硫酸妥布霉素注射液的肾毒性观察

硫酸妥布霉素注射液的肾毒性观察杨亚东杨友成（河南南阳市第一人民医院，南阳４７３０００）我院自使用硫酸妥布霉素注射液（商品名：泰星注射液）于临床以来，对药物的肾毒性进行了临床观察，现报告如下。１临床资料及方法全部采用入院时尿蛋白分析正常的肺部感染（包括...     

川芎嗪对鼠肺纤维化组织钙含量及钙调素活性的影响

目的：观察川芎嗪对博莱霉素所致鼠肺纤维化组织钙含量及钙调素活性的影响，探讨川芎嗪防治肺纤维化的机制。方法：将32只SD大鼠一次性气管内注入博莱霉素A5制备肺纤维经模型，随机分为2组：模型组(n=16)及川芎嗪组（n=16)，分析测定各组给药后d14,d28肺组织钙含量及钙调素活性，并与正常对照组（n=8)比较。结果：模型组肺组织钙含量及钙调素活性较正常组明显增高（P＜0．01），川芎嗪组各期钙含量及钙调素活性均低于模型组（P＜0．05）同时组织病理学显示肺泡炎及肺纤维化程度均较模型组明显减轻。结论：川芎嗪防治鼠肺纤维化的机制可能与降低肺组织钙含量及钙调素活性有关。     

青藤碱对实验性多柔比星肾病大鼠尿蛋白、IL-6影响的研究

目的：观察白细胞介素-6（IL-6）在多柔比星肾病大鼠肾组织及尿中的表达及青藤碱对其表达的影响。方法：雄性Wistar大鼠50只。随机分为正常组（10只）,肾病组（40只）。肾病组大鼠一次性尾静脉注射多柔比星5mg/kg,制备MCNS模型。注射后第7天检测所有大鼠24h尿蛋白定量,尿蛋白〉30mg/24h者为MCNS模型成功。采用酶联免疫吸附法检测各组大鼠肾组织及不同时期尿液中IL-6的表达。结果：①肾病组大鼠尿蛋白排泄量逐渐增加,各时期与正常组比较,均有显著性差异（P〈0.01）;②肾病组大鼠肾组织及尿中IL-6表达较正常组明显增加,治疗组IL-6的表达也增高,但较肾病组为低;3肾病组在不同时期尿及肾组织中IL-6的变化与24 h尿蛋白的排泄量呈正相关（P〈0.01）;4肾组织与尿中IL-6呈正相关（P〈0.01）。结论：①IL-6在MCNS尿及肾脏组织中存在异常表达,青藤碱可减少蛋白尿减轻肾损害;②IL-6可能是蛋白尿发生的原因之一。     

贝那普利对阿霉素肾病大鼠肾脏保护作用的研究

目的：观察贝那普利对阿霉素肾病大鼠形态学和肾皮质结蛋白表达改变的影响,探讨其对足细胞损伤的保护作用。方法：SD大鼠随机分为正常对照组、阿霉素肾病组和贝那普利治疗组。分别于给药4、7周后留取标本,检测24h蛋白尿、血肌酐,肾组织行形态学检查,应用免疫组化法检测肾皮质中结蛋白表达。结果：肾病组大鼠尿蛋白排泄明显高于对照组（P〈0．05）,且有明显的肾小球足细胞损伤的病理学改变。肾皮质结蛋白表达增加（P〈0．05）。贝那普利治疗后肾脏病理明显减轻,结蛋白表达降低（P〈0．05）。结论：在阿霉素肾病中,贝那普利可改善肾小球足细胞的损伤程度,降低结蛋白表达,对肾小球起保护作用。     

