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31.
Haeberlin Barbara Rubas Werner Nolen III Harold W. Friend David R. 《Pharmaceutical research》1993,10(11):1553-1562
Dexamethasone--D-glucuronide is a potential prodrug for colonic delivery of the antiinflammatory corticosteroid dexamethasone. Previous studies [T. R. Tozer et al., Pharm. Res. 8:445–454 (1991)] indicated that a glucoside prodrug of dexamethasone was susceptible to hydrolysis in the upper gastrointestinal tract. Resistance of dexamethasone--D-glucuronide to hydrolysis in the upper gastrointestinal tract was therefore assessed. Conventional, germfree, and colitic rats were used to examine enzyme levels along the gastrointestinal tract to compare the stability of two model substrates (p-nitrophenyl--D-glucoside and --D-glucuronide) and to evaluate the prodrug dexamethasone--D-glucuronide. Hydrolytic activity was examined in the luminal contents, mucosa, and underlying muscle/connective tissues in all three types of rats. Enzymatic activity (-D-glucosidase and -D-glucuronidase) was greatest in the lumen of cecum and colon of conventional rats. In contrast, germ-free rats exhibited relatively high levels of -D-glucosidase activity (about 80% of total activity in the conventional rats) in the proximal small intestine (PSI) and the distal small intestine (DSI). Rats with induced colitis (acetic acid) showed reduced levels of luminal -D-glucuronidase activity in the large intestine; however, -D-glucosidase activity was relatively unchanged relative to that of the conventional rat. Mucosal -D-glucuronidase activity was significantly lower in the colitic rats compared with that in the conventional animals. Despite reduced luminal levels of -D-glucuronidase activity in the colitic rats, there was still a sharp gradient of activity between the small and the large intestines. Permeability of the glucoside and glucuronide prodrugs of dexamethasone through a monolayer of Caco-2 cells was relatively low compared to that of dexamethasone. The results indicate that dexamethasone--D-glucuronide should be relatively stable and poorly absorbed in the upper gastrointestinal tract. Once the compound reaches the large intestine, it should be hydrolyzed to dexamethasone and glucuronic acid. Specificity of colonic delivery in humans should be even greater due to lower levels of -D-glucuronidase activity in the small intestine compared with that in the laboratory rat. 相似文献
32.
采用免疫组化的方法,选取地塞米松和P物质分别代表内分泌和神经因素,研究了它们单独作用及共同作用时对L4、L5脊神经节和脊髓后角Ⅰ、Ⅱ层CGRP免疫反应性的影响,并用显微图像分析系统进行相对定量分析处理;同时用热板测痛法测量了痛阈的变化。结果表明①地塞米松尾静脉注射后痛阈升高,L4、L5脊神经节和脊髓后角Ⅰ、Ⅱ层CGRP免疫反应减弱,提示地塞米松可能有抑制痛觉信息一级传入的作用;②P物质鞘内注射后痛阈降低,L4、L5脊神经节和脊髓后角Ⅰ、Ⅱ层CGRP免疫反应增强,P物质可能有促进痛觉信息一级传入的作用;③地塞米松和P物质共同作用后痛阈有所降低,L4、L5脊神经节和脊髓后角Ⅰ、Ⅱ层CGRP免疫反应强度介于二物质单独作用之间,似乎二者的作用发生了“中和”,但免疫反应仍较对照组增强。结果提示痛觉的一级传入可能受神经-内分泌相互作用的影响。 相似文献
33.
大鼠内毒素性休克肺ET-1 mRNA和bcl-2的表达及山莨菪碱、地塞米松对肺的保护作用 总被引:2,自引:0,他引:2
目的探讨内皮素(ET)-1 mRNA和原癌基因bcl-2在大鼠内毒素性休克肺损伤中的作用及山莨菪碱、地塞米松对肺的保护作用. 方法 24只SD大鼠随机分为4组(n=6):Ⅰ组(对照组)静注等量生理盐水;Ⅱ组(休克组)静脉注射脂多糖(LPS)5 mg/kg;Ⅲ组静注山莨菪碱4 mg/kg后0.5 h再静注LPS 5 mg/kg;Ⅳ组静注地塞米松4 mg/kg后0.5 h再静注LPS 5 mg/kg.观察5 h后取肺组织测定ET-1 mRNA和bcl-2. 结果肺组织ET-1 mRNA表达,Ⅲ、Ⅳ组与Ⅰ组比较差异无显著性,Ⅱ组与Ⅰ、Ⅲ、Ⅳ组比较差异有非常显著性(P<0.01).bcl-2阳性细胞率Ⅱ组轻微增加,Ⅲ、Ⅳ组显著增加,Ⅰ组阴性表达. 结论 ET-1 mRNA和bcl-2可介导大鼠内毒素性休克时肺的损伤.山莨菪碱和地塞米松可能是通过抑制ET-1 mRNA的表达和促进bcl-2的表达而起到对肺的保护作用. 相似文献
34.
