国产大剂量顺铂肾毒性的临床研究

顺铂(Cisplatin,DDP)的肾毒性一直是临床应用受限制的主要因素。近年来由于应用水化利尿、分次静滴和高渗盐水等保护肾功能的方法,DDP的肾毒性已明显减轻,但在国外因DDP肾损伤致死的报道仍时有所见。为了解国产DDP对我国患者的肾毒性,本研究采用多种指标综合观察了国产大剂量 DDP对肾损伤情况,现报道如下。     

L-精氨酸预防大剂量顺铂所致急性肾毒性的临床研究

一、材料与方法1998年 8月～ 2 0 0 0年 4月间选择大剂量顺铂化疗患者6 3例 ,其中肺癌 36例 (非小细胞肺癌 30例 ) ,其他肿瘤 2 7例。顺铂每周期用量为 10 0ｍｇ/ｍ2 ,常规水化、利尿。其他化疗药物均在第 4天开始给予。精氨酸的用量每天为 5ｇ/ｍ2或 10ｇ/ｍ2 ,加入 5 %葡萄糖 5 0 0ｍｌ中静滴 ,在用顺铂的当日应用。所有入组患者均进行自身对照 ,每周期化疗前及化疗后 2 4ｈ查尿 β2 ＭＧ以评价疗效。精氨酸预防顺铂肾毒性的疗效评价标准 ,按中国医学科学院肿瘤医院制定的硒对降低顺铂肾毒性的疗效标准进行评价 ;实体瘤的疗效评价根据Ｗ…     

L—精氨酸预防大剂量顺铂所致家兔急性肾毒性的实验研究

目的：观察L－精氨酸预防大剂量顺铂所致的家兔急性肾毒性的疗效。方法：2－3kg的家兔16只,雌、雄各半,随机分为4组（亦雌、雄各半）：A组为对照组,B组为单用顺铂组,C组为顺铂联合高剂量L－精氨酸组（1．3g/kg),D组为顺铂联合低剂量L－精氨酸组（0．5g/kg),顺铂用量均为6mg/kg,用药后72小时处死家兔取其肾脏观察病理变化。结果：A组正常;B组区域性肾小管上皮细胞坏死、脱落,坏死的肾小管内充满大量的坏死物及蛋白管型;C组未见肾小管上皮细胞坏死、脱落,管腔内偶见蛋白管型,D组零星区域肾小管上皮细胞坏死、脱落,管腔内见多量坏死物及蛋白管型。结论：L－精氨酸可有效预防顺铂所致的家兔急性肾毒性,且以高剂量（1．3g/kg)为优。     

左旋精氨酸预防大剂量顺铂急性肾毒性的剂量探讨

目的探讨左旋精氨酸预防大剂量顺铂急性肾毒性的最佳剂量。方法选择128例肿瘤病人,随机分为A、B、C3组,3组病人顺铂的剂量及用法相同,均为100mg/m2,分两天(第1、2天)给药。3组病人左旋精氨酸的用量分别为每天5g/m2、10g/m2和15g/m2,于化疗的当天在顺铂后应用,每例病人加与不加精氨酸周期的两周期化疗形成自身对照,每例病人化疗前及化疗后24h均检测尿β2-MG、血尿素氮(BUN)、血肌酐(Cr)及血尿酸,观察3组病人加与不加精氨酸周期化疗前后各观察指标的变化,并比较3组的疗效。结果血BUN、Cr及尿酸无论在加精氨酸周期还是在不加精氨酸周期,化疗前后检测值均无明显变化,该3项指标不宜作为早期急性肾功能损害的检测指标。而A、B、C3组病人化疗后的尿β2-MG值在加与不加精氨酸周期分别为0.9120±0.6618与1.5167±0.7908(P<0.05)、0.5404±0.5810与1.4616±0.8120(P<0.01)及0.4998±0.6210与1.5210±0.7710(P<0.01),均有明显差别,B组的结果差别极其显著,C组的结果差别也极其显著。A、B、C3组的显效率及总有效率分别为40.9%及59.1%、68.2%及90.9%、77.5%及97.5%,经X2检验,A、B两组的显效率及总有效率均差别显著,B、C两组的显效率及总有效率均无显著性差别。结论左旋精氨酸有效预防大剂量顺铂急性肾毒性的最佳剂量为每天10g/m2,增加剂量并不增加疗效。     

