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1.
《Drug metabolism and pharmacokinetics》2020,35(1):56-70
Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CLh) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CLh involving OATP1B-mediated hepatic uptake. CLh can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CLh and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction. 相似文献
2.
Interneurons immunoreactive for vasoactive intestinal polypeptide (VIP) are integral elements of columnar organization patterns in the rat cerebral cortex. By application of the sensitive mirror technique, the co-localization of VIP with the classical inhibitory neurotransmitter γ-aminobutyric acid (GABA) and the acetylcholine-synthesizing enzyme, choline acetyltransferase (ChAT), was investigated in neocortical neurons. Furthermore, the frequency of co-localization of ChAT with GABA was determined. In a sample of 118 VIP-immunoreactive neurons, mostly from the primary somatosensory cortex, it was demonstrated that virtually all of them reveal immunoreactivity for GABA and, therefore, are to be GABAergic. Moreover, 34% of mostly bipolar, VIP-positive neurons contained ChAT and are, thus, supposedly cholinergic as well. Co-localization of VIP and ChAT varied according to cortical laminae. Finally, 88% of a total of 60 ChAT-immunoreactive neurons were also immunostained for GABA. It is concluded that almost all VIP-immunoreactive neurons and most of the cholinergic neurons in rat neocortex represent partly overlapping subpopulations of inhibitory interneurons utilizing GABA. 相似文献
3.
二巯基丙磺酸钠解救毒鼠强中毒的疗效分析 总被引:1,自引:0,他引:1
目的:探求急性毒鼠强中毒(ATI)的临床解毒方法。方法:应用二巯基丙磺酸钠解救ATI34例,进行疗效观察,并与既往常规治疗的23例进行对照比较。结果:治疗组获得满意疗效,3例死亡,有效率91.2%;对照组预后欠佳,死亡13例,有效率43.5%。结论:二巯基丙磺酸钠(Na—DMPS)对ATI具有良好的止痉作用,可明显提高治疗效果。 相似文献
4.
Yang Hee Kim Young In Moon Young Hee Kang Jung Sook Kang 《Nutrition Research And Practice》2007,1(4):298-304
This study was conducted to investigate the hypocholesterolemic effect of simvastatin (30 mg/kg BW) and antioxidant effect of coenzyme Q10 (CoQ10, 15 mg/kg BW) or green tea (5%) on erythrocyte Na leak, platelet aggregation and TBARS production in hypercholesterolemic rats treated with statin. Food efficiency ratio (FER, ADG/ADFI) was decreased in statin group and increased in green tea group, and the difference between these two groups was significant (p<0.05). Plasma total cholesterol was somewhat increased in all groups with statin compared with control. Plasma triglyceride was decreased in statin group and increased in groups of CoQ10 and green tea, and the difference between groups of statin and green tea was significant (p<0.05). Liver total cholesterol was not different between the control and statin group, but was significantly decreased in the group with green tea compared with other groups (p<0.05). Liver triglyceride was decreased in groups of statin and green tea compared with the control, and the difference between groups of the control and green tea was significant (p<0.05). Platelet aggregation of both the initial slope and the maximum was not significantly different, but the group with green tea tended to be higher in initial slope and lower in the maximum. Intracellular Na of group with green tea was significantly higher than the control or statin group (p<0.05). Na leak in intact cells was significantly decreased in the statin group compared with the control (p<0.05). Na leak in AAPH treated cells was also significantly reduced in the statin group compared with groups of the control and CoQ10 (p<0.05). TBARS production in platelet rich plasma was significantly decreased in the groups with CoQ10 and green tea compared with the control and statin groups (p<0.05). TBARS of liver was significantly decreased in the group with green tea compared with the statin group (p<0.05). In the present study, even a high dose of statin did not show a cholesterol lowering effect, therefore depletion of CoQ10 following statin treatment in rats is not clear. More clinical studies are needed for therapeutic use of CoQ10 as an antioxidant in prevention of degenerative diseases independent of statin therapy. 相似文献
5.
目的探讨初次献血对红细胞膜Na+-K+-ATP酶活性的影响.方法应用比色法分别检测50例符合献血条件的健康初次献血者献血前后的红细胞膜Na+-K+-ATP酶活性,并对结果进行分析.结果初次献血者献血前后红细胞膜Na+-K+-ATP酶活性分别为3.121±0.441和2.907±0.397 μmol.Pi/107 RBC.h,两者比较无明显差异(P>0.05).结论初次献血对红细胞膜Na+-K+-ATP酶活性无影响,献血不会造成红细胞功能损伤. 相似文献
6.
