内皮素和氧化氮在环孢素A肾毒性中的作用

环孢素Ａ的肾毒性限制了其广泛应用，毒性机理仍未完全明确。近来发现环孢素Ａ毒性损害的主要部位在内皮细胞，因此内皮细胞产生的内皮素和氧化氮在环孢素Ａ肾毒性中的作用引起高度重视，现就其研究进展作一综述。     

内皮素和氧化氮在环孢素A肾毒性中的作用

环孢素Ａ的肾毒性限制了其广泛应用，毒性机理仍未完全明确。近来发现环孢素Ａ毒性损害的主要部位在内皮细胞，因此内皮细胞产生的内皮素和氧化氮在环孢素Ａ肾毒性中的作用引起高度重视，现就其研究进展作一综述。     

冬虫夏草对体外线粒体钙离子负荷和缺血性急性肾功能衰竭大…

本文观察了冬虫夏草对体外大鼠肾皮质线粒体钙离子负荷和缺血性急性肾功能衰竭大鼠肾皮质线粒体钙离子，及其对线粒体ＡＴＰ酶的影响。实验结果证实，冬虫夏草可减轻实验性缺血性急性肾功能衰竭大鼠皮质线粒体钙离子内流和保护ＡＴＰ酶的活性，从而改善了肾功能，冬虫夏草减轻线粒体钙离子内流的机制与钌红选择性抑制线粒体膜钙离子通道不同，可能与其保护线粒体膜ＡＴＰ酶，改善线粒体能量代谢有关。     

环孢素A的慢性肾毒性

环孢素Ａ的慢性肾毒性是影响临床同种肾移植术后病人长期存活的重要因素之一，其机理仍不清楚。目前研究认为，转化生长因子β等细胞因子在环孢素Ａ慢性肾毒性发病中起重要的作用。本文对这方面的研究作一综述。     

阿霉素合用化疗耐受逆转剂对肾癌细胞的体外逆转试验

目的　探讨逆转肾癌细胞对化疗药物的耐受。　方法　采用四种不同类型的逆转剂：异博定、 Ｂｕｔｈｉｏｎｉｎｅ ｓｕｌｆｏｘｉｍｉｎｅ （ Ｂ Ｓ Ｏ） 、三苯氧胺、环孢素 Ａ,以单药或多药组合的方式与阿霉素联合应用,与肾癌细胞共同培养。 Ｍ Ｔ Ｔ 染色法检测细胞生长抑制率。　结果　单药应用中以异博定的逆转效果最好,对肾癌细胞生长抑制率达３４ ％ （ Ｐ＜ ００５） ,多药组合中以异博定＋ Ｂ Ｓ Ｏ＋ 三苯氧胺更为有效,对肾癌细胞生长抑制率达５０８ ％ （ Ｐ＜ ００５） 。　结论　多药组合逆转较单药应用更为有效。两种不同逆转机制的逆转剂联用,较两种同为 Ｐ１７０ 的逆转剂联用效果更好。     

n－3多价不饱和脂肪酸对应用环孢素A小鼠肾组织氧自由基形成的影响

ｎ－３多价不饱和脂肪酸对应用环孢素Ａ小鼠肾组织氧自由基形成的影响卞晓明郭加强近年来有关环孢素Ａ（ＣｓＡ）肾毒性方面的研究较多，但有关肾毒性与氧自由基的关系报道很少。曾有研究表明ＣｓＡ可导致肾组织氧自由基形成增多。ｎ－３多价不饱和脂肪酸（ｎ－３ＰＵＦＡ...     