目的 :探讨黄芩甙、地塞米松对大鼠感染性脑水肿白细胞介素 1(IL 1β)、肿瘤坏死因子α(TNF α)的影响。方法 :应用大鼠感染性脑水肿模型 ,采用干湿法、原子吸收分光光度法、ELISA测定各组脑组织水含量、钠离子含量及脑匀浆上清液中IL 1β,TNF α水平的变化 ;在光镜下观察各组脑组织的细胞形态学改变。结果 :在大鼠感染性脑水肿(感脑 )组脑水含量、钠离子、IL 1β、TNF α含量均比生理盐水 (对照 )组明显增高 (P <0 .0 1)。在黄芩甙和地塞米松两组则上述指标均下降 ,低于感脑组 (P <0 .0 5 ) ;而两组间各指标比较差异无显著性 (P >0 .0 5 ) ;脑组织水含量与IL 1β ,TNF α含量成正相关 (r分别为 0 9381,0 8349,P <0 .0 1)。对照组脑组织结构正常 ,感脑组织脑组织可见弥漫的灶性水肿区 ;黄芩甙和地塞米松组水肿明显减轻。结论 :黄芩甙、地塞米松对大鼠感染性脑水肿有保护作用 ,效果相近 ;作用机制与抑制IL 1β ,TNF α过度产生有关 相似文献
35.
目的:观察地塞米松对犬视网膜超微结构的影响。方法:取犬4只,右眼玻璃体和房水内注射盐水(为盐水组),左眼玻璃体和房水内注射地塞米松(为激素组),24h后处死,电镜观察视网膜超微结构有无改变,并与对照组进行比较。结果:盐水组和激素组与对照组比较视网膜超微结构无改变。结论:地塞米松对犬视网膜超微结构无影响。,Objective:To observe the influence of dexamethasone on dog's retina ul-trastructure. Methods:We injected normal saline into the vitreous body and aqueous humor ofthe right eyes while injecting dexamethasone into the left eyes in four dogs. After 24 hours, wekilled the dogs to observe ff their retina ultrastructure had altered, and compared with the re-sults of the control group. Results :In comparision with the control group,there was any changein retina ultrastructure in neither the normal saline group nor the hormone group. Conclusion:Dexamethasone has no influence on the retina uitrastructure of dogs. 相似文献
36.
地塞米松·葡聚糖的合成及其肠内容物中的转释特性 总被引:13,自引:5,他引:8
目的 探讨地塞米松·葡聚糖 (平均相对分子质量 5× 10 5 )作为结肠定位地塞米松前体药物的可能性 .方法 以琥珀酸酐为交联剂 ,合成地塞米松前体药物 .将前体药物与大鼠胃肠道不同部位内容物一起孵育 ,检测地塞米松的释放情况 .结果 经高效液相色谱 (HPL C)分析 ,10 0 mg所合成的前体药物中载有地塞米松 9.2 mg.在 16 0 min的孵育时间内 ,前体药物在大鼠结肠及盲肠内容物中释放出地塞米松的量是其在小肠近端及小肠远端内容物中释放量的 2 .7倍 ,在胃内容物中无地塞米松的释放 .结论 地塞米松前体药物能在盲肠、结肠内容物中特异地释放出地塞米松 ,因此地塞米松·葡聚糖 (平均相对分子质量 5× 10 5 )可以作为结肠定位地塞米松前体药物 ,有选择性地将地塞米松运送到结肠 相似文献
37.
地塞米松诱导幼龄大鼠胸腺细胞凋亡模型 总被引:4,自引:0,他引:4
目的:建立一个比较实用且成型时间短的地塞米松诱导大鼠胸腺细胞凋亡模型。方法:给幼龄大鼠(4周 ̄5周)腹腔注射地塞米松(0.02g/kg)采用形态学(光镜和电镜)、DNA琼脂糖凝胶电泳、流式细胞光度分析等方法研究3、6、9、15、24h等不同注射时间胸腺细胞凋亡变化。结果:在15h内,地塞米松诱导的大鼠胸腺细胞凋亡百分率随时间延长,凋亡发生率从6.2%逐渐增至58.5%,注射地塞米松15h,在光镜和 相似文献
38.
Stephen J Getting Roderick J Flower Mauro Perretti 《British journal of pharmacology》1997,120(6):1075-1082
- The role played by endogenous lipocortin 1 in the anti-migratory action exerted by dexamethasone (Dex) on monocyte recruitment in an in vivo model of acute inflammation was investigated by use of several neutralizing polyclonal antibodies raised against lipocortin 1 or a lipocortin 1-derived N-terminus peptide (peptide Ac2-26). The efficacy of peptide Ac2-26 in inhibiting monocyte and polymorphonuclear leucocyte (PMN) recruitment was also tested.
- Intraperitoneal (i.p.) injection of zymosan A (1 mg) produced a time-dependent cell accumulation into mouse peritoneal cavities which followed a typical profile of acute inflammation: PMN influx was maximal at 4 h post-zymosan (between 15 and 20×106 cells per mouse), and this was followed by an accumulation of monocytes which peaked at the 24 h time-point (between 10 and 15×106 cells per mouse).
