7-(4-氯苄基)-7,8,13,13a-四氢小檗碱氯化物在犬体内的药代动力学和药效学

以 QT校正 ( QTc)延长百分率为效应指标 ,用药代动力学 -药效学 ( PK- PD)结合模型对家犬 iv1 .0 ,2 .0 mg· kg-1的 7- ( 4 -氯苄基 ) - 7,8,1 3,1 3a-四氢小檗碱氯化物 ( CPU860 1 7)后在体内的处置和效应作定量分析 .给家犬 iv CPU860 1 7后的血药浓度经时过程符合二房室模型 ,药物的效应与效应室浓度之间的关系符合 S形 Emax模型 .CPU860 1 7的 PK- PD性质在所用剂量范围内均为非剂量依赖性 .     

对氯苄基四氢小檗碱氯化盐光学异构体的结构确证

目的:确证对氯苄基四氢小檗碱氯化盐的四个光学异构体的结构.方法:通过对对氯苄基四氢小檗碱氯化盐四个光学异构体的氢谱(1H NMR)、碳谱(13C NMR,DEPT135)、氢-氢相关谱(1H-1H COSY)、碳氢相关谱(HMQC)、碳氢远程相关谱(HMBC)的解析,对所有的1H NMR,13C NMR谱的信号进行了归属.结果及结论:确证了对氯苄基四氢小檗碱氯化盐的四个光学异构体的光学结构.     

对氯苄基四氢小檗碱对正常及甲状腺功能亢进大鼠离体主动脉环的作用

研究对氯苄基四氢小檗碱（ＣＰＵ－８６０１７）对去氧肾上腺素（Ｐｈｅ）所致大鼠主动脉环收缩的影响．作正常大鼠主动脉环在有钙或无钙Ｋ－Ｈ液,及左甲状腺素所致甲亢大鼠主动脉环在无钙Ｋ－Ｈ液中Ｐｈｅ累积浓度－收缩曲线,ＣＰＵ－８６０１７对上述条件下的主动脉环收缩均有抑制,使量效曲线右移,最大收缩力降低,ｐＤ２′分别为４．１２,６．０８和４．３３．结果提示ＣＰＵ－８６０１７对受体操纵性Ｃａ２＋通道的阻滞作用强于对电压依赖性Ｃａ２＋通道的阻滞作用,甲亢使细胞内Ｃａ２＋释放增多,ＣＰＵ－８６０１７作用因此减弱     

氯苄律定对小鼠缺氧心脏线粒体的保护作用

氯苄律定〔化学名 :7 (4 氯苄 ) 5 ,8,13 ,13ａ四氢小檗碱氯化物 ,ＣＢＴＢ〕是我校研究多年的抗心律失常化合物 ,具有复合型Ⅲ类抗心律失常的电生理特征[1] ,开发前景良好。本文用常压缺氧模型和异丙肾上腺素 (Ｉｓｏｐｒｅｎａｌｉｎｅ ,Ｉｓｏ)加重缺氧模型 ,探讨预防性给予氯苄律定对缺氧小鼠心肌线粒体的保护作用。1　材料与方法1 1　药品　ＣＢＴＢ纯品 ,中国药科大学药化研究室提供 ;Ｌ 甲状腺素 ,Ｓｉｇｍａ产品 ;普萘洛尔 (Ｐｒｏ) ,无锡第四制药厂生产。1 2 　动物分组　小鼠 ,昆明种 ,♀♂各半 ,体重 (2 0± 2 ) ｇ ,饲料 ,饮水…     

7-(4-氯苄基)-7,8,13,13a-四氢小檗碱在家兔体内的代谢产物分析

AIM　To explore the biotransformation of compound 7-(4-chlorbenzyl)-7,8,13,13a-tetrahydroberberine in the rabbit. METHODS　Analyze the rabbit bile sample with HPLC, LC/MS and LC/NMR. RESULTS　A metabolite and unchanged 7-(4-chlorbenzyl)-7,8,13,13a-tetrahydroberberine were found in the rabit bile, the metabolite was characterized and its structure was elucidated. CONCLUSION　Compound 7-(4-chlorbenzyl)-7,8,13,13a-tetrahydroberberine is metabolized by demethylation at 10-OCH3 position.     

