共查询到20条相似文献,搜索用时 15 毫秒
1.
Hanna GM 《Die Pharmazie》2004,59(4):251-256
1H NMR methodology is described for the determination and characterization of the dietary supplement S-adenosyl-L-methionine (SAM), recently introduced to the US market, utilizing a 400 MHz spectrometer without the need of pure reference standards. The developed methodology is able to assess chemical structure, differentiate between biologically-active (S)-diastereomer and biologically-inactive (R)-diastereomer, and determine the ratio of each in the dietry supplement formulation. The determination of the percentage of declared SAM was based on the integrals for the methyl proton of 2-methyl-2-propanol served as an internal standard at delta 1.24 and the methine proton H1' of SAM ribose ring at delta 6.06. The percentage of the active diastereomer was calculated from the relative intensities of the sulfonium methyl singlets corresponding to the major component (S)-diastereomer at delta 2.98 and the minor (R)-counterpart at delta 2.93. The accuracy was established by analyzing synthetic mixtures of the analyte and the internal standard. Excellent agreement was verified between the assay results and the quantities of analyte in the mixture. The mean +/- SD recovery values for SAM and its (R)-diastereomer impurity from a set of 10 synthetic mixtures were 99.6 +/- 0.8% and 22.5 +/- 0.1%, respectively. Using 10 lots, the percentage of SAM ranged from 0 to 110.7% of the declared value and the percentage of the active (S)-diastereomer ranged from 0 to 82.3%. 相似文献
2.
3.
Effects of dexfenfluramine on aristolochic acid nephrotoxicity in a rat model for Chinese-herb nephropathy 总被引:8,自引:0,他引:8
Debelle F Nortier J Arlt VM De Prez E Vienne A Salmon I Phillips DH Deschodt-Lanckman M Vanherweghem JL 《Archives of toxicology》2003,77(4):218-226
Chinese-herb nephropathy (CHN) is a progressive renal interstitial fibrosis initially reported after concomitant intake of an anorexigen, (dex)fenfluramine, and a Chinese herb ( Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acid (AA). We thus tested the possible enhancing effect of the active enantiomer dexfenfluramine (DXF) on AA nephrotoxicity in a rat model for CHN. Groups of 12 salt-depleted male Wistar rats received daily subcutaneous injections of 7 mg/kg body weight DXF (DXF group), 7 mg/kg body weight AA (AA group), a combination of the same doses of AA and DXF (AA+DXF group), or vehicle (control group) for up to 35 days. Six animals per group were killed on day 10 and the remaining six on day 35. Renal function was evaluated by determining serum creatinine and urinary leucine aminopeptidase activity. Histological evaluation of kidney samples was performed and tubulointerstitial injuries were semiquantified. The DXF group did not differ from controls for any parameter. Similarly elevated serum creatinine levels, decreased leucine aminopeptidase enzymuria, and renal lesions were observed in the AA and the AA+DXF groups after both 10 and 35 days. The formation of specific AA-DNA adducts in liver and renal tissue samples was assessed by the (32)P-postlabelling method. Specific AA-DNA adduct levels were significantly increased in kidney tissues from AA+DXF rats compared with AA rats. These functional and histological data suggest that DXF does not enhance AA nephrotoxicity in a rat model for CHN. Further investigations are needed to clarify the mechanism by which DXF may enhance AA-DNA adduct formation. 相似文献
4.
Hanna GM 《Die Pharmazie》2006,61(3):188-193
Regulatory enantiomeric purity direct determination for (S)-(+)-methamphetamine, the widely abused DEA schedule II controlled substance, and (R)-(-)-desoxyephedrine, over-the-counter nasal inhaler decongestant were developed using 400 MHz 1H NMR spectroscopy. The efficient enantiomeric differentiation was obtained using a diamagnetic chiral solvating agent to dissimilarly perturb the NMR spectra of the enantiomeric solutes. Nonequivalence behavior was studied in terms of all variables that affect population and intrinsic spectra of the fast diastereomeric solvates. Assignment of enantiomer configuration was based on the relative field position of the resolved enantiomeric signals. Optimization of experimental conditions provided significant resolved enantiomeric signals suitable for quantification. Utilizing the relative intensities of the corresponding enantiomeric signals of the N-CH3 assigned to (S)-(+)-methamphetamine and (R)-(-)-desoxyephedrine, the analysis of synthetic enantiomeric mixtures by the proposed methods demonstrated excellent agreements with the known values of the enantiomers present. The mean +/- SD recovery values for the (R)-(-)-enantiomer was 99.9 +/- 0.4% of added antipode (n = 7). The optically pure enantiomer was used to establish the minimum amount detected by the proposed NMR spectroscopic method. 相似文献
5.