PACAP is a hypothalamic hypophysiotropic factor that acts upon a number of pituitary cells, including gonadotrophs. In the gonadotroph-derived αT3-1 cell line, PACAP acts via PVR1 receptors to stimulate adenylyl cyclase and phosphoinositidase C. PACAP-stimulated cAMP accumulation is inhibited by protein kinase C-activating phorbol esters in these cells and the current work was undertaken primarily to establish whether it is also subject to homologous regulation. In acute experiments, PACAP27-stimulated cAMP accumulation (intracellular plus extracellular) was measured (in the presence of phosphodiesterase inhibitor) both in intact cells and in cell membranes. The peptide increased cAMP accumulation, but initial rates of PACAP27-stimulated cAMP accumulation were reduced to between 10 and 50% within 10 min of stimulation in both cells and membranes. The initial rate of forskolin-stimulated cAMP accumulation was maintained in membranes but not in intact cells (although the deviation from linearity was less pronounced than with PACAP27). Thus, rapid homologous desensitization to PACAP27 occurs in intact αT3-1 cells, but is not entirely receptor specific. Rapid homologous desensitization of PACAP27-stimulated cAMP accumulation also occurred in the presence of a protein kinase C activating phorbol ester, which inhibited cAMP accumulation without altering the kinetics of the PACAP27 effect. Brief pre-treatment (3 min) with PACAP27 also reduced the ability of PACAP27, but not gonadotrophin-releasing hormone, to cause a spike-type elevation of cytosolic Ca2+ concentration (a consequence of phosphoinositidase C activation). In chronic desensitization studies, pre-treatment for 6 h with PACAP27 caused a dose-dependent (IC50 approximately 10 nM) reduction of PACAP-stimulated cAMP accumulation and down regulated cell surface PVR1 receptors (to approximately 50%). Thus, it appears that PACAP27-stimulated (PVR-1 receptor mediated) adenylyl cyclase undergoes rapid homologous desensitization in αT3-1 cells, which is paralleled by homologous desensitization of PACAP27-stimulated phosphoinositidase C activity and involves mechanisms distinct from those underlying heterologous desensitization by phorbol esters. Chronic desensitization of PACAP-stimulated cAMP accumulation and down-regulation of cell surface PVR-1 receptors also occurs in these cells although the receptor loss may not entirely explain the observed desensitization. 相似文献
7.
Cesare M.N. Terracciano David Tweedie Kenneth T. MacLeod 《Pflügers Archiv : European journal of physiology》1997,433(4):540-542
. We have estimated sarcoplasmic reticulum calcium content using rapid application of caffeine on voltage clamped, isolated
guinea-pig ventricular myocytes. Caffeine induces the release of calcium from the sarcoplasmic reticulum and this calcium
is extruded from the cells by the sarcolemmal Na/Ca exchange. Integrating the inward Na/Ca exchange current thus allows estimations
of sarcoplasmic reticulum calcium content. Ventricular myocytes were stimulated to reach new steady-states by action potential
voltage clamps of varying duration. Once contractile steady-state had been reached caffeine was rapidly applied in place of
the next action potential and sarcoplasmic reticulum calcium content measured. Prolonging the action potential duration increased
sarcoplasmic reticulum calcium content and vice-versa. This calcium loading may underlie the positive inotropic effect of
increased action potential duration.
Received: 11 July 1996 / Received after revision: 15 October 1996 / Accepted: 26 November 1996 相似文献
8.
S. V. Revenko L. V. Borovikova D. V. Borovikov V. V. Ermishkin 《Bulletin of experimental biology and medicine》1997,124(4):945-947
Mechanical and thermal excitability of cutaneous feline polymodal C-fiber units is maintained under the action of subcutaneous
tetrodotoxin injected in concentrations suppressing the mechanosensitivy of Aβ-units. A number of features of inhibition and excitation of C-fiber polymodal sensory units can be explained by existence
of tetrodotoxinresistant Na channels in their termination.
Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 10, pp. 369–371, October, 1997 相似文献
9.
Growth of cultured NlE-115 neuroblastoma cells in 1 μM A23187 for 2 days to elevate internal Ca reduced both membrane Na current and the transient, but not steady state, component of outward K current. Na channel mRNA abundance was reduced by an average value of 45% without effect on Kv3.1. Increases in internal Ca may therefore control excitability by independent regulation of Na and K channel mRNA abundance in neurons. 相似文献
10.
蝎毒多肽提取物对肺癌荷瘤裸鼠血流变学的影响 总被引:2,自引:0,他引:2
目的观察蝎毒多肽提取物(PESV)对肺癌荷瘤裸鼠血流变学的影响。方法移植肺癌荷瘤裸鼠随机分为PESV组(皮下注射PESV)与对照组(皮下注射生理盐水)。采用FASCO-300型全自动表观黏度快测仪对两组的全血黏度进行检测。结果与对照组相比,PESV组血流变学指标均有不同程度的降低,尤其是全血低切表观黏度、全血高切表观黏度、Casson黏度、Casson屈服应力均明显低于对照组(P〈0.01)。结论PESV可降低荷瘤裸鼠血液黏度,对肺癌荷瘤裸鼠肿瘤转移能力有明显的抑制作用。 相似文献