中草药肾病研究现状

因中草药应用不当导致肾功能损害屡有发生。本文对马兜铃属植物药引起肾损害的有关报道以及相关的研究内容作一综述 ,主要包括马兜铃属植物药物及其成分、马兜铃酸的药代动力学、马兜铃酸属药物的肾脏损害的表现及其发生机制等     

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。     

中药的忧伤——由马兜铃属植物毒性谈起

马兜铃事件已事发多年，马兜铃酸的致毒性又有新发现，国际癌症研究中心（IARC）工作组会议最近也认为马兜铃属的某些品种对人类有一级致癌性。马兜铃酸主要存在于马兜铃属某些种的植物中，木通科木通、防已科防已等植物尚未见含有马兜铃酸的报导，但有些国家混淆了广防己、     

关注马兜铃酸对人民健康的危害

由马兜铃酸引发的肾病,称为马兜铃酸肾病。早在1964年就有吴松寒首报服用木通所致急性肾功能衰竭病例,揭开了马兜铃属植物药材致肾毒害的面纱。此后马红梅等检索了关木通引起肾毒害者34例,其中在国内的21例中,10例死亡,9例需肾透析,仅2例病情较稳定;在国外的13例中,5例需肾透析,2例肾移植,3例肾功能障碍,仅3例停药后病情逐步改善。在用马兜铃酸静脉注射试治癌症实验中,日剂量1mg/kg,连续3天或3天以上的10例中,有几例死于肾急性中毒性肾变性,故认为马兜铃酸在人体内有积蓄性,可见马兜铃酸对人体的危害十分严重。马兜铃酸在化学上分为A、B、C、D、E等数种,存在于马兜铃属植物的根、茎和果实中。凡含有此类成分的植物,均含有马兜铃酸A,然后才有其它成分与之共存。由此,可认为这类成分在植物体内均由马兜铃酸A衍变产生。国产马兜铃属植物有39种,在相关的中药材书籍中记载供药用者已达26种之多。《中国药典》2000年版一部收载4种马兜铃属植物计5种药材,它们是:广防已（广防已的根）、马兜铃（北马兜铃或马兜铃的果实）、天仙藤（北马兜铃或马兜铃的茎）、关木通（东北马兜铃的茎）、青木香（马兜铃的根）,此5种药材均含有马兜铃酸类成分。由马兜铃属植物药材组成的成方制剂,《中国药典》2000年版收载含马     

微博

@健康管理:日前,方舟子发表博文指出,"猴枣散在医院里推销很厉害,医生为牟利毒害小孩。猴枣散含马兜铃科植物细辛,有马兜铃酸,会对肾脏造成不可逆损伤,千万别用"。而目前,美英法日等国及我国港台地区已禁用含马兜铃酸的中药和保健品,但国内至少仍有36种含马兜铃酸的中成药作为处方药在售。     

微博

@健康管理：日前,方舟子发表博文指出,＂猴枣散在医院里推销很厉害,医生为牟利毒害小孩。猴枣散含马兜铃科植物细辛,有马兜铃酸,会对肾脏造成不可逆损伤,千万别用＂。而目前,美英法日等国及我国港台地区已禁用含马兜铃酸的中药和保健品,但国内至少仍有36种含马兜铃酸的中成药作为处方药在售。     

UPLC-UV测定细辛地上和地下部位中的马兜铃酸A

马兜铃酸因被证实具有肾毒性而引起广泛的重视[1,2],尤其近年来美国FDA有关法令中,已明确提出禁止使用含有马兜铃酸的药物,因此马兜铃科植物的安全性受到质疑.     

马兜铃酸致肾损害的特点及防治

目的探讨马兜铃酸致肾损害的特点及防治.方法收集与马兜铃酸有关的不良反应,分析其安全性.结果与结论合理应用含马兜铃酸的中药,了解其发病机制是减少肾损害的关键.     

