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61.
Dagmar Busse Jose Cosme Philippe Beaune Heyo K. Kroemer Michel Eichelbaum D. Busse H. K. Kroemer M. Eichelbaum 《Naunyn-Schmiedeberg's archives of pharmacology》1995,353(1):116-121
The calcium channel blocker verapamil [2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] undergoes extensive biotransformation in man. We have previously demonstrated cytochrome P450 (CYP) 3A4 and 1A2 to be the enzymes responsible for verapamil N-dealkylation (formation of D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile]), and verapamil N-demethylation (formation of norverapamil [2,8-bis(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile]), while there was no involvement of CYP3A4 and CYP1A2 in the third initial metabolic step of verapamil, which is verapamil O-demethylation. This pathway yields formation of D-703 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] and D-702 [2-(3,4-dimethoxyphenyl)-8-(4-hydroxy-3-methoxyphenyl)6-methyl-2-isopropyl-6-azaoctanitrile]. The enzymes catalyzing verapamil O-demethylation have not been characterized so far. We have therefore identified and characterized the enzymes involved in verapamil O-demethylation in humans by using the following in vitro approaches: (I) characterization of O-demethylation kinetics in the presence of the microsomal fraction of human liver, (II) inhibition of verapamil O-demethylation by specific antibodies and selective inhibitors and (111) investigation of metabolite formation in microsomes obtained from yeast strain Saccharomyces cerevisiae W(R), that was genetically engineered for stable expression of human CYP2C8, 2C9 and 2C18.In human liver microsomes (n=4), the intrinsic clearance (CLint), as derived from the ratio of V
max/Km, was significantly higher for O-demethylation to D-703 compared to formation of D-702 following incubation with racemic verapamil (13.9±1.0 vs 2.4±0.6 ml*min-1
*g-1 mean±SD; p<0.05), S-Verapamil (16.8±3.3 vs 2.2±1.2 ml* mini*g-1, p<0.05) and R-verapamil (12.1±2.9 vs 3.6 ±1.3 ml*min-1
* g-1; p<0.05), thus indicating regioselectivity of verapamil O-demethylation process. The CLint of D-703 formation in human liver microsomes showed a modest but significant degree of stereo selectivity (p<0.05) with a S/R-ratio of 1.41±0.17. Anti-LKM2 (anti-liver/kidney microsome) autoantibodies (which inhibit CYP2C9 and 2C19) and sulfaphenazole (a specific CYP2C9 inhibitor) reduced the maximum rate of formation of D-703 by 81.5±4.5% and 45%, that of D-702 by 52.7±7.5% and 72.5%, respectively. Both D-703 and D-702 were formed by stably expressed CYP2C9 and CYP2C18, whereas incubation with CYP2C8 selectively yielded D-703.In conclusion, our results show that enzymes of the CYP2C subfamily are mainly involved in verapamil O-demethylation. Verapamil therefore has the potential to interact with other drugs which inhibit or induce these enzymes. 相似文献
62.
Purpose. The inhibitory effects of omeprazole on diazepam metabolism in vitro and in vivo are compared in the rat.
Methods. 3-hydroxylation and N-demethylation of diazepam was investigated in the presence of a range of omeprazole concentrations (2-500µM) in hepatic microsomes and hepatocytes. Zero order infusions together with matched bolus doses of omeprazole were used to achieve a range of steady state plasma concentrations (10-50mg/ L) and to study the diazepam-omeprazole interaction in vivo.
Results. The 3-hydroxlation pathway was more prone to inhibition (KIs 108 ± 30 and 28 ± 11 µM in microsomes and hepatocytes, respectively) than the demethylation pathway (KIs of 226 ± 76 and 59 ± 27 µM in microsomes and hepatocytes, respectively). In both in vitro systems, the mechanism of inhibition was competitive with Km/KI ratios larger than 1 for the 3HDZ pathway and smaller than 1 for the NDZ pathway. There was an omeprazole concentration dependent decrease in diazepam clearance in vivo which could be modelled using a simple inhibition equation with a KI of 57µM (19.8mg/L). In contrast there was no statistically significant change in the steady state volume of distribution for diazepam in the presence of omeprazole.
Conclusions. The in vivo KI for the omeprazole: diazepam inhibition interaction shows closer agreement with the KI values obtained in hepatocytes than with those observed in microsomes. 相似文献
63.
