中药马兜铃酸的研究进展

本文总结了马兜铃酸的化学结构、含马兜铃酸的中草药及中成药、马兜铃酸的药理作用和毒性作用、马兜铃酸肾病。通过本文的综述,使医药人员对马兜铃酸有一个全面、正确的认识,以指导临床安全、合理、规范使用含有马兜铃酸的中药。     

马兜铃酸毒性作用的研究进展

从动物实验、体外实验、临床研究等方面综述国内外马兜铃酸肾毒性作用的研究进展,尤其是目前研究最多的以急、慢性肾小管间质病变为主的肾损害.提出马兜铃酸的毒性应以预防为主,严格掌握用药剂量和时间,同时加强临床血药浓度的监测,从各方面减少其毒性作用的发生.     

马兜铃酸肾病及其防治

概述了含马兜铃酸的中草药所致肾毒性的发病机制、临床表现及预防治疗措施,提示应正视中草药使用不当可能导致的不良反应,强调合理应用中草药.     

马兜铃属植物肾毒性研究进展

目的：综述马兜铃属植物肾毒性研究进展。方法：查阅国内外有关献。结果：内容涉及马兜铃属植物肾毒性的主要症状、病理改变特点、作用机制及其防治。结论：马兜铃属植物作为常用中药，其潜在毒性和对肾脏的损害应引起重视。     

马兜铃酸肾病的临床与机制研究进展

含马兜铃酸类成分中药导致的肾损害-马兜铃酸肾病近年受到国内外医药学界的广泛关注,本文根据10年来的临床与药学研究,从马兜铃酸肾病的临床特征、相关药物以及马兜铃酸的代谢过程、毒性作用及致病机制等方面进行了探讨,并提出了今后的研究方向。     

马兜铃酸类化合物使用现状及肾脏毒性研究进展

马兜铃酸类化合物是一类广泛存在于多种天然药物中的物质,具有抗病毒、抗炎等多种疗效.但是,较强的肾毒性阻碍了马兜铃酸类化合物更加广泛的利用.虽然已有部分药材被禁用,但至今仍有大量含有马兜铃酸类化合物的药材,故对马兜铃酸类化合物进行研究仍十分有必要.本文将对含有马兜铃酸类化合物的天然药物的使用现状和肾毒性研究进展进行综述.     

马兜铃酸肾不良反应及质量控制研究进展

马兜铃酸为硝基菲类有机酸类化合物,是马兜铃、关木通、细辛等植物的主要成分。马兜铃酸药理作用广泛,有抗感染、抗肿瘤、增强细胞免疫等功能。本文总结了马兜铃酸肾毒性研究进展及其分子结构,并对近5年不同中药材和中成药中马兜铃酸质量控制的研究进行综述,对比分析不同检测方法的优缺点,为今后对马兜铃酸的进一步研究及临床合理应用提供依据。     

马兜铃酸肾病研究的新进展

根据近年有关研究和报道对含马兜铃酸中药的毒性成分、马兜铃酸的代谢、马兜铃酸肾病的发病机制、临床特征及其诊断方法进行综述,旨在对马兜铃酸的毒理学及马兜铃酸肾病的诊治加深认识。     

马兜铃酸毒理学性研究与启示

有关马兜铃酸的毒理实验国内外均有报道,尤其国外在毒理学方面做了大量研究.大量的实验提示:马兜铃酸的肾毒性与剂量呈相关性;遗传毒性研究提示马兜铃酸具有致突变作用;在对大鼠和小鼠的长期毒性研究中发现:动物可发生局部和全身肿瘤,且肿瘤的发生与给药时间和剂量呈相关性;并发现动物的主要毒性与人的不良反应有相关性.马兜铃酸的相关实验研究提醒有关方面应重视马兜铃酸问题,使传统中药更好地发挥防病治病作用.     