Acute nephrotoxicity of aristolochic acids in mice 总被引:1,自引:0,他引:1
Sato N Takahashi D Chen SM Tsuchiya R Mukoyama T Yamagata S Ogawa M Yoshida M Kondo S Satoh N Ueda S 《The Journal of pharmacy and pharmacology》2004,56(2):221-229
Aristolochic acids (AA), present in Aristolochia plants, are the toxin responsible for Chinese herbs nephropathy (CHN), a rapidly progressive tubulointerstitial nephritis (TIN). To clarify the mechanisms of the development of CHN, we tried to induce TIN in mice using AA. Three strains of inbred mice, BALB/c, C3H/He and C57BL/6, received 2.5 mg kg(-1) of AA or AA sodium salt (AANa) daily by intraperitoneal or oral administration, 5 days a week for 2 weeks. Serum and renal tissue were obtained at sacrifice. Twelve-hour urine samples were individually collected in a metabolic cage at one-week intervals. In the AA-injected groups, severe tubular injury, with the appearance of acute tubular necrosis, and rare cell infiltration into the interstitium, were seen in BALB/c mice. C3H/He mice also developed TIN with prominent cell infiltration into the interstitium and interstitial fibrosis. In C57BL/6 mice, only mild and focal tubulointerstitial changes were seen. Serum creatinine and blood urea nitrogen increased in BALB/c and C3H/He mice. Immunofluorescent study revealed no deposition of immune components in kidneys. In the AANa-treated groups, TIN was also seen in all groups, but even more severe tubulointerstitial changes were induced by intraperitoneal injection. Further examination using purified AAI, AAII, AAIVa and aristolactam I (ALI) revealed that AAI induced strong nephrotoxicity in mice, and that AAII resulted in mild nephrotoxicity. However, AAIVa and ALI caused no nephrotoxicity in this experimental system. There are strain differences in mice in their susceptibility to AA nephropathy. AAI exerted the strongest nephrotoxic effect in mice. 相似文献
6.
Shinya Shibutani Huan Dong Naomi Suzuki Shiro Ueda Frederick Miller Arthur P Grollman 《Drug metabolism and disposition》2007,35(7):1217-1222
Ingestion of herbal remedies containing aristolochic acids (AAs) is associated with the development of a syndrome, designated aristolochic acid nephropathy (AAN), which is characterized by chronic renal failure, tubulointerstitial fibrosis, and urothelial cancer. To distinguish the component(s) of AA responsible for these varied toxic effects, we administered 2.5 mg/kg/day of AA-I or AA-II for 9 days, either i.p. or p.o., to male C3H/He mice. Tissues were then collected and subjected to biochemical and histopathologic examination. Genotoxicity was assessed by determining quantitatively the level of aristolactam-DNA adducts in various tissues using (32)P-postlabeling/polyacrylamide gel electrophoresis and an internal standard. In the primary target tissues, represented by the renal cortex, medulla, and bladder, we found similar levels of DNA adducts derived from AA-I and AA-II. However, in nontarget tissues, the liver, stomach, intestine, and lung, the levels of aristolactam-DNA adducts derived from AA-I were significantly higher than those derived from AA-II. Histopathologic analysis revealed tubular cell necrosis and interstitial fibrosis in the renal cortex of AA-I-treated mice but only minimal changes in the renal cortex of mice treated with AA-II. We conclude that AA-I and AA-II have similar genotoxic and carcinogenic potential, and, although both compounds are cytotoxic, AA-I is solely responsible for the nephrotoxicity associated with AAN. 相似文献
7.
