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21.
特异性荧光偏振免疫法监测521例肾移植后环孢素A全血浓度3275次 总被引:2,自引:0,他引:2
目的通过监测肾移植后病人环孢素A(CsA)全血浓度 ,提出CsA在三联免疫抑制用药方案中的理想治疗窗。方法用特异性荧光偏振免疫法测定CsA全血浓度 ,对521例病人监测3275次 ,按术后时间及临床表现分组比较。结果肾移植后<1 ,、1~3、3~6、6~12个月、1~2和>2年的CsA全血谷浓度的理想治疗窗应分别为250~450、200~400、150~300、100~250、100~200和100~180μg/L。结论CsA全血浓度在上述范围内 ,中毒反应和排异反应明显减少 相似文献
22.
David S. Park Paul Manowitz Stanley Stein Ronald D. Poretz 《Alcoholism, clinical and experimental research》1996,20(2):234-239
Several electrophoretic forms of human platelet arylsulfatase A (ASA), including variant type IIIa and normal type IVa , have been identified by nondenaturing polyacrylamide gel electrophoresis. An alcoholic population that we have analyzed is enriched in variant type IIIa compared with nonalcoholic psychiatric and normal controls. Individuals with the IIIa enzyme possess greatly reduced levels of ASA activity. To understand further the structural basis for the differences and their potential biological consequences, the nature of the ASA variant expressed by fibroblasts from different individuals was explored. The electrophoretic patterns of fibroblast ASA from the IIIa and IVa individuals differ in degree of phosphorylation. Furthermore, fibroblast ASA from IIIa individuals lacks an N -linked glycan found in ASA from IVa individuals. In addition, differences in peptide and/or posttranslational modification unrelated to the N -linked carbohydrate or phosphorylation exist between the fibroblast ASA from IIIa and IVa individuals. The finding that both fibroblasts and platelets exhibit related electrophoretic isoform patterns characteristic of the donor's ASA type allows for the use of fibroblasts to study the impact of ethanol on the metabolism of cells possessing different ASA types. 相似文献
23.
应用标准微电极技术,研究了关附甲素对豚鼠右心室乳头肌动作电位最大除极速率(Vmax)的频率依赖性抑制作用(RDB),并与美西律,奎尼丁,劳卡尼进行了比较. 在相同刺激间隔(300 ms),产生50%左右RDB的药物浓度下,美西律的RDB开始最快,其第2个Vmax所产生的抑制已占RDB的64%,奎尼丁,劳卡尼和关附甲素的RDB开始速率常数分别为每个动作电位0.165, 0.076和0.136. 美西律,奎尼丁,劳卡尼和关附甲素产生RDB的恢复时间常数分别为1.4, 9.0, 18.2和44.0 s,而且它们的恢复时间常数是不依赖于药物浓度而变化的,结果提示,关附甲素是一个慢动力学钠通道阻滞剂. 相似文献
24.
Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine 总被引:1,自引:0,他引:1
L. C. Kirkwood R. L. Nation & A. A. Somogyi 《British journal of clinical pharmacology》1997,44(6):549-555
Aims Using human liver microsomes from donors of the CYP2D6 poor and extensive metabolizer genotypes, the role of individual cytochromes P-450 in the oxidative metabolism of dihydrocodeine was investigated.
Methods The kinetics of formation of N- and O -demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P-450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti-CYP2D6) antibodies were studied.
Results Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N -demethylation derived from the single enzyme Michaelis-Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N -demethylation in both extensive and poor metabolizers. The CYP3A inducer, α-naphthoflavone, increased N -demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar K m values. The kinetic constants for O -demethylation were significantly different in extensive and poor metabolizers. The extensive metabolizers had a mean intrinsic clearance to dihydromorphine more than ten times greater than the poor metabolizer. The CYP2D6 chemical inhibitors, quinidine and quinine, and LKM1 antibodies inhibited O -demethylation in extensive metabolizers; no effect was observed in microsomes from a poor metabolizer.