冬虫夏草防治氨基糖甙急性肾衰的分子生物学机理

探讨冬虫夏草对氨基糖甙急性肾衰的防治机理。方法应用斑点杂交和免疫组化等方法，动态观察了冬虫夏草对庆大霉素急性肾衰大鼠肾组织表皮生长因子（ＥＧＦ）前体ｍＲＮＡ、ＥＧＦ、ＥＧＦ受体及尿ＥＧＦ含量的影响。结果冬虫夏草治疗能显著增加损伤早期肾ＥＧＦ前体ｍＲＮＡ表达及肾皮质ＥＧＦ含量，而不影响肾ＥＧＦ受体的数量，同时使尿ＥＧＦ排出量的增加提早出现，肾小管的病变减轻，肾功能恢复加快。结论冬虫夏草可能通过增加肾组织ＥＧＦ前体ｍＲＮＡ表达，促进肾内ＥＧＦ合成，增加肾皮质ＥＧＦ含量，从而加速肾小管再生修复和急性肾衰的恢复     

中医药防治环孢素A慢性肾毒性的研究进展

大量资料表明器官移植病人服用环孢素Ａ(ＣＳＡ) 12个月以上可能发生进行性肾功能不全 1,而慢性移植肾失功80 %是由环孢素Ａ的慢性肾毒性所致。目前现代医学尚无有效的防治慢性ＣＳＡ肾毒性的措施 ,随着我国器官移植水平的提高 ,研究中医药防治慢性ＣＳＡ肾毒性有重要意义。本文仅将近年来中医药在防治慢性ＣＳＡ肾毒性方面的进展作一介绍。1　环孢素Ａ慢性肾毒性的发病机理ＣＳＡ是由一种不完全真菌属 ＴｏｌｙｐｏｃｌａｄｉｕｍｉｎｆｌａｔｕｍＧａｍｓ在生长过程中产生的多肽混合物经纯化、分离而成 ,为目前应用于器官移植主要的免疫…     

环孢素致离体肾小管上皮细胞损伤时的氨基酸代谢及甘、丙氨酸的保护作用

目的研究环孢素Ａ（ＣｓＡ）的肾毒性机制。方法制备了体外ＣｓＡ致肾小管上皮细胞（ＴＥＣ）损伤模型，对ＴＥＣ内氨基酸组成、含量、ＡＴＰ水平及乳酸脱氢酶（ＬＤＨ）释放率等指标进行了一系列检测。结果（１）经ＣｓＡ处理，ＴＥＣ内氨基酸水平没有明显变化；（２）体外投入甘、丙氨酸对ＣｓＡ所致的损伤可起保护作用，其作用与投入时机及剂量有关，而与Ｎａ＋－Ｋ＋－ＡＴＰ酶的抑制无直接联系。结论ＣｓＡ肾中毒时对细胞内氨基酸代谢影响不大，甘、丙氨酸对ＣｓＡ性肾损伤有明确的保护作用，其作用发挥可不依赖正常的能量代谢     

肾移植术后监测环孢素浓度的临床意义

为了进一步探讨环孢素Ａ理想的治疗窗范围，指导临床合理应用免疫抑制剂，以减少急性排斥反应发生和肝肾毒性反应，对肾移植术后５１０例患者进行了ＣｓＡ血浓度测定，实验结果表明；术后不同时期各组间ＣｓＡ的浓度范围有显著差异，认为监测ＣｓＡ浓度有利于减少急性排斥反应和肝，肾毒性反应发生。     

Cyclosporine Sparing with Mycophenolate Mofetil, Daclizumab and Corticosteroids in Renal Allograft Recipients: The CAESAR Study

Although the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus are highly effective immunosuppressants, they are associated with serious side effects. There is great interest in immunosuppressive regimens that permit reduction or elimination of CNIs, while maintaining adequate immunosuppression and acceptable acute rejection rates. Patients (n = 536) receiving their first renal allograft were randomized to one of three immunosuppressant regimens: daclizumab, mycophenolate mofetil (MMF), corticosteroids (CS) and low-dose CsA (target trough levels of 50-100 ng/mL), weaned from month 4 and withdrawn by month 6; daclizumab, MMF, CS and low-dose CsA; or MMF, CS and standard-dose CsA. Mean GFR 12 months after transplantation (primary end point) was not statistically different in the CsA withdrawal and low-dose CsA groups (both 50.9 mL/min/1.73 m(2)) vs. the standard-dose CsA group (48.6 mL/min/1.73 m(2)). At 12 months, the incidence of biopsy-proven acute rejection was significantly higher in the CsA withdrawal group (38%) vs. the low- or standard-dose CsA groups (25.4% and 27.5%, respectively; p < 0.05). In summary, a regimen of continuous low-dose CsA with MMF, CS and daclizumab induction is a clinically safe and effective immunosuppressive regimen in renal transplant recipients.     