某些异喹啉类生物碱对大鼠脑内单胺的影响

1-四氢巴马汀(1-THP)和四氢小檗碱(THB)与dl-THP一样都能降低脑内单胺和升高酸性代谢产物DOPAC,HVA和5-HIAA。它们作用的强弱次序为dl-THP<1-THP相似文献   

某些异喹啉类生物碱对大鼠脑内单胺的影响

1-四氢巴马汀(1-THP)和四氢小檗碱(THB)与dl-THP一样都能降低脑内单胺和升高酸性代谢产物DOPAC,HVA和5-HIAA。它们作用的强弱次序为dl-THP<1-THP相似文献   

四氢原小檗碱同类物与多巴胺D2受体作用的定量构效关系

四氢原小檗碱同类物是一类新型的脑内多巴胺受体阻滞剂。本文用Ｆｒｅｅ－Ｗｉｌｓｏｎ法研究了一组四氢原小檗碱同类物与多巴胺Ｄ２受体作用的定量构效关系。结果表明：Ｃ－２位上的ＯＨ和Ｃ－１２位上的Ｃｌ使四氢原小檗碱同类物与多巴胺Ｄ２受本的亲和力增强,Ｃ－１１位上的立体位阻可能使亲和力降低,Ｃ－１０位上的取代基可能对亲和力影响不大。     

海洋真菌09-1-1-1次级代谢产物的研究

目的从海洋真菌的代谢产物中寻找新的具有抗真菌活性的化合物。方法以稻瘟霉生物模型筛选海洋真菌,获得编号09-1-1-1的活性菌株,从其发酵液中分离活性代谢产物。结果从发酵液中分离到2个化合物,鉴定其结构为3a,12c-二氢-8-羟基-6-甲氧基-7H-呋喃[3′,2′∶4,5]呋喃[2,3-c]呫吨-7-酮(Ⅰ,sterig-matocystin)和1,3,6,8-四羟基-2-(1-羟己基)-9,10-蒽二酮(Ⅱ,averantin)。结论稻瘟霉生物模型用于筛选海洋真菌活性代谢产物成本低、快速又方便。化合物Ⅱ对109稻瘟霉菌丝的生长最小抑制浓度为1.6μg.mL-1。     

CPU-86017及其手性衍生物对麻醉小鼠血压和大鼠血管活性作用的比较

目的：研究Ⅲ类抗心律失常药对氯苄基四氢小檗碱（CPU-86017）及其12个手性衍生物，分别观察其对麻醉小鼠血压及大鼠血管活性的作用。方法：zh-005～zh-008为对硝基苄基四氢小檗碱溴化物的4个立体异构体，zh-009～zh-012为N-苄基四氢小檗碱氯化物的4个立体异构体。通过对麻醉小鼠i．v．3mg／kgCPU-86017或zh-005～zh-012并连续观察3h，研究其对小鼠血压的影响；通过对大鼠离体主动脉梯度给予CPU-86017或zh-009～zh-012，研究其对去氧肾上腺素（Phe）或KCI引发的血管收缩活性的影响。结果：CPU-86017在改变对氯苄基为对硝基苄基或N-苄基后，只有zh-006对血压的影响最小，提示其i．v．毒性亦最小。CPU-86017的4个立体异构体，对a1A效应（ROC）呈现立体选择性抑制，而对电压依赖钙通道（VOC）抑制的立体选择性不明显。结论：对氯苄基四氢小檗碱类化合物与血管α1A受体的结合能力，可能取决于结构式中C-13a的构型。     

LC/DAD/MSD技术研究大鼠胆汁中盐酸非洛普的II相代谢产物

目的研究大鼠服药后胆汁中盐酸非洛普(DDPH)II相代谢产物.方法收集大鼠空白胆汁及给药后12h内的胆汁,以LC/DAD/MSD技术判断II相代谢产物峰位.以HPLC法制备II相代谢产物馏分并以β-葡糖醛酸酶水解,再进行分析;同时将与II相代谢产物相应的I相代谢产物对照品按相同条件进行分析对照.结果大鼠给药后胆汁色谱图中峰M₇,M₈和M₉为DDPH的II相代谢产物,它们的β-葡糖醛酸酶水解产物分别为M₃,M₂和M₁.结论β-1-O-{3,5-二甲基-4-[-2-甲基-2-(3,4-二甲氧基苯乙氨基)-乙氧基]-苯基}-葡糖醛酸(M₇),β-1-O-{2,4-二甲基-3-[2-甲基-2-(3,4-二甲氧基苯乙氨基)-乙氧基]-苯基}-葡糖醛酸(M₈)和β-1-O-{2-甲氧基-4-[1-甲基-2-(2,6-二甲基苯氧基)-乙氨基-乙基]-苯基}-葡糖醛酸(M₉)为大鼠ipDDPH后产生的II相代谢产物.     