Conclusions CYP2D6 is the major enzyme mediating O -demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A. 相似文献
Methods The kinetics of formation of N- and O -demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P-450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti-CYP2D6) antibodies were studied.
Results Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N -demethylation derived from the single enzyme Michaelis-Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N -demethylation in both extensive and poor metabolizers. The CYP3A inducer, α-naphthoflavone, increased N -demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar K
Conclusions CYP2D6 is the major enzyme mediating O -demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A. 相似文献
25.
The effect of Cyclosporin A (CsA) on prostaglandin E2 (PGE2 ) production in human gingival fibroblasts challenged with tumor necrosis factor alpha (TNF-α) was studied. TNF-α (1-100 ng/ml) dose-dependently stimulated PGE2 ; formation in 24 h cultures. CsA (1-100 ng/ml) did not induce PGE2 ; formation itself but potentiated TNF-α induced PGE; formation in gingival fibroblasts in a manner dependent on the concentrations of both CsA and TNF-α. TNF-α (10 ng/ml) stimulated the release of [3 H]-arachidonic acid (A.A) from prelabelled fibroblasts that was potentiated by CsA (100 ng/ml). Addition of exogenous unlabelled AA (5-20 μM/ml) to the cells resulted in enhanced PGE2 : formation that was not potentiated by CsA (100 ng/mi). Furthermore. CsA (100 ng/ml) did not further increase the level of cyclooxygenase-2 mRNA induced by TNF-α (10 ng/ml). although PGE2 formation was enhanced. The results indicate that CsA and TNF-α act in concert on PGE2 formation in gingival fibroblasts. which may be of importance in the pathogenesis of gingival overgrowth induced by the drug. 相似文献
26.
The role of proteolytic enzymes in the hCG-induced increase in testicular vasopermeability and neutrophil extravasation was studied using protease inhibitors. An intra-testicular injection of hCG together with incubation medium conditioned by polymorphonuclear leucocytes (PMNs) caused a significant increase in vasopermeability and a coincident extravasation of PMN's from the postcapillary venules in the rat testis. When p-aminobenzamidine, a serine protease inhibitor which inhibits urokinase-type plasminogen activator, was administered together with hCG in the incubation medium, both the permeability increase and PMN extravasation were prevented. Aprotinin, another serine protease inhibitor, and Eglin C, a specific neutrophil elastase and cathepsin G inhibitor were, however, without effect. None of these inhibitors caused any non-specific vascular effects in the testis at the concentrations used. These results support the concept that the hCG-induced increase in vasopermeability in the rat testis is related to extravasation of PMNs and suggest that urokinase-type plasminogen activator is involved in migration of these cells through the postcapillary venular walls. 相似文献
27.
Rolf W. Hartmann Martin Frotscher Dorothea Ledergerber Gerald A. Wchter Gertrud L. Grün Tom F. Sergejew 《Archiv der Pharmazie》1996,329(5):251-261
In search of potential drugs for the treatment of estrogen- and androgen-dependent cancer as well as the prophylaxis of metastases, tetralones, tetralins, and dihydronaphthalenes bearing a OCH3 substituent at the benzene nucleus and an imidazol-4-yl, imidazol-1-yl, or 1,2,4-triazol-1-yl substituent in 2-position were synthesized with and without C1-spacer between the rings (compounds 2 – 26 ). The compounds were tested in vitro for inhibition of the three target enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA2 (citrated human whole blood). To examine selectivity, some compounds were further tested in vitro for inhibition of P450 18 (bovine adrenal mitochondria), P450 see (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vivo, selected compounds