顺铂的肾毒性作用及其防治

顺铂(cisplatin)是一种广谱抗癌药物,但其对肾脏的毒性作用,在一定程度上限制了它的应用。单用顺铂时,肾毒性发生率高达28～36％。近年来许多学者致力于探讨顺铂的肾毒性机理及其防治方法,并取得了一定进展。本文对此作一简要综述。 一、肾毒性及其机理 顺铂的肾毒性作用主要是由金属铂离子产生。血浆中高浓度的铂离子在用药后6小时就可对肾小管产     

顺铂肾毒性预防的研究进展

顺铂是临床应用最广泛的抗癌药物，如何减轻其肾毒性是当前的研究热点，并且已取得可喜进展，如调整给药时间，控制水铂，血浆铂峰浓度，改变谷胱甘肽含量，应用高氯液体，止吐剂，微量元素，氨基酸，抗生素，糖皮质激素，含苯甲酸基团药物，硫代氨基甲酸酯类药物，中药等均可不同程度地降低顺铂的肾毒性，对其临床应用具有重要意义。     

顺铂肾毒性作用的初步实验研究

顺铂(DDP)的肾毒性作用是影响临床应用的关键因素,其机理目前尚不清楚。本文进行了初步动物试验观察,以提供初步参考材料。     

国产大剂量顺铂耳毒性的临床观察

耳毒性是顺铂(cis-platin,DDP)的一个重要毒副反应。近年来随着水化利尿和高渗盐水等措施的应用,DDP用量明显提高,肾毒性虽有所减低但耳毒性却相应加重。大剂量DDP用法不当可导致完全失听,多数报道耳毒性的发生率在50％左右,而国产大剂量DDP治疗后耳毒性的发生率却未见报道。为此,我们进行了DDP治疗后耳毒性的观察。     

大蒜素对顺铂肾毒性的保护作用

目的：研究大蒜素对顺铂（DDP）导致的人胚肾HEK293细胞氧化损伤的保护作用并探讨其作用机制。方法：体外培养HEK293细胞,MTT法分别测定不同浓度大蒜素和DDP对HEK293细胞生长的影响,以及大蒜素预处理对DDP诱发细胞毒性的影响。进一步将HEK293细胞分为对照组（未加入DDP和大蒜素）、DDP组（20 mg/L）、大蒜素组（2 mg/L）、大蒜素（4 mg/L）+DDP（20 mg/L）组,黄嘌呤氧化酶法检测各组细胞内超氧化物歧化酶（SOD）活力,硫代巴比妥酸法测定细胞内丙二醛（MDA）含量,二硫代二硝基苯甲酸法测定还原型谷胱甘肽（GSH）的含量。结果：与对照组相比,DDP导致细胞存活率显著降低,且呈剂量效应关系（P < 0.01）。大蒜素预处理后,对DDP（20 mg/L）所致细胞存活率的抑制作用有显著改善（P < 0.01）。与DDP组相比,大蒜素能显著抑制DDP所致细胞内MDA含量的升高以及SOD活力和GSH含量的下降（P < 0.01）。结论：大蒜素可拮抗DDP所致HEK293细胞氧化损伤,对顺铂肾毒性具有明显的保护作用。     