Toxicities of aristolochic acid I and aristololactam I in cultured renal epithelial cells

Aristolochic acid nephropathy, a progressive tubulointerstitial renal disease, is primarily caused by aristolochic acid I (AA-I) intoxication. Aristololactam I (AL-I), the main metabolite of AA-I, may also participate in the processes that lead to renal damage. To investigate the role and mechanism of the AL-I-mediated cytotoxicity, we determined and compared the cytotoxic effects of AA-I and AL-I on cells of the human proximal tubular epithelial (HK-2) cell line. To this end, we treated HK-2 cells with AA-I and AL-I and assessed the cytotoxicity of these agents by using the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, flow cytometry, and an assay to determine the activity of caspase 3. The proliferation of HK-2 cells was inhibited in a concentration- and time-dependent manner. Cell-cycle analysis revealed that the cells were arrested in the S-phase. Apoptosis was evidenced by the results of the annexin V/propidium iodide (PI) assay and the occurrence of a sub-G1 peak. In addition, AA-I and AL-I increased caspase 3-like activity in a concentration-dependent manner. These results also suggested that the cytotoxic potency of AL-I is higher than that of AA-I and that the cytotoxic effects of these molecules are mediated through the induction of apoptosis in a caspase 3-dependent pathway.     

马兜铃酸I在大鼠体内的毒代动力学

目的采用重复多次给药毒性研究的三种剂量对马兜铃酸I进行毒代动力学的初步研究，了解在毒性实验条件下马兜铃酸I所达到的全身暴露与毒性之间的内在联系，为安全性评价和毒性机制的研究提供参考资料。方法分别灌胃给予大鼠马兜铃酸I 30、15、5mg·kg^-1，每天1次，连续14d，测定不同时间点的血浆药物浓度，用DAS药动学程序对血药浓度-时间数据进行拟合并计算毒代动力学参数。结果高、中、低三个剂量组的半衰期（t1/2）分别为（14．29±3．98）、（41．67±21．96）、（144．83±50．43）h，达峰时间（Tmax）分别为（0．10±0．06）、（0．08±0．00）、（0．08±0．00）h，峰浓度（Cmax）分别为（3．02±1．72）、（2．39±2．00）、（1．47±0．78）mg·L^-1，曲线下面积AUC（0-24）分别为（8．47±3．08）、（9．36±2．31）、（7．49±0．46）mg·L^-1·h。AUC及Cmax与剂量均不呈比例，且三种剂量的半衰期相差较远。结论马兜铃酸I能迅速吸收入血，随后浓度逐渐降低，于24h后仅存微量。在毒性剂量下，马兜铃酸I在大鼠体内的毒代动力学过程出现了一定程度的变化，具有非线性动力学性质。     

肾脏有机阴离子转运体在尿酸转运中的作用研究进展

尿酸是嘌呤核苷酸类和游离碱基转化过程中的最终酶产物,肾脏有机阴离子转运体在维持体内尿酸的重吸收与分泌之间的平衡有显著性意义。尿酸的重吸收和分泌失衡是导致高尿酸血症的主要原因。研究肾脏有机阴离子转运体在尿酸转运中的作用有重要意义。     

Molecular mechanism of ochratoxin a transport in the kidney

The mycotoxin, ochratoxin A (OTA), is thought to be responsible for Balkan endemic nephropathy. OTA accumulates in several tissues, especially in the kidneys and liver. The excretion of OTA into urine is thought to be mainly by tubular secretion, presumably via the organic anion transport system. Recently, several families of multispecific organic anion transporters have been identified: organic anion transporters (OATs), organic anion-transporting polypeptides (OATPs), oligopeptide transporters (PEPTs), and ATP-binding cassette (ABC) transporters, such as MRP2 and BCRP. These renal transporters mediate the transmembrane transport of OTA and play a pivotal role in the development of OTA-induced nephrotoxicity.     