N. I. Triantafyllou K. Voumvourakis I. Zalonis K. Sfagos V. Mantouvalos S. Malliara C. Papageorgiou 《Acta neurologica Scandinavica》1992,85(1):10-13
Auditory event-related potentials (AERP) were elicited in 47 patients with relapsing-remitting (RR) multiple sclerosis (MS) and 24 age-matched controls. MS patients had significantly prolonged N2 and P3 latencies as well as low P3 amplitude compared with controls. Seven of them exceeded 3 standard deviations from the control mean values. The observed N2 and P3 alterations are associated with the patients' disability status as it is defined by the Kurtzke expanded disability status scale (EDSS), but are not related to the duration of the disease. A possible cognitive decline as reflected in the observed AERP components alterations in MS patients is subsequently discussed. 相似文献
64.
胃癌组织中KAI1、nm23及P53的表达及其临床意义 总被引:5,自引:4,他引:1
目的:探讨正常胃黏膜、不典型增生胃黏膜及癌组织中KAI1、nm23及P53蛋白的表达.方法:应用SP法免疫组化检测22例正常胃黏膜,65例不典型增生胃黏膜及74N胃癌组织中的KAI1、nm23及P53蛋白的表达.结果:正常胃黏膜、不典型增生胃黏膜及胃癌组织中,KAI1和nm23阳性率呈降低趋势,组间差异性有统计学意义(x2=20.885, P<0.001;x2=29.133,P<0.05):P53蛋白阳性表达率呈增加趋势,组间差异性有统计学意义(x2=21.954,P<0.001).Fisher精确概率检验显示:在胃癌组中不同的浸润深度、有无淋巴结转移和脉管侵犯组内KAI1、nm23及 P53组阳性表达率的差异性有统计学意义(x2 =20.885,P<0.001;x2=29.133,P<0.05;x2= 21.954,P<0.001);而在年龄、性别组间的差异性无统计学意义.Spearman等级相关分析显示 KAI1与nm23表达呈正相关(r=0.859,P<0.05); KAI1与P53表达呈负相关(r=-0.859,P<0.05), nm23与P53表达呈负相关(r=-0.874,P<0.05) 结论:抑癌基因KAI1与nm23的缺失以及P53 蛋白的过表达可能是胃癌发生、发展及浸润和转移的重要原因之一. 相似文献
65.
(1)目的 研究5型腺病毒载体(Ad5)携带P16基因对恶性脑胶质瘤细胞系TJ899生长状态的影响。(2)方法 免疫组化(SP法)测定P16蛋白表达,MTT(methly thiazolyl tetrazolium,MTT)法测定恶性脑胶质瘤细胞系生长状态,克隆形成实验。(3)结果 重组体腺病毒能介导P16外源基因在恶性脑胶质瘤细胞系TJ899细胞中阳性表达,6d时肿瘤细胞生长抑制率为93%,并且能显地抑制肿瘤细胞的克隆形成能力。(4)结论 腺病毒介导P16基因能在肿瘤细胞中表达。并能明显抑制肿瘤细胞生长的状态。 相似文献
66.
Heukrodt Carol; Powazek Morris; Brown Warren S.; Kennelly Denise; Imbus Charles; Robinson Herb; Schantz Stacy 《Journal of pediatric psychology》1988,13(2):223-236
The long-term effects of disease and treatment on electrophysiologicalmeasures of neurocognitive function were studied in childrenwho had survived acute lymphoblastic leukemia (ALL) for at least4 years and were currently in remission. We report here changesin cognitive processing time as shown by the latency of theP3 wave of the auditory event-related EEG potential (ERP). P3latency was significantly prolonged in long-term ALL surivors,as well as in patients successfully trreated for solid tumors(ST)outside the CNS who received similar chemotherapy but did notreceive prophylactic treatment to the CNS. P3 latencies werestrongly correlated with measures of school performance andIQ in these individuals. The similarity in P3 latency betweenthe ALL and ST groups suggests that the treatments used on thesepateints produce changes in electrophysiological responses thatare associated with mild, but significant, cognitive deficits. 相似文献
67.