川芎嗪治疗后肝纤维化组织中Ⅰ型胶原平均光密度表达的比较

目的：观察川芎嗪对大鼠实验性肝纤维化作用的治疗效果，并探讨其作用机制。方法：采用四氯化碳（CCL4）诱导大鼠肝纤维化模型，将实验动物随机分为正常对照组（N）5只、肝纤维化模型组（H）20R、川芎嗪治疗组（TMP）20只，除正常对照组以外其它两组均给予40％四氯化碳（CCL4）花生油溶液0．3ml／100g腹腔注射，每周2次，共6周。川芎嗪组于肝纤维化模型建立后给予盐酸川芎嗪（TMP）60mg／kg经口灌胃，1次／d，连续治疗60天；其余两组同时给予同等剂量的生理盐水。于60天后分别处死各组大鼠。用HE石蜡组织切片观察各组光镜下肝组织结构变化；用免疫组织化学方法染色观察肝组织中Ⅰ型胶原（Collagen typeⅠ，CoⅠ）表达的变化，并利用计算机图像分析技术测量正常对照组、肝纤维化模型组及川芎嗪治疗组CoⅠ表达的平均光密度。结果：免疫组织化学S-P法染色显示TMP能明显抑制肝组织中CoⅠ水平的表达，CoⅠ在川芎嗪治疗组中的表达明显低于肝纤维化模型组，CoⅠ在川芎嗪治疗组与肝纤维化模型组之间有显著性差异（P〈0．01）；CoⅠ在川芎嗪治疗组与正常对照组中呈高表达，CoⅠ在川芎嗪治疗组与正常对照组之间差异无显著性（P〉0．05）。结论：川芎嗪对四氯化碳（CCL4）诱导的大鼠实验性肝纤维化有明显的保护和治疗作用。     

银杏达莫注射液与川芎嗪对实验糖尿病肾病大鼠NO的作用

研究银杏达莫注射液（杏丁）、川芎嗪对实验糖尿病大鼠肾脏NOS系统的作用。方法：以链脲佐菌素（STZ）制备动物模型。实验大鼠分为四组：糖尿病对照组A（16只,分早、晚期对照各8只）,杏丁治疗糖尿病肾病组B（16只,分早、晚期对照各8只）,川芎嗪治疗糖尿病肾病组C（16只,分早、晚期对照各8只）,正常组D（16只,分早、晚期对照各8只）。分别测定第1周末尿微白蛋白（UAE）、肌酐清除率（Ccr）,各期尿及肾皮质NO2^-／NO3^-、肾皮质NOS活性、肾脏病理分析。结果：①第1周末肌酐清除率（Ccr）、尿微白蛋白（UAE）在A、B、C组均明显升高;②A组早期尿及肾皮质NO2^-／NO3^-、’肾皮质NOS活性明显升高,晚期明显下降;③B组、c组杏丁、川芎嗪治疗后均能使尿及肾皮质NO2^-／NO3^-、肾皮质NOS活性升高;④与A组比较B、C组早期治疗肾小球FN含量明显增加,B、C组晚期治疗则明显下降。结论：①糖尿病肾病早期NO增加,随之下降。②杏丁、川芎嗪能作用于糖尿病患者的NOS系统,使NO增加。杏丁、川芎嗪使NO增加的结果导致早期糖尿病肾脏的损害加重,晚期则有保护肾功能的作用。实验结果为临床正确使用杏丁、川芎嗪提供了理论依据。     

锌金属硫蛋白对镉中毒小鼠肾损伤的修复作用

目的：研究锌金属硫蛋白（Zn-MT）对镉中毒小鼠肾损伤的修复作用。方法：以昆明种小鼠作为研究对象，染镉14d建立亚急性镉中毒模型，随后经口给予Zn-MT。收集24h尿液，测定尿N－乙酰－β－D－氨基葡萄糖苷酶（NAG酶）活性作为衡量肾脏损伤程度的一项指标，同时电镜观察肾组织形态学变化；测定并分析肾组织上清液中脂质过氧化代谢产物一丙二醛（MDA）水平、超氧化物歧化酶（SOD）、谷胱甘肽过氧化酶（GSH－Px)活性。结果：Zn-MT可明显降低肾组织中MDA水平，使肾组织中SOD、GSH－Px活力有一定程度的恢复，此时尿NAG酶活性降低表明肾损伤程度减轻，且上述作用呈明显的剂量－反应关系；电镜下观察到给予Zn-MT后肾组织形态学病变有所减轻。结论：Zn-MT可对镉中毒小鼠肾组织脂质过氧化损伤起到一定的修复作用。     