去马兜铃朱砂莲提取物对小鼠伤害性疼痛的影响

朱砂莲为马兜铃科马兜铃属植物,性味苦、辛、寒。其主要功能清热解毒,消肿止痛。但其化学成分马兜铃酸可直接损伤肾小管及间质,致近端肾小管刷状缘脱落、坏死。有报道广西朱砂莲药材水提物和醇提物均能明显的抑制小鼠巴豆油致耳廓肿胀、腹腔毛细血管通透性亢进;且能明显减少醋酸致小鼠扭体次数及延长热板致病的潜伏期有镇痛作用。本课题旨在利用现代工艺技术进行提取、萃取、去除朱砂莲中有害成分马兜铃酸,并观察其对光热疼痛模型小鼠的影响,以期开发安全有效的中药镇痛剂。     

马兜铃属植物的化学(Ⅱ)异马兜铃酸与马兜铃酸的关系

作者等前于土青木香(Aristolochia debilis, S. et Z.)中分出一种m.p. 275℃(分解)的黄色结晶(Ⅰ),从其元素分析、游离酸及其甲酯的熔点看来,均与異马兜铃酸(Ⅱ)一致.经继续研究,证明(Ⅰ)应与马兜铃酸(Ⅲ)相同,因此作这二种化合物的检查.按马兜铃酸是马兜铃属植物的一个共有成分,而異马兜铃酸则系1935年Krishnaswamy,Manjunath,Rao等氏从印度马兜铃(A. indica)中分出.Rosenmund,Reichstein等曾怀疑这二种成分可能是同一化合物,但没有充分的证据。     

3H羟基斑蝥胺的药物代谢动力学研究

将氚标记的羟基斑蝥胺在大鼠体内研究了药物代谢动力学。所得血药浓度-时间数据依一定程序在709电子计算机上拟合曲线,并计算有关参数。结果表明,静脉注射后符合二房室开放型模型,其药代动力学参数为:t1/2α0.067hr,t1/2β2.208hr,V_d(面积)1.237l/kg,V₁0.264l/kg,K_el1.470 hr^-1,清除率0.388l/hr/kg。灌胃后可以单室开放型模型描述,其药代动力学参数为:K_α2.990hr^-1,K_el0.257hr^-1,V_d1.603l/kg,t1/22.693hr,t_max0.90hr,C_max0.745μg/ml,F94.15%。尚将本药以静脉和灌胃两种途径给药后直接观察在大鼠体内的组织分布和在尿粪胆汁中的排泄,结果表明本药分布广,主要经肾排泄,且排泄较快,与药代动力学分析结果相一致。     

The Metabolic Fate of the Anti-HIV Active Drug Carrier Succinylated Human Serum Albumin after Intravenous Administration in Rats

The pharmacokinetics and metabolic fate of the intrinsically active (anti-HIV) drug carrier succinylated human serum albumin (Suc-HSA) was studied in rats. Suc-HSA was prepared by derivatizing HSA with 1,4-[¹⁴C]-succinic anhydride, a modification by which all available εNH₂-groups in HSA were converted into carboxylic groups.

After iv injections of 0.3, 1.0, 3.0 and 10.0 mg/kg in freely moving rats, Suc-HSA showed a dose dependent elimination pattern, indicating a saturable elimination pathway. The Michaelis-Menten parameters V_max and K_m were 98.7 μg.min^?1.kg^?1 and 8.5 μg.ml^?1 respectively. The kinetics of Suc-HSA was influenced by anaesthesia. In anaesthetised animals, V_max and K_m were found to be 26.9 μg.min^?1.kg^?1 and 0.26 μg.ml^?1, respectively. This implies an intrinsic clearance of 100ml.min^?1.kg^?1, which is about 10-fold higher as compared to 12 ml.min^?1.kg^?1 in freely moving animals.

