. Using an exponential survival-time regression model, the hazard ratios for the covariates experimental group (control, sugar substitute, fluoride), age, gender, surface type and posteruptive surface age was estimated. This analysis was repeated using two alternative definitions of the caries transitions. RESULTS: The analyses confirmed that caries rates are higher in occlusal surfaces, and that posteruptive surface age influences caries rates. Moreover, it also confirmed that fluoride affects the outcome of ongoing caries activity more than the initiation of caries. CONCLUSIONS: Survival-time analysis of caries transitions allows for the extraction of much more information from caries trials than does the traditional DMF-based analysis, and traditional DMF incremental values may easily be derived from the models. 相似文献
88.
Caffeine-induced impairment of insulin action but not insulin signaling in human skeletal muscle is reduced by exercise 总被引:6,自引:0,他引:6
Thong FS Derave W Kiens B Graham TE Ursø B Wojtaszewski JF Hansen BF Richter EA 《Diabetes》2002,51(3):583-590
We investigated the effects of caffeine ingestion on skeletal muscle glucose uptake, glycogen synthase (GS) activity, and insulin signaling intermediates during a 100-min euglycemic-hyperinsulinemic (100 microU/ml) clamp. On two occasions, seven men performed 1-h one-legged knee extensor exercise at 3 h before the clamp. Caffeine (5 mg/kg) or placebo was administered in a randomized, double-blind fashion 1 h before the clamp. During the clamp, whole-body glucose disposal was reduced (P < 0.05) in caffeine (37.5 +/- 3.1 micromol x min(-1) x kg(-1)) vs. placebo (54.1 +/- 2.9 micromol x min(-1) x kg(-1)). In accordance, the total area under the curve over 100 min (AUC(0--100 min)) for insulin-stimulated glucose uptake in caffeine was reduced (P < 0.05) by approximately 50% in rested and exercised muscle. Caffeine also reduced (P < 0.05) GS activity before and during insulin infusion in both legs. Exercise increased insulin sensitivity of leg glucose uptake in both caffeine and placebo. Insulin increased insulin receptor tyrosine kinase (IRTK), insulin receptor substrate 1-associated phosphatidylinositol (PI) 3-kinase activities, and Ser(473) phosphorylation of protein kinase B (PKB)/Akt significantly but similarly in rested and exercised legs. Furthermore, insulin significantly decreased glycogen synthase kinase-3alpha (GSK-3alpha) activity equally in both legs. Caffeine did not alter insulin signaling in either leg. Plasma epinephrine and muscle cAMP concentrations were increased in caffeine. We conclude that 1) caffeine impairs insulin-stimulated glucose uptake and GS activity in rested and exercised human skeletal muscle; 2) caffeine-induced impairment of insulin-stimulated muscle glucose uptake and downregulation of GS activity are not accompanied by alterations in IRTK, PI 3-kinase, PKB/Akt, or GSK-3alpha but may be associated with increases in epinephrine and intramuscular cAMP concentrations; and 3) exercise reduces the detrimental effects of caffeine on insulin action in muscle. 相似文献
89.
Thommessen B Thoresen GE Bautz-Holter E Laake K 《Cerebrovascular diseases (Basel, Switzerland)》2002,13(3):184-186
We studied the validity of the aphasia item of a widely used stroke scale - the Scandinavian Stroke Scale (SSS) - in discriminating between aphasia and normal language function in 33 stroke patients of an acute stroke unit. They were assessed by a nurse using the aphasia item from the SSS and by a speech and language therapist carrying out a full evaluation of the language function. The latter served as the 'gold standard'. The agreement between the nurses' and the speech and language therapist's scoring was good (weighted kappa = 0.74, 95% CI 0.51-0.97), and the sensitivity and specificity of the SSS aphasia item were also satisfactory. However, the predictive value of a positive test was as low as 0.55 (95% CI 0.23-0.83), indicating nearly every second of the positives being false positive. Using the aphasia score of the SSS as a diagnostic aid for aphasia after stroke results in a high rate of false positives and inflates the prevalence figures for aphasia in epidemiological studies of stroke. 相似文献
90.
Brion F Nilsen BM Eidem JK Goksøyr A Porcher JM 《Environmental toxicology and chemistry / SETAC》2002,21(8):1699-1708
In this study, an enzyme-linked immunosorbent assay (ELISA) was developed to quantify vitellogenin (Vtg) in zebrafish (Danio rerio). Zebrafish Vtg (zf-Vtg) was purified from whole-body homogenates of estradiol-exposed zebrafish, and polyclonal antibodies against zf-Vtg were raised. Using purified zf-Vtg as a standard and anti-zf-Vtg antibodies (DR-264), a competitive ELISA method was set up and validated. The working range of the assay is from 1 to 30 ng/ml (20-80% binding), and the detection limit is 0.4 ng/ml for purified zf-Vtg. In whole-body homogenates samples, the practical detection limit is higher than that for purified Vtg (40 ng/ml) due to matrix effect. The intra- and interassay variations were 4.7% and 14%, respectively, at 50% binding (n = 36). Its usefulness to detect changes in Vtg concentration in other cyprinid fish was also tested. In addition, the assay was used to assess Vtg induction in male zebrafish exposed to 17beta-estradiol (E2). Exposure of male zebrafish to 0.1, 1, 10, and 100 microg/L of E2 for 7 d led to a Vtg induction from the lowest concentration. The results show the suitability of the developed ELISA to quantify Vtg inductions in zebrafish, the cross-reactivity of DR264 antibodies with commonly used cyprinids, and the potential of zf-Vtg induction as a sensitive biochemical endpoint that could be used to detect estrogenic properties of chemical substances. 相似文献