造影剂对单侧输尿管梗阻大鼠血中性粒细胞明胶酶相关脂质运载蛋白及肾 Bax mRNA的影响

目的：研究造影剂对单侧输尿管梗阻大鼠血中性粒细胞明胶酶相关脂质运载蛋白（ NGAL）及肾Bax mRNA的影响。方法 SD大鼠制备可复性的完全性左侧输尿管梗阻模型,随机分为假手术组、对照组与造影剂组;检测肾形态学变化、血NGAL、肾小管细胞凋亡及肾组织Bax mRNA的表达。结果造影组在注射后第1天,大鼠左右肾体积、肾实质厚度和重量差异显著,造影剂组NGAL含量及Bax mRNA表达与对照组比较显著升高（ P＜0．05）,注射药物后第1天及第3周造影剂组大鼠血清NGAL及Bax mRNA与对照组比较均显著升高（ P＜0．05）,注射药物后第3周后造影剂组大鼠左侧肾小管细胞凋亡与模型组比较显著升高（ P＜0．05）。结论造影剂对单侧肾积水大鼠肾有一定的损伤作用,Bax介导的肾小管细胞凋亡可能是重要机制。     

槲皮素对环孢素A所致肾毒性的保护作用

目的：观察槲皮素（quercetin,Que）对环孢素A（cyclosporineA,CsA）肾毒性的影响。方法：大鼠28只随机分为4组：正常对照组、Que（40mg/kg）组、CsA（40mg/kg）模型组、CsA（40mg/kg）＋Que（40mg/kg）组。以上各组动物每天给药1次,连续给药15d。各组大鼠于给药d10及d14分别置于代谢笼中收集24h尿液检测尿蛋白含量和尿N-乙酰-β-D-氨基葡萄糖苷酶（NAG）活性;于末次给药4h后处死大鼠,测血清BUN、Cr和肾组织还原型谷胱甘肽（GSH）、丙二醛（MDA）含量及超氧化物歧化酶（SOD）、谷胱甘肽-S-转移酶（GST）、谷胱甘肽过氧化物酶（GSH-Px）、过氧化氢酶（CAT）活性;肾组织10%甲醛溶液固定,石蜡包埋,HE染色,光镜观察其形态学变化。结果：Que对CsA所致的尿蛋白、尿NAG、BUN、Cr、肾组织MDA含量的升高均有显著降低作用,并明显增加肾组织GSH含量及GST、SOD、GSH-Px、CAT活性,对CsA引起的肾小管病理性损伤也有较好的保护作用。结论：Que对CsA所致的肾脏毒性具有明显的保护作用。     

颐和春口服液对肾阳虚大鼠肾损伤的保护作用

目的观察颐和春口服液对肾阳虚大鼠肾功能的保护作用,并初步探讨其机制。方法用腺嘌呤灌胃制备肾阳虚大鼠模型。实验分为正常对照组、肾阳虚模型组、肾阳虚阳性药物治疗组和肾阳虚颐和春治疗组。给药10d后观察颐和春口服液对肾阳虚大鼠体重、肾指数、肾功能及肾形态学改变,并从凋亡和抗氧化方面探讨其保护机制。HE染色观察肾形态学改变、生化法测定血清谷胱甘肽过氧化物酶（GSH-PX）、血尿素氮（BUN）和肌酐（Cr）,末端标记法测定肾组织凋亡。结果颐和春可改善肾阳虚引起的大鼠体重下降,使肾指数增加,降低血清肌酐（Cr）和尿素氮（BUN）水平,改善肾形态学表现,减轻肾小管上皮细胞凋亡,提高血清谷胱甘肽过氧化酶（GSH-PX）活性。结论颐和春口服液对肾阳虚大鼠肾功能有明显的保护作用,可能与提高抗凋亡和抗氧化能力有关。     

Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects (8): Protective effect of pyridoxal-5'-phosphate against tobramycin nephrotoxicity