Hiroko Koizumi Chikako Yasui Torn Fukaya Tetsuo Ueda Akira Ohkawara 《Experimental dermatology》1994,3(1):40-44
Abstract Substance P is a neuropeptide which is present in peripheral C nerve endings and released from them. Free nerve endings of C nerve are present in human epidermis. The effects of substance P on the transmembrane signaling system of pig epidermal sheets were previously reported. In these studies, a small amount of cells other than keratinocytes contaminated the epidermal sheets and the species difference from human was also noticed. Therefore we investigated the effects of substance P on cultured normal human epidermal keratinocytes. Alteration of intracellular free calcium (Ca2+) in single living keratinocytes was studied using an inverted fluorescence microscope and Ca2+ -sensitive dye, Fura 2-AM. Treatment of normal human epidermal kertinocytes with substance P resulted in an increase in inositol 1,4,5-trisphosphate and in intracellular Ca2+. Substance P inhibited DNA synthesis of the keratinocytes in a dose-dependent manner. These results are consistent with the view that substance P stimulates phosphatidylinositol-4,5-bisphosphate hydrolysis of human keratinocytes, resulting in inositol 1,4,5-trisphosphate-Ca2+ signal. 相似文献
68.
Mice immunized against anti-substance P (anti-SP) monoclonal antibodies produced anti-SP anti-idiotypic antibodies (SPAb2). In a previous report. SPAb2 antibodies were found to have in vitro biological activity i.e. to behave either as agonists or as antagonists for substance P (SP) depending on the biological test. In this study, the involvement of SPAb2 in vivo biological activity has been tested. Because of the possible implication of SP in the generation and transmission of nociceptive information, we have tested the responsiveness of SPAb2 responding mice in behavioral nociceptive tests. SPAb2 mice showed very small behavioral variations in the hot plate test as compared with a control group of mice immunized against an unrelated monoclonal antibody. In the formalin test, however, SPAb2 mice displayed a significant increase in paw licking time, which was significantly correleted with SPAb2 serum concentration. These results are discussed in terms of the use of SPAb2 as pharmacological tools for studying the biological properties of SP receptors and more generally of auto anti-idiotypic antibodies in modulating behavior responses. 相似文献
69.
目的:探讨背根神经节(DRG)内P物质(SP)、降钙素基因相关肽(CGRP)免疫阳性神经元与阴茎包皮系带感觉信息传递之问的关系。方法:通过荧光金(FG)逆行标记对大鼠阴茎包皮系带内神经末梢的来源作追踪定位,并结合SP、CGRP免疫荧光标记法,研究大鼠DRG内FG标记阳性神经元中SP、CGRP免疫阳性神经元的形态和分布。结果:FG逆行标记结果发现,大鼠阴茎包皮系带内的神经末梢起源于第6腰髓对应的背根神经节(L6-DRG)和第1骶髓对应的背根神经节(S1-DRG)的神经元。对这些神经元分别作SP、CGRP免疫荧光标记后发现,标记细胞大小不等,分别呈深红色和深绿色,沿神经束成行排列或散在分布。FG/SP、FG/CGRP双标记阳性细胞均为中小型,其数量分别占FG逆行标记阳性细胞总数的1/3和1/2,FG/SP/CGRP三标记阳性细胞占FG逆行标记阳性细胞总数的1/5。结论:大鼠L6-DRG和S1-DRG内的SP、CGRP免疫阳性神经元可能参与阴茎包皮系带感觉信息的传递。 相似文献
70.
恩必普软胶囊改善慢性脑供血不足患者认知功能的临床分析 总被引:1,自引:0,他引:1
李晓玲 《脑与神经疾病杂志》2007,15(4):260-262
目的:探讨dl-3-正丁基苯酞软胶囊(恩必普软胶囊)治疗慢性脑供血不足的临床疗效及对慢性脑供血不足病人认知功能改善的影响。方法:将60例慢性脑供血不足病人随机分为治疗组和对照组,每组30例,治疗组口服dl-3-正丁基苯酞软胶囊,每次200毫克,每日3次;对照组口服复方丹参片,每次4片,每日3次,疗程为8周,治疗前后进行疗效评价和P300数据采样,同时给予同步MMSE、HDS量表评分。结果:治疗组总有效率为70%,对照组总有效率为53.3%,2组治疗后比较差异有显著意义(P<0.05);治疗组治疗前、后MMSE和HDS量表得分情况比较,均有明显改善(P<0.01),与对照组治疗后比较差异有显著意义(P<0.05);治疗组治疗前、后P300波潜伏期及P300波幅差异均有显著意义(P<0.05),与对照组治疗后比较均有显著差异(P<0.05)。结论:dl-3-正丁基苯酞软胶囊对慢性脑供血不足病人安全有效。 相似文献