Influence of SDZ RAD vs. MMF on gastric emptying in renal transplant recipients

SDZ RAD and mycophenolate mofetil (MMF) are increasingly used in the prevention of renal allograft rejection. SDZ RAD, having a macrolide structure, and MMF, known with gastrointestinal side-effects, may have gastric motility modifying properties. Gastric emptying was examined 1 yr after renal transplantation in eight patients taking corticosteroids (CS), cyclosporin A (CsA) and SDZ RAD and six patients treated with CS, CsA and MMF. Comparing the two groups, no significant differences in gastric emptying of solids and liquids were noted. Compared with normal volunteers, solid gastric emptying was faster in the SDZ RAD group and similar in the MMF group. It is concluded that in stable renal transplant recipients treated with MMF, gastric emptying was normal. Because of the impact on drug absorption and gastrointestinal symptoms, further studies are indicated to corroborate the potential prokinetic properties of SDZ RAD.     

CYP3A4 and P-Glycoprotein Activity in Healthy Controls and Transplant Patients on Cyclosporin vs. Tacrolimus vs. Sirolimus

This study aimed to determine the impact of maintenance immunosuppressive therapy with cyclosporin A (CsA), tacrolimus (FK506) and sirolimus (Rapa) on the in vivo activity of both intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (PGP) in renal transplant patients. The activity of these four elimination pathways was measured by the recently validated intravenous (iv) and per oral (po)14C erythromycin breath and urine test. In addition, overall hepatic P450 activity was measured by the (13)C aminopyrin breath test. Three groups of stable renal transplant patients on maintenance therapy with corticosteroids (CS) and mycophenolate mofetil (MMF) plus either CsA or FK506 or Rapa were examined. A significant increase in intestinal CYP3A4 activity and a significant decrease in hepatic and intestinal PGP activity was seen in patients on CsA in comparison with those on FK506 or Rapa (p < 0.01). A similar analysis in six healthy volunteers at baseline and after intake of CsA, FK506 and Rapa confirmed the results seen in the patients. There was no difference in CYP3A4 and PGP activity in the patients taking either FK506 or Rapa and healthy controls. These data suggest that a different pattern of drug interactions might be expected in patients treated with CsA vs. FK506/Rapa.     

Addition of sirolimus to cyclosporine delays the recovery from delayed graft function but does not affect 1-year graft function

Delayed graft function (DGF) has long been identified as one of the main correlates of poor graft survival in cadaveric renal transplantation, but the factors that affect its onset and duration are not fully elucidated. The impact of two immunosuppressive protocols on the incidence and length of DGF among kidney transplant recipients of a suboptimal organ was evaluated. Patients were randomly treated with corticosteroids (CS); low-dose cyclosporine (CsA) and sirolimus (SRL; group 1; n = 42); or CS, full-dose CsA, and mycophenolate mofetil (group 2; n = 48). All recipients received immunoprophylaxis with basiliximab. After 3 mo, group 1 discontinued CsA and continued with SRL, whereas group 2 continued the same treatment. The incidence of DGF was similar in the two groups (group 1 = 52.4%; group 2 = 58.3%), whereas its duration was significantly higher in the group 1 (19.0 +/- 6.0 versus 10.3 +/- 3.2 d; P = 0.001). Both groups showed 100% actuarial graft and patient survival at 1-yr. Among DGF patients, serum creatinine (sCr) at discharge was significantly worse in group 1 (sCr, 3.0 +/- 1.0 versus 1.5 +/- 0.2 mg/dl; calculated creatinine clearance, 31.2 +/- 9.3 versus 61.1 +/- 10 ml/min; P = 0.001). During the first year, the former group displayed a significant improvement of graft function, such that at 1-yr, no difference could be measured between groups (sCr, 1.8 +/- 0.5 versus 1.7 +/- 0.4 mg/dl; calculated creatinine clearance, 51.5 +/- 10.2 versus 53.3 +/- 9.4 ml/min). In conclusion, in de novo renal transplanted patients, the administration of SRL, in combination with low-dose CsA, is associated with a delayed recovery from DGF but does not worsen 1-yr graft function.     