We investigated the effect of pyridoxal-5'-phosphate (PALP) on tobramycin (TOB)-induced nephrotoxicity in rats. Paper electrophoretic analysis showed that in the mixture of TOB and PALP, the spot corresponding to TOB alone almost disappeared and the spot associated with TOB overlapped with that associated with PALP, although the spots of TOB alone and PALP alone were observed as single spots on the cathode and anode sides, respectively. The overlapping of both compounds indicated that TOB could directly interact with PALP in vitro. In the assay of TOB binding to renal brush border membranes (BBMs), PALP significantly inhibited the binding of TOB to BBMs by interacting with TOB outside of BBMs vesicles. Intrarenal TOB levels in rats receiving TOB and PALP were lower than those in rats given TOB alone. Combination with PALP markedly suppressed the urinary protein content, urinary N-acetyl-beta-D-glucosaminidase activity and blood urea nitrogen content elevated by TOB, and also reduced the degree of TOB-induced renal tubular cell necrosis. These results indicate that PALP protects the rat kidneys from TOB-induced nephrotoxicity and that the protective effect of PALP may be due to the reduced intrarenal TOB concentration and less binding to TOB to BBMs induced by the interaction of PALP with TOB.     

Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects (4). Effects of tobramycin alone and in combination with latamoxef on the stability of rat kidney lysosomal membranes

Effects of tobramycin (TOB) alone and in combination with latamoxef (LMOX) on the stability of rat kidney lysosomal membranes were investigated. Rats were injected with doses of TOB (90 mg/kg/day, s.c.) alone. LMOX (2,000 mg/kg/day, s.c.) alone or TOB (90 mg/kg/day, s.c.) and LMOX (2,000 mg/kg/day, s.c.) for 5 consecutive days. The rat kidney lysosomes were isolated on the 1st, 3rd and 5th days and incubated in a 0.25 M sucrose solution containing 1 mM EDTA (pH 7.0) at 37 degrees C for 20 min. After incubation, the activity of N-acetyl-beta-D-glucosaminidase (NAG) released from lysosomes was measured, and the percent NAG release was calculated as an index of the stability of lysosomal membranes. The percent releases of NAG from lysosomes of TOB alone-treated rats were 40 and 50% greater than those of normal rats on the 1st and 3rd days, respectively. On the other hand, treatment with TOB and LMOX suppressed the NAG release from lysosomes with TOB alone by about 80 to 100%. There were insignificant slight increases in the percent NAG release in LMOX alone-treated rats on the 3rd and 5th days. In addition, the in vitro study indicated that incubation of the lysosomal fraction from kidneys of normal rats with TOB (30 micrograms/ml) significantly increased the NAG release, compared with that of the non-treated lysosomal fraction. However, the preincubated mixture of TOB (30 micrograms/ml) and LMOX (50 micrograms/ml) in vitro significantly suppressed the release of NAG from lysosomes by 85%. These results suggest that the suppression of the releases of NAG from lysosomes by the combination of TOB with LMOX may contribute to the protective effect of LMOX against TOB nephrotoxicity.     

Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects (9): Protective effect of inositol hexasulfate against tobramycin-induced nephrotoxicity

We examined the protective effect of inositol hexasulfate (IS6) against tobramycin (TOB)-induced nephrotoxicity. In the electrophoretic analysis, TOB alone and IS6 alone were observed as single spots on the cathode and anode sides, respectively. However, in the mixture of TOB and IS6 preincubated at 37 degrees C for 3 hr, the tailing of the spots of TOB and IS6 were observed from the origin to the cathode and the anode sides, respectively, and the overlapping of the spots of TOB and IS6 was recognized at the origin. These results indicated that TOB directly interacted with IS6 in vitro. Assay of TOB binding to rat kidney brush border membranes (BBMs) indicated that IS6 inhibited the binding of TOB to BBMs through an interaction of TOB and IS6. No significant reduction in intrarenal TOB level was observed in the rats given TOB (90 mg/kg, s.c.) and IS6 (153 or 610 mg/kg, s.c.). However, the treatment of rats with a combination of TOB and IS6 reduced the degree of necrosis of renal tubular cells and also suppressed the increases in urinary protein, urinary enzyme activities, blood urea nitrogen and plasma creatinine induced by TOB. Additionally, we detected a complex of TOB and IS6 in the urine of rats given both compounds simultaneously. These results indicate that IS6 protects against TOB-induced nephrotoxicity and that the protective action of IS6 may be due to the inhibition of TOB binding to BBMs through an interaction of TOB with IS6.     