- Dex administration to mice reduced zymosan-induced 4 h PMN infiltration and 24 h monocyte accumulation with similar efficacy: approximately 50% of inhibition of recruitment of both cell types was achieved at the dose of 30 μg per mouse (∼1 mg kg−1, subcutaneously (s.c.)). Maximal inhibitions of 64% and 67% on PMN and monocyte recruitment, respectively, were measured after a dose of 100 μg per mouse (∼3 mg kg−1, s.c.).
- Dex (30 μg s.c.) inhibited monocyte (53%) and PMN (69%) accumulation in response to zymosan application in mice which had been treated with a non-immune sheep serum (50 μl s.c.). In contrast, the steroid was no longer active in reducing cell accumulation in mice which had been passively immunized against full length human recombinant lipocortin 1 (serum LCS3), or against lipocortin 1 N-terminus peptide.
- Treatment of mice with vinblastine (1 mg kg−1, intravenously (i.v.)) produced a remarkable leucopenia as assessed 24 h after administration. This was accompanied by a 60% reduction in 4 h-PMN influx, and by a 27% reduction in 24 h-monocyte accumulation, measured after zymosan administration. The inhibitory effect of Dex on monocyte recruitment was not significantly modified in vinblastine-treated mice, with 36% and 57% of inhibition calculated at the dose of 30 μg Dex, and 70% and 60% of inhibition at 100 μg Dex, in vehicle- and vinblastine-treated mice, respectively.
- Treatment of mice with peptide Ac2-26 dose-dependently attenuated PMN influx at 4 h post-zymosan with a significant effect at 100 μg per mouse (45% of inhibition, n=9, P<0.05) and a maximal effect of 61% inhibition at the highest dose tested of 200 μg s.c. (n=14, P<0.05). No effect of peptide Ac2-26 (200 μg s.c.) was seen on zymosan-induced 24 h monocyte recruitment. In contrast, administration of 200 μg peptide Ac2-26 every 6 h was effective in reducing the number of monocytes harvested from the inflamed peritoneal cavities at 24 h post-zymosan: 9.40±0.58×106 monocytes per mouse (n=13) and 5.74±0.34 monocytes per mouse (n=14) in vehicle- and peptide Ac2-26-treated mice, respectively (P<0.05).
- Finally, peptide Ac2-26 produced a concentration-dependent inhibition of the rate of phagocytosis of mouse resident peritoneal macrophages as measured by flow cytometry, with a maximal reduction of 34% at the highest concentration tested of 100 μg ml−1 (n=8 experiments performed in duplicate; P<0.05).
- In conclusion, this study suggests that in vivo monocyte recruitment during acute inflammation is, at least in part, under the negative modulatory control of endogenous lipocortin 1 (as seen after administration of Dex by using the specific antisera) and exogenous lipocortin 1 mimetics (as observed with peptide Ac2-26). In addition to the neutrophil, we can now propose that the monocyte also can be a target for the in vivo anti-inflammatory action of lipocortin 1.
39.
Dexamethasone effects on cerebral protein synthesis prior to and following hypoxia-ischemia in immature rat 总被引:3,自引:0,他引:3
We hypothesized that the neuroprotection against cerebral hypoxic-ischemic damage observed with dexamethasone treatment in immature rats is related to a change in cerebral protein synthesis. Six-day-old Wistar rats were injected with either vehicle (10 ml/kg) or dexamethasone (0.1 mg/kg) 24 h prior to cerebral hypoxia-ischemia. Local cerebral protein synthesis (incorporation of 14C-leucine into proteins) was measured in 7-day-old rats during normoxia, during hypoxia-ischemia, and after hypoxia-ischemia which was produced with right carotid artery ligation and 2-h exposure to 8% O2. In normoxic controls, cerebral protein synthesis was similar in dexamethasone and vehicle-treated animals. During hypoxia-ischemia, local cerebral protein synthesis decreased markedly (p < 0.0001) in ischemic regions ipsilateral to the occlusion, irrespective of treatment. After hypoxia-ischemia, protein synthesis declined even further in vehicle-treated animals. Reductions in protein synthesis were substantially more severe in vehicle- than dexamethasone-treated animals, particularly after hypoxia-ischemia (p < 0.0001). Thus, neuroprotection with dexamethasone is not related to a reduction in basal levels of cerebral protein synthesis, but is associated with an improved protein synthesis during and following hypoxia-ischemia. 相似文献
40.
平阳霉素联合地塞米松治疗颌面部大面积海绵状血管瘤 总被引:4,自引:0,他引:4
目的:观察平阳霉素(PYM)联合地塞米松(DXM)治疗颌面部大面积海绵状血管瘤的临床疗效和不良反应。方法:对9例临床确诊的颌面部范围6cm×7cm~10cm×12cm之间的大面积海绵状血管瘤,采用每周1次多点多方向瘤腔内注射药物,比较治疗前后患者的反应和肿瘤的形成变化。结果:全部病例肿瘤消失,无明显不良反应,经8个月~46个月观察,临床治愈率为100%。结论:PYM联合DXM能够治愈颌面部大面积海绵状血管瘤,具有完整保存组织正常形态和功能的特点,克服了单独使用PYM带来的不良反应,提示两药在治疗上有协同作用。 相似文献