Intravenous administration of a sub-saturable dose of 3.0mg.kg^?11,4-[¹⁴C]-Suc-HSA to freely moving rats resulted in a biphasic elimination with an initial t1/2 of 20 min and a terminal t1/2 of 40 hrs. Excretion of metabolites in urine and faeces lasted for at least 48 hours. About 70% of the radioactive dose was excreted in urine, whereas maximally 2% was detected in faeces. Suc-HSA was degraded to its individual amino acids including succinylated lysine (the only radioactive product formed). Succinylated lysine was not further metabolised and mainly excreted via the urine. Immunohistochemical staining showed that even after 48 hrs Suc-HSA could be detected in livers. Together with the urinary excretion patterns, this points to a gradual degradation of Suc-HSA.     

山豆根碱的体内动力学研究

山豆根碱(dauricine)是从防己科植物蝙蝠葛(Menisppermnm dauricum D C.)中提取的酚性生物碱之一,是异喹啉类生物碱。动物实验证明有较好的降压效果。为此我们进行了山豆根碱的体内动力学研究。     

何首乌有效成分二苯乙烯苷的药代动力学研究

目的建立小鼠和兔血浆中二苯乙烯苷浓度的HPLC测定方法,研究何首乌中二苯乙烯苷在小鼠和兔体内的药代动力学行为。方法用Diamonsil^TM C₁₈色谱柱(250 mm×4.6 mm,5 μm),以乙腈-甲醇-1%甲酸(15∶18∶67)为流动相,流速1.0 mL·min^-1,检测波长320 nm。结果线性范围为0.41～42.0 μg·mL^-1(γ=0.9999),最低检测浓度为0.051 μg·mL^-1。高、中、低3种不同浓度的平均回收率分别为97.98%,101.7%和104.5%,日内精密度RSD分别为8.7%,2.9%和5.5%。小鼠和兔iv二苯乙烯苷后药代动力学行为均符合二室模型,药代动力学参数分别为:T_1/2α=1.9,2.7 min;T_1/2β=8.3,13.5 min;K₂₁=6.6,4.2 h^-1;K₁₂=3.8,3.0 h^-1;K₁₀=16.0,11.2 h^-1;V_c=0.090,0.198 L·kg^-1;AUC=6.918,4.530 mg·h·L^-1;CL=1.445,2.208 L·h^-1·kg^-1。小鼠ig给药后二苯乙烯苷在胃肠道内的吸收不规则,且血药浓度很低,药代动力学行为不符合房室模型。结论建立了二苯乙烯苷血药浓度的HPLC测定方法,阐明了二苯乙烯苷的药代动力学特征。方法的专属性高,操作简便,结果准确。     

Comparison of a new orally potent tripeptide HIV-1 protease inhibitor (anti-aids drug) based on pharmacokinetic characteristics in rats after intravenous and intraduodenal administrations

Recently, a series of KNI compounds such as KNI-227 and KNI-272 has been synthesized and shows potent and selective HIV-1 protease inhibitory activity in vitro. In this study, we developed an HPLC assay system for KNI-227 and KNI-272 in rat plasma and examined the pharmacokinetic characteristics in rats after both intravenous (i.v.) and intraduodenal (i.d.) administrations to obtain the disposition characteristics and bioavailabilities of these new anti-AIDS drugs. After i.v. administration of KNI-227, 10.0mg kg^?1, the mean terminal elimination half-life, t_1/2λz, was 0.808±0.161(SE)h, the total body clearance, CL_tot, was 11.7±3.3 ml min^?1 and the distribution volume at steady state (V_d,ss) was 1410.460 ml kg^?1. On the other hand, after i.v. administration of KNI-272, 10.0mg kg^?1, t_1/2λz was 2.86±0.78 h, CL_tot was 15.3±1.4 ml min^?1 and V_d,ss was 3440.670 ml kg^?1. In the case of the i.d. administration of drugs, the mean peak plasma concentrations, C_max, of KNI-227 and KNI-272 were 0.374±0.110μg ml^?1 and 0.900±0.093 μg ml^?1, respectively. The bioavailabilities (BA) of KNI-227 and KNI-272 to infinity, BA^(0-∞), were 5.90% and 42.3%, respectively. As compared with the lead compound, KNI-174, the BA of KNI-272 was improved about 10 times. Although the anti-AIDS virus activity of these two drugs has not been investigated in vivo, KNI-272 is expected to be a better candidate for oral anti-AIDS therapies.     