目的 分析含有马兜铃酸成分的药物引起马兜铃酸肾病的临床特点和规律。方法 回顾性研究 111例服用含马兜铃酸成分的药物致肾损害患者的临床资料,分析马兜铃酸肾病的临床特点、服药及治疗方法等。结果 111例患者中,女性多于男性(2.58∶1),大于50岁的101例(90.99%);年龄(63.70±11.67)岁;平均用药时间(8.08±6.94)年;涉及冠心苏合丸和龙胆泻肝丸共106例(95.50%);血肌酐升高108例,尿素氮升高106例,血红蛋白降低103例,多见低比重尿、轻中度蛋白尿和潜血;B 超检查示肾脏均不同程度受损。肾脏病理活检为肾小管损害。多数患者起病隐匿,进展程度不一,与年龄、服药时间不成正比,临床上肾功能呈进行性损害, 多数不可逆、预后较差。结论 肾损害患者个体差异较大,肾损伤与服用马兜铃酸药物时间长短、剂量不平行;马兜铃酸肾病进展迅速,且停止服用含马兜铃酸药物后病情依然进展。加强药物警戒工作,实施早期的诊断和有效的干预,有助于减少马兜铃酸肾病的发生,延缓其发展。 相似文献
8.
Studies on the metabolism of aristolochic acids I and II 总被引:3,自引:0,他引:3
G Krumbiegel J Hallensleben W H Mennicke N Rittmann H J Roth 《Xenobiotica; the fate of foreign compounds in biological systems》1987,17(8):981-991
1. After oral administration of aristolochic acid I (AAI) and aristolochic acid II (AAII) to rats, the following metabolites were isolated from the urine and their structures elucidated: aristolactam I, aristolactam Ia, aristolochic acid Ia, aristolic acid I and 3,4-methylenedioxy-8-hydroxy-1-phenanthrenecarboxylic acid (metabolites of AAI); or aristolactam Ia, aristolactam II and 3,4-methylenedioxy-1-phenanthrenecarboxylic acid (metabolites of AAII). A further metabolite of AAII having a lactam structure has not yet been isolated in pure form. 2. The metabolic pathways have been elucidated by administration of various metabolites. 3. The principal metabolite of AAI in rats was aristolactam Ia; 46% of the dose was excreted in the urine in form of this metabolite and 37% in the faeces. The other substances were minor metabolites. Those metabolites of AAII whose structures have been elucidated were minor metabolites; the largest proportion consisted of aristolactam II, which accounted for 4.6% in the urine and 8.9% in the faeces. 4. The mouse was the only animal which had the same metabolite patterns of AAI and AAII as those found in the rat. Not all the metabolites listed above were found in urine from guinea pigs, rabbits, dogs and man. 相似文献
9.
《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(8):981-991
1. After oral administration of aristolochic acid I (AAI) and aristolochic acid II (AAII) to rats, the following metabolites were isolated from the urine and their structures elucidated: aristolactam I, aristolactam Ia, aristolochic acid Ia, aristolic acid I and 3, 4-methylenedioxy-8-hydroxy-1-phenanthrenecarboxylic acid (metabolites of AAI); or aristolactam Ia, aristolactam II and 3,4-methylenedioxy-1-phenanthrenecarboxylic acid (metabolites of AAII). A further metabolite of AAII having a lactam structure has not yet been isolated in pure form.2. The metabolic pathways have been elucidated by administration of various metabolites.3. The principal metabolite of AAI in rats was aristolactam Ia; 46% of the dose was excreted in the urine in form of this metabolite and 37% in the faeces. The other substances were minor metabolites. Those metabolites of AAII whose structures have been elucidated were minor metabolites; the largest proportion consisted of aristolactam II, which accounted for 4.6% in the urine and 8.9% in the faeces.4. The mouse was the only animal which had the same metabolite patterns of AAI and AAII as those found in the rat. Not all the metabolites listed above were found in urine from guinea pigs, rabbits, dogs and man. 相似文献
10.