氨磷汀对顺铂肾毒性损伤的保护作用及其机制的研究

目的 观察顺铂的肾毒性损伤部位、形式与肾功能检查结果的相关性,以了解细胞凋亡的发生机制和氨磷汀的保护机制是否与肾组织Fas和FasL表达改变有关。方法 随机将大鼠分成3组,即对照组（生理盐水）、顺铂组（6mg／kg）和氨磷汀组（顺铂6mg／kg＋氨磷汀200mg／kg）,取其血清标本和肾组织,分别做血清BUN、Cr检测和肾组织病理学检查,并用原位缺口末端标记法（TUNEL）做肾组织凋亡细胞检测、Fas和FasL免疫组化染色,再用图像分析软件对其做阳性细胞计数和染色总灰度值测定。结果 顺铂组动物血清BUN、Cr值均明显高于对照组和氨磷汀保护组,3d时,差异已有统计学意义（P〈0．05）;5d时,两者差异分别为P〈0．01和P〈0．05;10d时,恢复正常。顺铂组肾小管上皮细胞坏死和凋亡均很严重,其凋亡细胞计数明显高于对照组和氨磷汀组（P值均〈0．01）,肾组织Fas和FasL表达的总灰度值,明显高于对照组和氨磷汀组（P值均〈0．01）。结论 氨磷汀对顺铂的肾毒性损伤有保护作用,其机制可能与抑制肾组织Fas和FasL的表达有关。     

Effects of mycophenolate mofetil on cisplatin-induced renal dysfunction in rats

Purpose Inflammation and oxidative stress are important events among the plethora of mechanisms involved in cisplatin (CDDP)-induced nephrotoxicity. The aim of this study was to evaluate the effect of mycophenolate mofetil (MMF), an immunosuppressive, in the protection against CDDP-induced renal dysfunction. Methods Rats were divided into four groups; untreated-control group, CDDP-treated group (7 mg/kg, single intraperitoneal dose), MMF-treated group (40 mg/kg/day orally for 5 successive days) and the fourth group was treated with both drugs and MMF treatment was started 1 day prior to CDDP administration. Nephrotoxicity was assessed 7 days after the CDDP treatment by measuring serum indices of nephrotoxicity, kidney weight as a percentage of total body weight, kidney’s tissue peroxidative alterations and total nitrate/nitrite concentration (NOx) and the results were confirmed histopathologically. Results Rats treated with CDDP showed marked nephrotoxicity as evidenced from the significant increase in serum creatinine and urea levels and decrease in serum calcium and albumin levels. Kidneys of CDDP-treated rats showed significant increases in kidney weight and malondialdehyde (MDA) production level and decreases in total NOx concentration, glutathione peroxidase (GPx) activity and reduced glutathione (GSH) content levels. Histopathological assessment of kidneys of CDDP-treated rats revealed extensive tubular necrosis with “sloughing off” of the renal tubular lining cells, intratubular hyaline casts and mononuclear cell infiltration. Treatment with MMF significantly protected the rats against CDDP-induced nephrotoxicity. The rise in serum creatinine and urea levels, kidney weight and kidney tissue MDA production, depletion of “endogenous antioxidant reserve” including GPx activity and reduced GSH content levels and the deleterious histopathological changes induced by CDDP treatment were significantly mitigated by MMF treatment. Conclusions MMF treatment dramatically ameliorates CDDP-induced renal dysfunction.     

Protection against cisplatin-induced nephrotoxicity by Spirulina in rats

Purpose: Cisplatin (CP)-induced nephrotoxicity is associated with the increased generation of reactive oxygen metabolites and lipid peroxidation in kidney, caused by the decreased levels of antioxidants and antioxidant enzymes. The purpose of this study was to evaluate the role of Spirulina, blue–green alga with antioxidant properties, in the protection of cisplatin-induced nephrotoxicity in rat. Methods: Rats were treated with CP (6 mg/kg bw, single dose, intraperitoneally). Spirulina (1,000 mg/kg) was administered orally for 8 days and CP treatment was given on day 4. Nephrotoxicity was assessed, 6 days after the CP treatment, by measuring plasma urea, creatinine, urinary N-acetyl-(d-glucose-aminidase) (β-NAG) and histopathology of kidney. Results: Rats treated with CP showed marked nephrotoxicity as evidenced from the significant elevation in plasma urea, creatinine and urinary β-NAG. Histological assessment revealed marked proximal tubular necrosis and extensive epithelial vacuolization in the kidney of CP-treated rats. Superoxide dismutase, catalase and glutathione peroxidase were decreased and lipid peroxidation was increased in kidney tissue. Pretreatment with Spirulina protected the rats from CP-induced nephrotoxicity. The rise in plasma urea, creatinine, urinary β-NAG, plasma and kidney tissue MDA and histomorphological changes were significantly attenuated by Spirulina. In vitro studies using human ovarian cancer cells revealed that Spirulina did not interfere with the cytotoxic effects of CP on tumor cells. Conclusions: In summary, Spirulina significantly protected the CP-induced nephrotoxicity through its antioxidant properties.     