Expression of histone deacetylase-1 and p300 in aristolochic acid nephropathy models

Aristolochic acid nephropathy (AAN) is mainly caused by aristolochic acid I (AAI), but the actual mechanism is still uncertain. The current study explored the correlation among the expression of Smad7, p300, histone deacetylase-1 (HDAC1) and the development of AAN using transmission electron microscopy (TEM), RT-PCR, and western blotting in the AAN mouse model and in the AAN cell model. TEM revealed that the renal tubular epithelial cells from the AAI-treated mice presented organelle damages and nuclear deformation. We found that a certain dose of AAI caused renal fibrosis and induced renal tubular epithelial cells to differentiate into myofibroblasts. There was a gradual increase in the expression of HDAC1 mRNA and protein observed using RT-PCR and western blotting in the AAN cell model compared with the control group. Gradual decrease in the expression of Smad7 and p300 mRNA and protein was revealed in the AAN mouse and cell models compared with the control group. These results suggest that AAI dose dependently contributed to the development of AAN, and HDAC1 and p300 participate in the modulation of TGF-β/Smad pathway-mediated renal interstitial fibrosis.     

马兜铃酸Ⅰ肾毒性的实验研究

目的观察马兜铃酸Ⅰ对SD大鼠的肾毒性反应,并评价其安全性。方法马兜铃酸Ⅰ以30,15,5mg/kg,ig,1次/d,连续14 d。结果给药后高剂量组主要表现为体重减轻、活动减少、少尿或无尿;淋巴细胞计数、单核细胞计数、红细胞计数、红细胞压积、总蛋白质、白蛋白、总胆固醇、K+和Na+等均显著低于对照组,而血小板计数、中性粒细胞计数、葡萄糖、尿素氮、肌酐和乳酸脱氢酶等升高;尿中白蛋白、乳酸脱氢酶、β-N-乙酰氨基葡萄糖苷酶等也显著升高,并有胆红素、白细胞和红细胞排出;肾脏脏器系数增大,肾小球出现红细胞堵塞,近曲小管上皮细胞变性较严重,伴有上皮细胞脱落,间质内可见较大面积的淤血、出血。结论在该试验条件下,马兜铃酸Ⅰ对SD大鼠的肾脏毒性反应较强,不仅作用于近曲小管,亦能损伤肾小球,其安全剂量小于5 mg/kg。     

朱砂莲中毒致急性马兜铃酸肾病

1名73岁女性患者,因胃部不适服用朱砂莲粉末约20g,10min后出现持续呕吐,经对症治疗未缓解。3d后出现少尿,尿常规显示:pH9.0,Glu( ),PRO(┼┼),KET( )。BUN17.8mmol/L,SCr708μmol/L,UA294.5μmol/L。B超显示双肾弥漫性实质病变。诊断为朱砂莲中毒所致的急性马兜铃酸肾病、急性肾衰竭。给予金水宝胶囊、多巴胺、呋塞米、碳酸氢钠、氢化可的松等治疗及血液透析,患者尿量逐渐增多,肾功能改善,症状消失。3个月后随访,肾功能稳定。     

加味附子理中汤治疗马兜铃酸肾病疗效的临床观察

目的:观察加味附子理中汤对马兜铃酸肾病(AAN)患者肾功能及临床症状的影响。方法:对27例具有脾阳虚证候群的AAN患者应用加味附子理中汤进行治疗,每天1剂,水煎服,4周为1个疗程。第2疗程结束后3d内评估疗效,观察指标为尿素氮、血肌酐、内生肌酐清除率、血常规(红细胞、血红蛋白)、24h尿蛋白定量、尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、尿渗透压以及畏寒肢冷、倦怠乏力、食少纳呆、恶心欲吐、面色晄白、腰酸膝软等临床症状分级积分。结果:治疗后患者肾功能得到明显改善,血肌酐、尿素氮、24h尿蛋白定量、尿NAG酶下降,内生肌酐清除率、尿渗透压升高,与治疗前比较差异均有统计学意义(P<0.05)。同时临床症状得到缓解,症状分级积分均低于治疗前(P<0.05)。患者临床总有效率为74.07%。结论:加味附子理中汤对AAN有较好的治疗作用。     