were examined in Sprague Dawley rats regarding P450 TxA2 inhibition, reduction of plasma testosterone concentration, antiuterotrophic activity (inhibition of the uterotrophic activity of androstenedione), reduction of plasma estradiol concentration (pregnant mares' serum gonadotropin-primed rats), and mammary tumor inhibiting activity (dimethylbenzanthracene-induced tumor; pre- and postmenopausal model). In the series of imidazol-4-yl compounds, which represent a novelty in the field of azole inhibitors of steroidogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 were found: 7-OCH3-2-(imidazol-4-ylmethylene)-1-tetralone ( 4 ) and 7-OCH3-2-(imidazol-4-ylmethyl)-tetralin ( 12 ) are among the most potent inhibitors of P450 arom in vitro known so far. Compound 4 is a selective inhibitor, whereas 12 shows in addition strong inhibition of P450 17. In contrast to 12 , the 6-OCH3 derivative (compound 11 ) is a selective inhibitor of P450 17, being 50 times more potent than ketoconazole. Some imidazol-1-yl compounds show a marked inhibition of P450 TxA2: 2-(imidazol-1-ylmethyl)-1-tetralone ( 13 ) is a selective inhibitor of P450 TxA2, whereas 7-OCH3-2-(imidazol-1-ylmethyl)-tetralin ( 17 ) as well as 2-(imidazol-1-ylmethyl)-tetralin ( 16 ) and 7-OCH3-2-imidazol-1-yl-3,4-dihydronaphthalene ( 25 ) additionally show strong inhibition of P450 arom and P450 17. Regarding the other steroidogenic P450 enzymes as well as corticosterone formation, the compounds show only little inhibitory activity. Aldosterone formation, however, is inhibited at low concentrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit aldosterone synthesis less than the well known inhibitor of P450 arom fadrozole. The compounds show activity in the aforementioned in vivo tests. 相似文献
28.
Satomi Kitagawa Yu Yamaguchi Emiko Sameshima Masaru Kunitomo 《Clinical and experimental pharmacology & physiology》1994,21(12):963-970
1. Endothelium-dependent relaxation in response to acetylcholine (ACh) and the calcium ionophore A 23187 was examined in aorta, coronary, basilar and renal arteries isolated from Watanabe heritable hyperlipidaemic (WHHL) rabbits of 2, 6 and 12 months of age, with normolipidaemic heterozygous WHHL rabbits as controls. 2. In the rings of WHHL rabbit aortae and coronary arteries preconstricted with vasoconstrictors, endothelium-dependent relaxation in response to ACh was attenuated with age compared to the heterozygous WHHL rabbits. A significant negative correlation was found between the total cholesterol content and the relaxation response to ACh in the aortae or coronary arteries from 6 and 12 month old WHHL rabbits. 3. In the rings of basilar arteries, endothelium-dependent relaxations to ACh were not modified with age. Similarly, in the rings of renal arteries, the relaxation response to ACh was not changed with age, but in the 6 and 12 month preparations, after the age of 6 months, a contraction following the relaxation appeared at higher concentrations of ACh (10?7 to 10?6 mol/L). The contraction was endothelium-dependent and inhibited by indomethacin. 4. A 23187-induced endothelium-dependent relaxations were also markedly attenuated in the aorta and significantly in the coronary artery with age. 5. Endothelium-independent relaxation to sodium nitroprusside was not changed in all arteries from WHHL rabbits of different ages. 6. These findings indicate that in the aorta and coronary artery of the WHHL rabbit, the endothelium-dependent relaxation to ACh and A 23187 becomes impaired with increasing age (i.e., with the progression of cholesterol deposition in the arterial wall) but is preserved in the basilar and renal artery. 相似文献
29.
建立了小鼠脾脏、胸腺细胞体外转化微量培养系统,确定了最佳实验条件.点蜡法充CO_2,简便易行,效果好.RPMI-1640培养基内补充胎牛血清,其浓度确定为在脾细胞培养为10%,在胸腺细胞培养为20%.脾细胞培养最适细胞密度为2~5×10~6/ml,Con A最适量为2~4μg/培养;胸腺细胞培养细胞最适密度为1×10~7/ml,Con A最适量为2~4μg/培养.两种已知免疫活性的药物在脾细胞培养体系有明确肯定的反应. 相似文献
30.
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