bFGF对慢性酒精中毒大鼠血清GPT、GOT活性的影响

目的：观察碱性成纤维细胞生长因子（bFGF）对慢性酒精中毒大鼠血清GPT、GOT活性的影响,探讨bFGF对酒精中毒所致的肝损伤是否具有保护作用。方法：选择成年Wistar雄性大鼠,采用白酒灌胃建立慢性酒精中毒模型,慢性酒精中毒模型建立成功的大鼠采用随机抽签法分为酒精中毒对照组、NS对照组和bFGF治疗组。另10只不灌白酒作为正常对照组。bFGF治疗组大鼠白酒灌胃的同时,1h后按12μg/kg剂量肌内注射,共14d。各组大鼠到相对应的时间点取血测定血清谷丙转氨酶（GPT）、谷草转氨酶（GOT）活性。结果：慢性酒精中毒后大鼠血清GPT、GOT活性比正常对照组均明显升高（P〈0.01）,用bFGF治疗酒精中毒大鼠后血清GPT、GOT活性均明显下降（P〈0.01）。结论：bFGF能降低酒精中毒大鼠后血清GPT和GOT活性,对酒精中毒所致的肝损伤具有保护作用。     

Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects (3). Protective effect of latamoxef against tobramycin nephrotoxicity and its protective mechanism

Effect of latamoxef (LMOX) against tobramycin (TOB)-induced nephrotoxicity was studied in rats. Treatment with TOB (90 mg/kg/day, s.c.) alone resulted in marked increases in the activities of urinary enzymes such as lactate dehydrogenase, N-acetyl-beta-D-glucosaminidase and lysozyme, urinary protein content and blood urea nitrogen, which peaked on the 7th or 10th day. The combination with LMOX (500, 1000 or 2000 mg/kg/day, s.c.) significantly suppressed increases in the parameters with TOB alone. The extent of this suppression roughly depended on the LMOX dosage. Although TOB alone caused pronounced histological changes such as extensive cortical proximal tubular cell necrosis, residual tubular basement membrane and cast formations in the renal cortex and medulla on the 7th day, these changes were apparently suppressed by combination with LMOX. In addition, intrarenal TOB concentrations in the rat given TOB alone were about 350, 500 and 1000 micrograms/g tissue wet weight at 3 hr, on day 3 and on day 5, respectively. On the other hand, there was a significant reduction (30-60%) in intrarenal TOB concentration by combination with LMOX. These results indicate that combination with LMOX obviously protects the rat kidney from TOB nephrotoxicity, and the protective effect may be partially due to suppression of intrarenal accumulation of TOB by LMOX.     

磷霉素对异帕米星致铜绿假单胞菌生物被膜局部感染大鼠肾毒性的影响

摘要 目的：通过磷霉素与异帕米星联合应用于铜绿假单胞菌生物被膜感染的大鼠模型，观察磷霉素对异帕米星致大鼠肾毒性的影响。方法：采用组织笼皮下埋植法建立大鼠铜绿假单胞菌生物被膜体内局部感染动物模型；大鼠随机分为4组：健康对照组、生理盐水组、阳性对照组（异帕米星300mg?kg-1）和联合用药组，每组6只；采用腹腔给药，分别检测给药前，给药2周和4周时，血清肌酐(SCr)、血尿素氮(BUN)、尿量(UPD)、尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)；4周时处死大鼠做肾组织病理标本光镜及透射电镜(TEM)观察。结果：随给药时间的延长，异帕米星组和联合用药组的SCr、BUN及NAG酶水平均增高。4周时联合用药组的SCr、BUN及NAG酶水平与对照组相比升高，但差异无统计学意义（P＞0.05），而异帕米星组与对照组、联合用药组相比显著升高（P＜0.05）。4周时的肾组织光镜观察和肾组织透射电镜观察显示：联合用药组的肾损害较异帕米星单药组显著减轻。结论：研究发现磷霉素可减轻异帕米星致肾毒性作用。     