Pharmacokinetics and pharmacodynamics of morphine-3-glucuronide in rats and its influence on the antinociceptive effect of morphine

In this study the pharmacokinetics and pharmacodynamics of morphine-3-glucuronide (M3G) were investigated in rats after i.v. administration as a bolus dose (86.7 μmol kg^?1) and as a constant rate infusion (2.9 μmol h^?1) over 5 days. After the bolus dose, the clearance (Cl) was 12.1 ± 0.6 ml min ^?1* kg, the volume of distribution at steady state (V_ss) 1.68 ± 0.89 1 kg^?1, the half-life of the first phase 13.2 ± 1.8 min and the halflife of the second phase 11.6 ± 7.7 h. After the constant rate infusion, Cl was 10.5 ± 1.7 ml min^?1*kg. The antagonistic effect of M3G on the antinociceptive effect of a bolus dose of morphine (35 μmol kg^?1) was tested during steady state concentrations of M3G on day 4 and to M3G naïve rats. No antinociceptive, hyperalgesic or withdrawal effects were observed as a result of M3G administration, but a significantly lower antinociceptive effect of morphine was found in the M3G infusion group compared to the control group. Systemically administered M3G antagonized the antinociceptive effect of morphine, but this cannot be the only explanation to the tolerance development observed after morphine administration.     

Pharmacokinetics of 14C-DMPS (sodium-1,3 14C-2,3-dimercaptopropane-l-sulphonate) in beagle dogs

The pharmacokinetics of labelled DMPS (sodium-1,3 ¹⁴C-2,3-dimercaptopropane-1-sulphonate) have been studied in four beagle dogs following bolus intravenous injection (65-7 μmolkg^?1) and oral administration (197μmol kg^?1). Following intravenous injection the main kinetic parameters were t_1/2 = 43min, V_β = 160 ml kg^?1, and plasma clearance Cl_p = 2.6ml min^?1 kg^?1. Following oral administration ¹⁴C-DMPS is rapidly absorbed with peak concentrations (478 ± 25 umol 1^?1) measured after 30–45 min. About 60 per cent of the oral dose was absorbed. Estimates of t_1/2, V_β, and Cl_p after oral administration were in close agreement with the values obtained in the intravenous study. ¹⁴C-DMPS is eliminated from the body by the kidneys. About 70 per cent of ¹⁴C-DMPS in dog plasma are bound to proteins. Binding is even higher in plasma from rat and man.     

In vitro metabolism of the epoxide substructure of cryptophycins by cytosolic glutathione S-transferase: Species differences and stereoselectivity

The enzyme kinetics of the glutathione (GSH) conjugation of cryptophycin 52 (C52, R-stereoisomer) and cryptophycin 53 (C53,?S-stereoisomer) by cytosolic glutathione S-transferases (cGSTs) from human, rat, mouse, dog and monkey liver were studied. V_max, K_m, and CL_int values for glutathione conjugation of C52 (R-stereoisomer) were 0.10?±?0.01?nmol?min^?1?mg^?1, 3.24?±?0.23?µM, and (3.15?±?0.09)?×?10^?2?ml?min^?1?mg^?1, respectively, in human cytosol. Due to limited solubility relative to the K_m, only CL_int values were determined in rat ((7.76?±?0.10)?×?10^?2?ml?min^?1?mg^?1) and mouse ((7.61?±?0.50)?×?10^?2?ml?min^?1?mg^?1) cytosol. Enzyme kinetic parameters could not be determined for C53 (S-stereoisomer). Microsomal GSH conjugation in human, rat, and mouse was attributed to cytosolic contamination. No GSH conjugation was seen in any biological matrix from dog or monkey. There was little GSH conjugation of C53 by cytosol or microsomes from any species. The metabolism of C52 and C53 by epoxide hydrolase was also investigated. No diol product was observed in any biological matrix from any species. Thus, cGSTs are primarily responsible for C52 metabolism.     