Design and NMR characterization of active analogues of compstatin containing non-natural amino acids 总被引:1,自引:0,他引:1
Mallik B Katragadda M Spruce LA Carafides C Tsokos CG Morikis D Lambris JD 《Journal of medicinal chemistry》2005,48(1):274-286
We present new findings in our drug discovery effort to develop an anticomplement therapeutic. We have designed several active analogues of compstatin by altering its amino acid composition at positions 4 and 9. The most effective analogues have tryptophan or fused-ring non-natural amino acids at position 4 and alanine or an unbranched single-methyl amino acid at position 9. Twenty-one of these analogues have 2-99-fold higher activities compared to the parent peptide compstatin. The analogue Ac-V4(2Nal)/H9A-NH(2) has the highest inhibitory activity with IC(50) 500 nM. NMR data, through NOE and chemical shift analysis, suggest the presence of interconverting conformers spanning the extended and helical regions of the Ramachandran plot, and they detect a predominant averaged conformer with coil structure and at least one flexible beta-turn, of type I. The fused-ring non-natural amino acids at position 4 contribute to the formation of the hydrophobic cluster of compstatin, which has been previously proposed, together with the beta-turn and a disulfide bridge, to be essential for binding to the target of compstatin, complement component C3. We propose that additional mechanisms may contribute to the structural stability of the analogues and to binding to C3, involving intra- and intermolecular electrostatic interactions of the pi-electron system of side chain aromatic rings. The presence of pi-pi interactions for Trp4-Trp7 was confirmed with a molecular dynamics simulation for the most active analogue with natural amino acids, Ac-V4W/H9A-NH(2). Alanine or aminobutyric acid at position 9 contribute to the weak propensity for helical structure of the residue segment 4-10 of the analogues, which may also play a role in increased activity. 相似文献
11.
Electroanalytical procedure for the determination of nephrotoxic aristolochic acid-I in the medicinal plant has been developed in the presence of potential interferences of lead and cadmium by square wave voltametry (SWV). Among the phosphate buffers of pH values at 5.0, 6.1, 6.5 and 7.0, the phosphate buffers of pH 6.1 yielded the most accurate analysis of AA-I in the presence of Pb2+ and Cd2+; Pb2+ was precipitated as Pb(HPO4) and did not appear in the SW voltammogram, while Cd2+ appeared at -0.564 V which was well resolved from AA-I at -0.416 V. When the Ip of AA-I was plotted vs. concentrations between 1.67 x 10(-8) M and 1.67 x 10(-6) M in the presence of Pb2+ and Cd2+, a linear calibration curve was obtained with a slope of 6 x 10(8) nA/M and a correlation coefficient of 0.9999. The present method was applied to determine AA in the dried natural products of Aristolochia contorta Bunge; Total AA in the dried root and the ripe fructus of Aristolochia contorta Bunge were found as 25 +/- 1 microg/g and 85 +/- 3 microg/g, respectively. 相似文献
12.
马兜铃酸肾病的临床病理分析 总被引:1,自引:0,他引:1
目的 探讨马兜铃酸肾病的临床病理特点。方法 回顾性分析3例马兜铃酸肾病患者的临床表现及病理资料。结果 2例急性马兜铃酸肾病临床表现为:消化道症状、肾功能减退、尿酶升高、电解质紊乱;病理诊断为急性肾小管坏死。1例慢性马兜铃酸肾病临床表现为:贫血、尿检异常、高血压、肾功能减退,病理诊断为慢性间质性肾炎。结论 含有马兜铃酸的中药有肾损害,可致马兜铃酸肾病,其临床表现病理变化有一定特点。 相似文献
13.
Jing Zhang Yuansheng Xiao Jiatao Feng Sophia L. Wu Xingya Xue Xiuli Zhang Xinmiao Liang 《Journal of pharmaceutical and biomedical analysis》2010
A novel method has been developed for the purification of aristolochic acids and aristololactams compounds from Aristolochia plants, a kind of typically toxic traditional Chinese medicine. In this method, Oligo (ethylene glycol) separation column which has “clustering function” for compounds in TCMs was used to produce the fractions containing the compounds with similar structures. A four-channel parallel preparative HPLC with C18 separation column was employed to purify the target compounds. The extraction sample of the blending of Radix Aristolochiae, Fructus Aristolochiae and Caulis Aristolochiae Manshuriensis was used to develop the method. Then, four aristolochic acids and three aristololactams were obtained using this method and the chemical identification was confirmed by Q-TOF-MS, 1H NMR and 13C NMR. Thus, this method can deal with more than one traditional Chinese medicine simultaneously. Additionally, the results demonstrated that this method was an effective way to purify target compounds selectively from TCMs. 相似文献
14.