LC/DAD/MSD技术研究大鼠服药胆汁中盐酸非洛普I相代谢产物

目的　研究大鼠服药后胆汁中盐酸非洛普(DDPH)I相代谢物。方法　大鼠做胆管插管,分别收集ipDDPH之前的空白胆汁及服药后12h内的服药胆汁,将大鼠胆汁以葡糖醛酸酶水解后进C-18SPE小柱进行纯化富集,再进行LC/DAD/MSD分析;同时将合成的6个DDPH模拟代谢物M₁-M₆的对照品混合液按相同条件进行LC/DAD/MSD分析对照。结果　大鼠服药胆汁色谱图中峰A,B,C,D,E和F分别与M₁,M₂,M₃,M₅,M₄和M₆的保留时间、紫外吸收光谱、分子量及碎片离子完全一致。结论　M₁,M₂,M₃,M₄,M₅和M₆为大鼠ipDDPH后产生的体内I相代谢物。     

Characterization of a new rat urinary metabolite of piperine by LC/NMR/MS studies

Potential of piperine, an active alkaloid of black and long peppers, to increase the bioavailability of drugs in humans is of great clinical significance owing to its omnipresence in food. In an attempt to further study the reported differences in its metabolism in rats and humans, a new major urinary metabolite was detected in rat urine and plasma using HPLC. The metabolite was partially purified using reverse phase column chromatography on Sephadex^®-LH 20 and characterized as 5-(3, 4-methylenedioxy phenyl)-2E,4E-pentadienoic acid-N-(3-yl propionic acid)-amide with the help of LC/NMR/positive ESI–MS studies. Complete mass fragmentation pattern could be assigned with MS/MS studies. The metabolite has a unique structure compared to the previously reported metabolites in that it retains methylenedioxy ring and conjugated double bonds while the piperidine ring is modified to form propionic acid group. Mechanism of formation of the metabolite by oxidation and cleavage of piperidine ring is proposed. Kidney appears to be the major excretion route for piperine metabolites in rats as no metabolite could be detected in feces.     

Development of LC/MS/MS assay for the determination of 5-ethyl-2-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-7-propyl-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (SK3530) in human plasma: application to a clinical pharmacokinetic study

5-Ethyl-2-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-7-propyl-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (SK3530) is a new phosphodiesterase type-5 inhibitor currently undergoing a Phase III investigation for the treatment of male erectile dysfunction. This study first describes a rapid and sensitive LC/MS/MS assay method for the quantification of SK3530 and its major metabolite, SK3541, in human plasma. The assay was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification (LLOQ), accuracy, and precision. The multiple reaction monitoring was based on the transition of m/z=532.5-->99.1 for SK3530, 488.6-->295.5 for SK3541, and 520.3-->99.1 for SK3304 (internal standard). The assay utilized a single liquid-liquid extraction and isocratic elution, and the LLOQ was 1 ng/ml using 0.2 ml human plasma. The assay was linear over a range from 1 to 1000 ng/ml for both SK3530 and SK3541, with correlation coefficients >0.9999. The mean intra- and inter-day assay accuracy ranged from 94.7 to 101.6% and 96.8 to 101.1% for SK3530 and 92.6-105.7% and 97.4-107.8% for SK3541, respectively. The mean intra- and inter-day precision was between 7.2-12.1% and 5.7-7.4% for SK3530 and 4.6-13.2% and 5.0-14.1% for SK3541, respectively. The developed assay was applied to a clinical pharmacokinetic study after oral administration of SK3530 in healthy male volunteers (dose 100 mg).     

Determination of methotrexate and its major metabolite 7-hydroxymethotrexate in mouse plasma and brain tissue by liquid chromatography-tandem mass spectrometry

Methotrexate (MTX) is an anticancer agent that is widely used in a variety of human cancers including primary central nervous system lymphoma (PCNSL). Important pharmacological properties that directly bear on the use of MTX in PCNSL, such as mechanisms that govern its uptake into brain tumors, are poorly defined, but are amenable to investigation in mouse models. In order to pursue such preclinical pharmacological studies, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for the determination of MTX and its metabolite, 7-hydroxymethotrexate (7-OH MTX) in plasma and microdialysate samples from brain tumors and cerebrospinal fluid (CSF) is needed. The plasma assay was based on 10 μl samples and following a protein precipitation procedure enabled direct injection onto a LC/MS/MS system using positive electrospray ionization. A column switching technique was employed for desalting and the clean-up of microdialysate samples from brain tissues.