常咯啉在实验性心律失常狗的药代动力学-药效动力学分析

用Harris冠脉结扎法诱发的心律失常狗研究常咯啉药代动力学-药效动力学。7只狗按83.33μg·kg^-1·min^-1静脉滴注60min,在给药期间和停药后不同时间记录ECG及测定血药浓度。C-T数据用药代程序计算药代参数;药效数据用药代-药效同步分析模型计算药效动力学参数,K₁₀, T_1/2,Vd,Cl分别为0.0087min^-1,78.03min,40.55ml·kg^-1和0.421ml·kg^-1·min^-1;K_eO和Ce(50)分别为0.0048min^-1和2.01μg·ml^-1.     

Pharmacokinetics of quinidine and three of its metabolites in man

Disposition parameters of quinidine and three of its metabolites, 3-hydroxy quinidine, quinidine N-oxide, and quinidine 10,11-dihydrodiol, were determined in five normal healthy volunteers after prolonged intravenous infusion and multiple oral doses. The plasma concentrations of individual metabolites after 7 hr of constant quinidine infusion at a plasma quinidine level of 2.9±(SD) 0.3 mg/L were: 3-hydroxy quinidine, 0.32±0.06 mg/L; quinidine N-oxide, 0.28±0.03 mg/L; and quinidine 10,11-dihydrodiol, 0.13±0.04 mg/L. Plasma trough levels after 12 oral doses of quinidine sulfate every 4 hr averaged: quinidine, 2.89±0.50 mg/L; 3-hydroxy quinidine, 0.83±0.36 mg/L; quinidine N-oxide, 0.40±0.13 mg/L; and quinidine 10,11-dihydrodiol, 0.38±0.08 mg/L. Relatively higher plasma concentrations of 3-hydroxy quinidine metabolite after oral dosing probably reflect first-pass formation of this quinidine metabolite. A two-compartment model for quinidine and a one-compartment model for each of the metabolites described the plasma concentration-time curves after both i.v. infusion and multiple oral doses. Mean (±SD) disposition parameters for quinidine from individual fits, after i.v. infusion were as follows: V ₁ ,0.37±0.09 L/kg; ₁,0.094±0.009 min ^–1; ₂, 0.0015±0.0002 min^–1; EX2, 0.013±0.002 min^–1;clearance (Cl_Q),3.86±0.83 ml/min/kg. Both plasma and urinary data were used to determine metabolic disposition parameters. Mean (±SD) values for the metabolites after i.v. quinidine infusion were as follows: 3-hydroxy quinidine: formation rate constant k_mf,0.0012±0.0005 min ^–1,volume of distribution, V_m,0.99±0.47 L/kg; and elimination rate constant, k_mu 0.0030±0.0002 min ^–1.Quinidine N-oxide: k_mf,0.00012±0.00003 min ^–1; V_m,0.068±0.020 L/kg; and k_mu,0.0063±0.0008 min ^–1.Quinidine 10,11-dihydrodiol: k_mf,0.0003±0.0001 min ^–1; V_m,0.43±0.29 L/kg; and k_mu,0.0059±0.0010 min ^–1.Oral absorption of quinidine was described by a zero order process with a bioavailability of 0.78. Concentration dependent renal elimination of 3-hydroxy quinidine was observed in two out of five subjects studied.This work was supported by funds from the grants GM 26691 and GM 28072 from the National Institute of General Medical Sciences, NIH. A. Rakhit was the recipient of a Training Grant Traineeship from NIH. T. W. Guentert is grateful for support from the Swiss National Science Foundation.Professor Sidney Riegelman. deceased April 4, 1981.