Yen-Hung Yeh Ya-Ting Lee Hung-Sheng Hsieh Deng-Fwu Hwang 《Food and chemical toxicology》2008,46(3):1157-1163
We compared the short-term toxicity of toxic components of aristolochic acid in rats. Twenty-four female Wistar rats were divided into 4 groups and treated orally every 3-days with 10 mg/kg each of aristolochic acid, aristolochic acid-I and aristolochic acid-II for 19 days. After treatment, the relative ratio of liver and kidney weight to body weight, the concentrations of RBC, hemoglobin and hematocrit in the blood, the levels of aspartate amino transferase, alanine amino transferase, alkaline phosphatase, blood urea nitrogen and creatinine in the plasma, and the levels of urinary urea nitrogen and creatinine in the urine were significantly increased. Body weight of rats and the levels of Na(+), K(+), Ca(2+) in the urine were significantly decreased, especially for groups treated with aristolochic acid and aristolochic acid-II. Pathological examination of liver and kidney also showed cell enlargement and lesions, especially for groups treated with aristolochic acid and aristolochic acid-II. The aristolochic acid exhibited significant toxicity, and the short-term toxicity of aristolochic acid-II and aristolochic acid was similar to each other. Renal but not hepatic failure induced by aristolochic acid could be prevented by pentoxifylline. 相似文献
15.
体外合成并应用多种质谱技术鉴定了马兜铃酸(aristolochic acid,AA)-脱氧鸟苷酸(2′-deoxyguanosine 5′-monophosphate,dGp)加合物。AA经酶活化或化学活化后与dGp反应,同时优化反应条件。应用液相色谱-串联质谱(LC-MS/MS)以及傅里叶变换离子回旋共振质谱(FT-ICRMS)精确质量数测定和同位素模式等检测技术对合成样品进行分析。在样品中分别检测到AA-dGp加合物准分子离子峰,子离子谱图提供了加合物结构信息。AA能在体外与dGp形成AA-dGp加合物,质谱分析方法可以快速、方便、准确分析与鉴定AA-dGp加合物。 相似文献
16.
Investigation of the metabolism and reductive activation of carcinogenic aristolochic acids in rats. 总被引:2,自引:0,他引:2
Wan Chan Hai-Bin Luo Yufang Zheng Yuen-Kit Cheng Zongwei Cai 《Drug metabolism and disposition》2007,35(6):866-874
The metabolic activation of aristolochic acids (AAs) that have been demonstrated to be mutagenic and carcinogenic was investigated. In vitro metabolism study indicated that AAs were metabolized to N-hydroxyaristolactam, which could be either reduced to aristolactams or rearranged to 7-hydroxyaristolactams via the Bamberger rearrangement. In vivo metabolism study is important because the intermediates (aristolactam-nitriumion) of the nitroreduction process are thought to be responsible for the carcinogenicity of AAs. Liquid chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry (MS/MS) were applied to the analyses of a series of positional isomers of hydroxyaristolactams in rat urine samples after the in vivo study of AAs. Three hydroxylated metabolites of aristolactam II and two hydroxylated metabolites of aristolactam I were identified. The structures of the positional isomers were elucidated from the interpretation of MS/MS spectra and theoretical calculations. In addition, several new metabolites were detected in the rat urine by high-resolution mass spectrometry and MS/MS, including those from the decarboxylation of AAs and the conjugations of acetylation, glucuronidation, and sulfation of aristolochic acid Ia. 相似文献
17.