胰岛素样生长因子-1与糖尿病大鼠肾脏病变的关系

目的:探讨胰岛素样生长因子-1(IGF-1)与糖尿病大鼠肾脏病变的关系.方法:观察链脲佐菌素(STZ)糖尿病大鼠6、10、14周空腹血糖(VBG)、血清IGF-1,24h尿白蛋白排泄率(UAER)及肾脏的病理变化,用免疫组化方法检测肾脏IGF-的表达.结果:实验组大鼠随着病程的延长,血清IGF-1较对照组显著下降,与对照组比较差异有统计学意义(P<0.01);免疫组化半定量分析显示,实验组大鼠肾组织IGF-1的表达较对照组升高,并随着病程的延长有下降趋势,差异有显著性.结论:肾组织IGF-1与糖尿病肾脏病变发生显著相关.提示IGF-1参与了DN的发生发展,其中IGF-1可能发挥保护性作用.     

胰岛素增敏剂治疗高尿酸血症的初步研究

目的：通过动物实验,验证胰岛素增敏剂治疗高尿酸血症的可行性,并从后者存在炎症反应和氧化应激的角度,探讨其作用的分子机制,为临床应用提供理论依据。方法：39只雄性Wistar大鼠随机分为正常对照组（简称正常组）;高尿酸血症模型组;治疗组。采用高嘌呤饮食制造高尿酸血症模型,制模成功后分组,给予治疗组饲料中添加马来酸罗格列酮（文迪雅,格兰素史克公司出品）0．8mg／kr/d。各组治疗观察12周,同时正常组和模型组分别予相应饲料。检测大鼠血尿酸（UA）、血糖等,ELISA法检测血单核细胞趋化蛋白-1（MCP-1）、血8-异前列腺素F2α（8-iso—PGF2ct）和肿瘤坏死因子-α（TNF—α）等。光镜观察大鼠肾脏的病理变化。结果：马来酸罗格列酮治疗后,与模型组比较,血糖、UA、MCP-1、8-iso—PGF2d、TNF—α明显下降（P值均〈0．05、0．01）。大鼠肾脏病理显示改善。结论：胰岛素增敏剂马来酸罗格列酮可以降低高尿酸血症试验大鼠血糖、UA、MCP-1、8-iso—PGF2α、TNF—α等,其分子机制可能与抑制炎症和氧化应激有关。     

益生菌对溃疡性结肠炎大鼠IL-1β、CD44的作用

目的：观察和探讨大鼠结肠促炎症性细胞因子IL-1β和细胞黏附分子CD44在UC大鼠模型中的表达,并分析和探讨枯草杆菌、肠球菌二联活菌肠溶胶囊在UC中的作用及对这两个因子的影响.方法：用乙酸溶液制备UC大鼠模型,将清洁级Wistar大鼠32只随机分成正常对照组、溃疡性结肠炎模型组、美沙拉嗪治疗组、美肠安和美沙拉嗪联合治疗组.7d后各组大鼠结肠标本行HE染色,观察镜下结肠病理变化,并通过酶联免疫吸附测定法（ELISA）测定各组大鼠血清中细胞因子IL-1β、CD44的表达水平.结果：模型组大鼠结肠黏膜可见脓性分泌物、糜烂及溃疡,两组治疗组显著改善UC大鼠结肠黏膜的病理变化,并且明显降低大鼠血清中细胞因子IL-1β、CD44的表达,其中美肠安联合美沙拉嗪治疗组的降低较美沙拉嗪治疗组更明显.结论：美肠安和美沙拉嗪联合使用可以明显降低IL-1β和CD44的表达,疗效优于单独使用美沙拉嗪.     

复方甘草酸苷对佐剂性关节炎大鼠血清中TNF-α、IL-1和IL-6表达水平的影响

目的:研究复方甘草酸苷对佐剂性关节炎大鼠血清中TNF-αIL-1和IL-6表达水平的影响,以探讨复方甘草酸苷对佐剂性关节炎的治疗作用.方法:通过给大鼠右后足跖部皮下注射完全弗氏佐剂(CFA)建立类风湿性关节炎的动物模型(AA),在致炎后第14d,大鼠继发性关节炎出现.开始在治疗组AA大鼠腹腔注射复方甘草酸苷注射液2mg...