Hydroxyl radical scavenger ameliorates cisplatin-induced nephrotoxicity by preventing oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria

Nephrotoxicity is the major dose-limiting factor of cisplatin chemotherapy. Reactive oxygen species generated in mitochondria are thought to be the main cause of cellular damage in such injury. The present study examined, in vivo, the protective potential of the hydroxyl radical scavenger dimethylthiourea (DMTU) against cisplatin-induced effects on renal mitochondrial bioenergetics, redox state and oxidative stress. Adult male Wistar rats (200 to 220 g) were divided into four groups of eight animals each. The control group was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml/100 g body weight). The second group was given only DMTU (500 mg/kg body weight, i.p, followed by 125 mg/Kg, i.p., twice a day until they were killed). The third group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The fourth group was given DMTU (500 mg/kg body weight, i.p.), just before the cisplatin injection (10 mg/kg body weight, i.p.), followed by injections of DMTU (125 mg/kg body weight, i.p.) twice a day until they were killed. Animals were killed 72 h after the treatment. Besides not presenting any direct effect on mitochondria, DMTU substantially inhibited cisplatin-induced mitochondrial injury and cellular death by apoptosis, suppressing the occurrence of acute renal failure. All the following cisplatin-induced effects were prevented by DMTU: (1) increased plasmatic levels of creatinine and blood urea nitrogen (BUN); (2) decreased ATP content, calcium uptake and electrochemical potential; (3) oxidation of lipids, including cardiolipin; and oxidation of proteins, including sulfhydryl, and aconitase enzyme, as well as accumulation of carbonyl proteins; (4) depletion of the antioxidant defense (NADPH and GSH) and (5) increased activity of the apoptosis executioner caspase-3. Our findings show the important role played by mitochondria and hydroxyl radicals in cisplatin-induced nephrotoxicity, as well as the effectiveness of DMTU in preventing the renal mitochondrial damage caused by cisplatin. These results strongly suggest that protection of mitochondria by hydroxyl radical scavengers may be an interesting approach to prevent the kidney tissue damage caused by cisplatin-chemotherapy.     

Protection against cisplatin-induced nephrotoxicity by recombinant human erythropoietin

Cisplatin (CDDP) is a potent nephrotoxin, and nephrotoxicity is its most important dose-limiting toxicity. In this study, we aimed to investigate the role of recombinant human erythropoietin (rhEPO) in the protection of cisplatin-induced nephrotoxicity and compare its efficacy with the cell-protective agent amifostine. All experiments were conducted on female Wistar albino rats. Animals were randomly assigned to four groups, each including six rats. Group A received only CDDP, group B received CDDP plus rhEPO, group C received CDDP plus amifostine, and group D received only rhEPO. At the end of 7 wk, hemoglobin (Hgb), hematocrite (Htc), blood urea nitrogen (BUN), and creatinine (Cr) levels were determined and kidneys of the rats were removed. The weights of the kidneys were measured and sent for histopathological examination. Proximal tubules from four areas of the kidney (outer cortex, inner cortex, the medullary ray, and outer stripe of outer medulla [OSOM]) were evaluated. There were statistically significant differences among the groups in terms of tubular scores, including overall renal tubular score, cortex, inner cortex, OSOM, and medullary ray tubular scores, and Htc levels. Group A rats had the worse tubular scores in all categories when compared to group D rats. When the results of groups B and C were compared, there were no differences in terms of BUN, Cr levels, and tubular scores, but the Htc level was significantly higher in group B. Group B rats had better overall and OSOM tubular scores when compared to group A. Group C also had better overall and OSOM tubular scores compared to group A. The present study showed for the first time that rhEPO plays an important role in the prevention of cisplatin-induced nephrotoxicity and it is as effective as amifostine.     