The in vivo disposition and in vitro transmembrane transport of two model radiometabolites of DOTA‐conjugated receptor‐specific peptides labelled with 177Lu

In vivo metabolism of the radiolabelled receptor‐specific peptides has been described; however, information regarding the pharmacokinetic behaviour of the degradation products within the body is very scarce. The present study was designed to obtain new knowledge on the disposition and elimination of low‐molecular radiometabolites of receptor‐specific peptides in the organism and to reveal the potential involvement of selected membrane transport mechanisms in the cellular uptake of radiometabolites, especially in the kidney. The study compared pharmacokinetics of two radiometabolites: a final metabolite of somatostatin analogues, ¹⁷⁷Lu‐DOTA‐DPhe, and a tripeptide metabolite of ¹⁷⁷Lu‐DOTA‐minigastrin 11, ¹⁷⁷Lu‐DOTA‐DGlu‐Ala‐Tyr. Their pharmacokinetics was compared with that of respective parent ¹⁷⁷Lu‐radiopeptide. Both radiometabolites exhibited relative rapid clearing from most body tissues in rats in vivo along with predominant renal excretion. The long‐term renal retention of the smaller radiometabolite ¹⁷⁷Lu‐DOTA‐DPhe was lower than that of ¹⁷⁷Lu‐DOTA‐DGlu‐Ala‐Tyr. An uptake of ¹⁷⁷Lu‐DOTA‐DPhe by human renal influx transporter organic cation transporter 2 was found in vitro in a cellular model. The study brings the first experimental data on the in vivo pharmacokinetics of radiometabolites of receptor‐specific somatostatin and gastrin analogues. The found results may indicate a negative correlation between the degree of decomposition of the parent peptide chain and the renal retention of the metabolite.     

甘草酸二铵对马兜铃酸致肾小管上皮细胞损害保护作用的实验研究

目的　探讨甘草酸对马兜铃酸 (aristolochic acid,AA)肾损害的保护作用 ,观察甘草酸是否可以减轻 AA对培养的肾小管上皮细胞的损害 ,并初步探讨其可能机制。方法　 5 % FCS RPMI- 16 4 0培养肾小管上皮细胞株 (L L C- PK1) ,采用结晶紫染色法观察细胞增殖 ;荧光染色观察活细胞数目 ;酶动力学检查 L DH活性 ,比色法检测 NAG水平 ;透射电镜观察细胞超微细胞结构。结果　1AA4 0、80、16 0μg/ ml可明显抑制细胞增殖 ,结晶紫 OD值显著减少 ,与无 AA对照组比较 P<0 .0 1。 2甘草酸二铵 (diammoniumglycyrrhizinate,DG)在 5、10、2 5 μg/ ml时结晶紫 OD值与无甘草酸对照组比较 P>0 .0 5 ,甘草酸在 5 0 μg/ ml时 P<0 .0 5 ,10 0 μg/ ml、2 0 0μg/ ml时 P<0 .0 1,提示大剂量甘草酸可改善 AA抑制细胞增殖的作用。 3在 AA4 0μg/ ml作用下随着时间延长 ,无甘草酸组的细胞存活数目逐渐减少 ,而甘草酸 (10 0μg/ ml、2 0 0μg/ ml)作用组 ,活细胞数目明显增多 ,提示高浓度甘草酸对细胞损伤有一定的保护作用。4甘草酸在 5、10、2 5 μg/ ml时 ,L DH释放率、NAG酶水平与无甘草酸对照组比较 P>0 .0 5 ,甘草酸在 5 0 μg/ ml时 P<0 .0 5 ,甘草酸在 10 0μg/ ml、2 0 0μg/ ml时 L DH释放率、NAG酶明显减少 ,与无甘草