盐酸小檗碱对肾移植受者环孢素A血浓度的影响

目的研究盐酸小檗碱(Ber)对肾移植受者环孢素A(CsA)血浓度的影响.方法33例肾移植后口服CsA+Ber的受者为试验组,27例单纯口服CsA的受者为对照组,以CsA全血浓度及肝、肾功能生化检测指标作为临床评价指标.结果试验组受者CsA全血浓度与合用Ber前比较,增幅达66.9%,与对照组比较差异有显著性(P<0.001),停用Ber后,CsA全血浓度显著下降.Ber与CsA合用对肝、肾功能无明显影响.结论Ber能显著升高肾移植受者CsA血浓度.在升高CsA血浓度的同时,Ber并不增加CsA的毒性反应.Ber与CsA合用有望成为一种节省CsA费用的方法.     

Effect of Cyclosporine a on Accumulation of Tetraethylammonium and p-Aminohippurate,and on Lipid Peroxidation in Rat Renal Microsomes and Cortical Slices

The effect of cyclosporine A (CsA) on lipid peroxidation (LPO) was assessed in renal cortical slices and renal microsomes. Cortical slices were incubated with 1500 μg/ml CsA and microsomes with 0.5–20 μg/ml under identical conditions (pH 7.4,37d`C) for 3 hours, and LPO monitored by the formation of malondialdehyde (MDA). CsA at concentrations of 3 μg/ml and higher caused a significant increase MDA in microsomes and renal cortical slices showed a time dependent release of MDA into the incubation medium. The influence of CsA on tetraethammonium (TEA) and p-ami-nohippurate (PAH) accumulation in renal cortical slices was investigated for up to 3 hours with concentration of CsA from 10 to 1000 μg/ml. CsA caused a time-and concentration-dependent decrease of TEA accumulation and higher concentrations of CsA decreased PAH accumulation in renal cortical slices. The results add further evidence to the suggestion that lipid peroxidation participate in CsA-induced impairment of kidney function.     

尼卡地平对肾移植受者环孢素A血浓度的影响

目的：研究尼卡地平对肾移植受者血压和环孢素A（CaA)全血谷值浓度的影响。方法：试验组62例肾移植术后肾功能恢复正常的受者服用尼卡地平，服药前后作自身对照；23例受者服用硝苯地平作为对照组，以CsA全血谷值浓度、CsA剂量、肌酐、血压作为临床评价指标。结果：试验组受者服用尼卡地平后CsA血药浓度显著升高、血压下降并维持在正常范围，与服用尼卡地平前比较，差异均有显著性意义（P＜0．01），6个月后环孢素剂量A减少达34．2％，对血肌酐无明显影响。结论：尼卡地平用于肾移植术后能有效治疗和预防高血压，并可提高CsA血药浓度，减少CsA用量和费用，并不增加CsA的毒性反应。尼卡地平与CsA合用可节省费用。     

Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A

Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A. BACKGROUND: Endothelins may play an important role in cyclosporine A (CsA)-induced renal vasoconstriction. Therefore, the effects of a mixed endothelin A and B receptor antagonist, bosentan (BO), on CsA were studied. METHODS: BO was given either alone or combined with CsA to healthy subjects in a double-blind, placebo-controlled, cross-over study. Standardized renal hemodynamics took place after a single dose of BO or placebo and after seven days of regular intake of CsA + BO or CsA + placebo. CsA was administered as a dose-adjusted regimen to achieve predetermined target trough levels. A pharmacokinetic study of CsA and BO was performed. RESULTS: A single dose of BO did not affect renal hemodynamics. After seven days of coadministration with CsA, BO significantly attenuated both the overall CsA-induced fall of renal plasma flow (RPF; placebo, 594 +/- 85; CsA + placebo, 490 +/- 93; CsA + BO, 570 +/- 106* mL/min, *P < 0.01) and the maximal RPF fall (P < 0.01) observed five hours after CsA intake. The CsA-induced rise of blood pressure and the decrease of glomerular filtration rate (GFR) were not influenced by comedication with BO. After seven days of CsA + BO, the area under the curve (AUC) of BO was nearly doubled compared with the AUC after a single dose of BO (P < 0.05). To reach the CsA target trough levels after seven days, the average CsA dose was increased by 35% when given with BO, as compared with placebo (P = 0.01). CsA exposure (trough levels, AUC) was not statistically different after CsA + placebo and after CsA + BO. CONCLUSIONS: Assuming CsA nephrotoxicity is mainly due to vasoconstriction, BO has the potential to attenuate the CsA renal toxicity by markedly blunting the renal hypoperfusion effect of CsA. A complex drug interaction between BO and CsA was observed.     

Evidence that alterations in renal metabolism and lipid peroxidation may contribute to cyclosporine nephrotoxicity

This study was designed to investigate aspects of renal xenobiotic metabolism and the renal cellular response to drug-induced injury, in mediating cyclosporine nephrotoxicity. The relation between CsA and renal enzyme activity has not previously been investigated. In this study, CsA induced alterations in rat renal cortical microsomal NADPH cytochrome P-450 reductase activity, microsomal and mitochondrial lipid peroxidation, and renal cortical glutathione levels were investigated. CsA, in vivo (50 mg/kg/day for 4 days), increased in vitro lipid peroxidation in microsomes and mitochondria. CsA produced a significant uncompetitive inhibition of renal NADPH cytochrome P-450 reductase activity. The low activity and maximal enzyme velocity (Vmax) suggest that the amount of renal enzyme available for metabolism may be a rate-limiting step and could contribute to the development of toxicity. CsA in vivo reduced the renal cortical glutathione ratio (GSH/GSSG), which may also reduce the renal cellular response to CsA injury. This study has demonstrated that CsA nephrotoxicity may, in part, be mediated by CsA-induced alterations in renal xenobiotic metabolism.     

Effect of cyclosporine A on accumulation of tetraethylammonium and p-aminohippurate, and on lipid peroxidation in rat renal microsomes and cortical slices

The effect of cyclosporine A (CsA) on lipid peroxidation (LPO) was assessed in renal cortical slices and renal microsomes. Cortical slices were incubated with 1500 micrograms/ml CsA and microsomes with 0.5-20 micrograms/ml under identical conditions (pH 7.4, 37 degrees C) for 3 hours, and LPO monitored by the formation of malondialdehyde (MDA). CsA at concentrations of 3 micrograms/ml and higher caused a significant increase MDA in microsomes and renal cortical slices showed a time dependent release of MDA into the incubation medium. The influence of CsA on tetraethammonium (TEA) and p-aminohippurate (PAH) accumulation in renal cortical slices was investigated for up to 3 hours with concentration of CsA from 10 to 1000 micrograms/ml. CsA caused a time- and concentration-dependent decrease of TEA accumulation and higher concentrations of CsA decreased PAH accumulation in renal cortical slices. The results add further evidence to the suggestion that lipid peroxidation participate in CsA-induced impairment of kidney function.