黄芪注射液预防多柔比星相关性心脏毒性反应的临床观察

目的:探讨黄芪注射液对多柔比星(阿霉素)相关性心脏毒性的保护作用。方法:58例恶性肿瘤患者,随机地分成观察组和对照组两组。观察组30例,在以ADM为主的一线方案化疗前3天予黄芪注射液50ml加入5%葡萄糖注射液250ml中静脉滴注,每日一次,两周一疗程;对照组28例,于化疗前3天开始服用VitE每次100mg,每日两次,辅酶Q10每次20mg,每日三次,两周一疗程。治疗前后检查心电图,超声心动图中左心室舒张末期内径(LVIDD)、左心室收缩末期内径(LVISD)、舒张早期与晚期充盈速度比值(A/E)、射血分数(EF)、短轴缩短率(FS)等各项指标。结果:在本组ADM化疗后,观察组与对照组间,虽然EF差异无显著性(P>0.05),但心电图异常改变及LVIDD、LVISD、A/E、、FS的差异有显著性(P<0.05)。结论:黄芪注射液是预防和减轻ADM引起的急性心脏毒性的较为理想的药物,对慢性心脏毒性发生的减轻也有益。     

硫普罗宁减轻顺铂肾毒性的临床观察

目的 研究硫普罗宁对顺铂所致肾毒性的减轻作用。方法 将病理证实的40例肿瘤患者随机分成两组,应用含顺铂为主的联合方案化疗。治疗组20例,化疗前1小时内静滴硫普罗宁0.2g/m²,随后给予大剂量顺铂（80～120mg/m²）化疗;对照组20例,仅给予大剂量顺铂（80～120mg/m²）化疗。比较两者化疗前后血BuN,血Cr,尿β₂MG的变化。结果 化疗第七天血BuN值治疗组较对照组差异有统计学意义（P<0.05）,化疗后第3天,尿β₂MG治疗组较对照组差异有统计学意义（P<0.01）。结论 硫普罗宁能减轻顺铂所致肾毒性。     

氨磷汀对顺铂致肾功能异常患者再化疗的肾脏保护作用

目的观察氨磷汀对顺铂（DDP）致肾功能异常患者再化疗的肾脏保护作用。方法对19例因DDP化疗致肾功能异常患者,再次应用含DDP方案化疗,静脉用DDP前30min加用氨磷汀250mg/m^2,治疗前及治疗后不同时间分别测定血尿素氮、血肌酐值,观察肾功能的变化情况。结果19例患者,有效4例,稳定12例,进展3例,总有效率达84.2%。结论DDP化疗后肾功能轻度异常患者,再次采用含DDP方案化疗时,加用氨磷汀可以防止肾功能的进一步损害。     

改良肠道水化对顺铂治疗肺癌的肾毒性的影响

目的：观察改良肠道水化对顺铂（PDD）治疗肺癌的肾毒性的影响.方法：212例肺癌予以PDD为主的联合化疗,PDD 75～80mg/m^2静滴,第1天,化疗当天通常静脉补液1 000～2 000ml,摄水量1 500～2 000ml,PDD后半小时静脉推注速尿,并予积极止吐处理,连续3天记录24小时出入量,化疗前后测定肾功能.结果：212例肺癌均顺利完成化疗,仅11例（5.1%）有一过性轻度肾功能异常,与常规水化方案相比未增加肾毒性,所有病例无胸闷、气急.结论：改良的肠道水化方案也能较好地预防顺铂的肾毒性,且补液量少,患者易接受,临床上是可行的.