Aristolochic acids (AAs), naturally occurring nephrotoxins and rodent carcinogens, are commonly found in medicinal plants such as Radix aristolochiae. The toxicity of AAs is believed to be associated with the formation of promutagenic AA-DNA adducts, and it has also been suggested that the nitro group in AAs might be important in the process. In order to investigate the role of the nitro group in AA-mediated cytotoxicity, the effects of denitroaristolochic acid II (dN-AAII), aristolochic acid II (AAII) and aristolochic acid I (AAI) on renal tubular epithelial Madin–Darby canine kidney (MDCK) cells were examined and compared. The cytotoxicity of AAI, AAII and dN-AAII was found to be time- and concentration-dependent. As determined by MTT assay, AAI was found to be most toxic in MDCK cells upon exposure for 24, 48 and 72 h, followed by AAII, and dN-AAII showed the least cytotoxicity. The effect of AAI and AAII on the integrity of cell membrane was found to be similar and appeared to be more prominent than that of dN-AAII. Based on the results obtained from the flow cytometric analysis, significant apoptosis in MDCK cells was observed with AAI and AAII at as low as 25 μmol/L following exposure for 24 h, whereas significant apoptosis was induced by dN-AAII at a much higher concentration, 300 μmol/L, suggesting that both AAI and AAII were significantly more cytotoxic than dN-AAII. In addition, the levels of reactive oxygen species (ROS) were increased following treatment with AAI, AAII and dN-AAII at concentrations of 5, 25 and 25 μmol/L, respectively, for 4 h. The results suggest that the nitro group plays an important role in AA-mediated cytotoxicity in MDCK cells and increased intracellular ROS levels may be associated, at least in part, with the cell injury observed in MDCK cells. 相似文献
18.
Huan Dong Naomi Suzuki Maria C Torres Radha R Bonala Francis Johnson Arthur P Grollman Shinya Shibutani 《Drug metabolism and disposition》2006,34(7):1122-1127
Aristolochic acids (AA) are nephrotoxic and carcinogenic nitroaromatic compounds produced by the Aristolochiaceae family of plants. Ingestion of these phytotoxins by humans results in a syndrome known as AA nephropathy, characterized by renal tubulointerstitial fibrosis and upper urothelial cancer. After activation by cellular enzymes, AA I and II react with DNA to form covalent adducts and as such represent potential biomarkers for studies of AA toxicity. Using site-specifically modified oligodeoxynucleotides as standards, we have developed a method for quantifying 7-(deoxyadenosin-N(6)-yl) aristolactam-DNA or 7-(deoxyguanosin-N(2)-yl) aristolactam-DNA adducts in tissues of Wistar rats using an assay in which (32)P-postlabeling techniques are coupled with nondenaturing polyacrylamide gel electrophoresis. The limit of detection with this technique is five adducts in 10(9) nucleotides for a 5-microg DNA sample. In contrast to previous reports, we find that the levels of AA adducts in renal tissues of Wistar rats treated p.o. with AA for 1 week with 5 mg/kg/day of AA I or AA II were much higher than that in the forestomach. Highest adduct levels were observed in rats treated with AA II, suggesting that this compound may be more genotoxic than AA I. Treatment of rats with aristolactam I, an end-product of AA I metabolism, resulted in a much lower level of adduction. This study establishes the feasibility of using AA-DNA adducts as intermediate biomarkers of exposure in studies of AA nephropathy and its associated urothelial cancer. 相似文献
19.
Aristolochic acids (AAs) are a family of structurally related nitrophenanthrene carboxylic acids existing in Aristolochia, Bragantia, and Asarum species. AAs have been proven to have nephrotoxic and carcinogenic toxicity. In this study, a novel pre-column fluorescence derivatization procedure followed by high-performance liquid chromatography-fluorescence detection (HPLC-FLD) is developed for the analysis of AAs in medicinal herbs. The nitro group in the phenanthrene ring of AAs was removed by NaBH4 in water–THF (2:1, v/v), resulting in the corresponding aristolic acids. The analysis of AAs in medicinal herbs was based of the sensitive fluorescence detection of aristolic acids after the chemical derivatization. Because the produced aristolic acids are highly fluorescent the limit of detection (LOD) of AAI and AAII were lowered to 0.06 and 0.04 ng/mL, respectively, which is at least an order of magnitude lower than those in the reported HPLC and LC–MS methods. Good linearity with correlation coefficients higher than 0.997 were obtained for AAI and AII in the calibration ranges of 0.2–800 ng/mL. The derivatization conditions such as reaction temperature, time and the amount of NaBH4 were optimized. The developed method provided satisfactory intra-day and inter-day precisions with RSDs less than 1.4% and 3.8%, respectively. The relative analytical error was less than 7% for the analysis of AAI and AAII in spiked matrix samples. 相似文献
20.
CHIBNALL AC 《British medical bulletin》1954,10(3):183-186