The methods were validated for MTX and 7-OH MTX in both plasma and microdialysate samples from brain tumor and CSF, and produced lower limits of quantification (LLOQ) in plasma of 3.7 ng/ml for MTX and 7.4 ng/ml for 7-OH MTX, and in microdialysate samples of 0.7 ng/ml for both MTX and 7-OH MTX. The utility of the method was demonstrated by estimation of pharmacokinetic (PK) and brain distribution properties of MTX and 7-OH MTX in conscious mice. The method has the advantages of low sample volume, rapid clean-up, and the simultaneous measurement of MTX and 7-OH MTX in plasma and brain tissues allowing detailed PK studies to be completed in individual mice.     

LC/MS分析大鼠体内氧化苦参碱及其主要代谢物LC/MS分析大鼠体内氧化苦参碱及其主要代谢物

目的研究氧化苦参碱在大鼠体内的主要代谢产物。方法以氧化苦参碱和苦参碱为对象优化液相色谱/电喷雾离子阱质谱(LC/ESI-ITMSⁿ)实验条件，分析总结其电喷雾质谱的一级电离规律和二级质谱裂解规律，作为氧化苦参碱大鼠体内代谢物结构分析的依据。健康大鼠腹腔肌注40 mg·kg^-1氧化苦参碱，收集0~24 h的尿样，尿样中的代谢物经C₁₈小柱进行富集与纯化后，在优化的LC/ESI-ITMSⁿ条件下进样分析。代谢物的结构推导主要依据代谢物的色谱保留时间及其电喷雾离子阱质谱(ESI-ITMSⁿ)电离规律。结果在大鼠尿样中有原药及其6种I相氧化及还原代谢产物，且主要代谢物为苦参碱。未发现II相代谢物。结论本法不仅操作简便、快速，而且灵敏度高、专属性强。该分析技术是研究药物代谢最有效的方法之一。     

腹腔镜胆囊切除术后早期梗阻性黄疸分析

目的分析腹腔镜胆囊切除术(LC)术后早期梗阻性黄疸的原因,探讨预防和处理措施。方法回顾总结2007年6月至2011年12月我院收治26例LC术后梗阻性黄疸患者临床资料。结果 26例LC术后梗阻性黄疸患者中胆道残留结石16例,钛夹钳夹胆总管或肝总管7例,胆囊癌2例,Oddi括约肌功能障碍1例。结论 LC术后梗阻性黄疸主要原因有胆道残留结石和钛夹损伤。     

N-deethylation and N-oxidation of etamiphylline: identification of etamiphylline-N-oxide in greyhound urine by high performance liquid chromatography-mass spectrometry

Millophyline-V^®, (etamiphylline camsylate) was administered intramuscularly to two racing greyhounds at a dose of 10 mg kg⁻¹. Unhydrolysed pre- and post-administration urine samples were extracted using mixed mode solid phase extraction (SPE) cartridges, the basic isolates derivatised as trimethylsilyl ethers and analysed by positive ion electron ionisation gas chromatography–mass spectrometry (GC/EI+/MS). The parent drug and one metabolite, N-desethyletamiphylline, were detected in urine for up to 72 h. For semi-quantification, urine samples were extracted on-line using a Prospekt sample handler. The analytes retained on the C₂ SPE cartridge were eluted by the mobile phase directly on to the analytical high performance liquid chromatography column and analysed by positive ion atmospheric pressure chemical ionisation (LC/APCI+) MS in the multiple selective-ion recording mode. A major peak containing both ions (m/z) 280 and (m/z) 252 was observed. Full scan LC/APCI+/MS of the unknown indicated that the ion at (m/z) 280 was formed by the loss of an oxygen atom [MH⁺ → (MH⁺ − O)]. Samples were analysed by positive ion electrospray ionisation LC/MS on two different instruments and the unknown compound was identified as an N-oxide of the tert. nitrogen atom of the 2-(diethylamino)ethyl substituent on N₇ of the theophylline nucleus. This compound has not been reported previously either as an in vivo or in vitro metabolite of etamiphylline in any species. Thermal decomposition of the N-oxide could lead to an increase the detection period of the parent drug during routine GC/MS screening of post-competition greyhound urine samples.