水飞蓟宾脱氢衍生物的研究进展

2,3-脱氢水飞蓟宾是水飞蓟素中的有效成分之一,有比水飞蓟宾更强的抗氧化和抗肿瘤活性,本文综述了水飞蓟宾脱氢衍生物---2,3-脱氢水飞蓟宾的研究进展。     

水飞蓟宾—卵磷脂复合物红外光谱和磁核磁共振波谱特征

目的：研究水飞蓟滨－卵磷脂复合物（SLC）中水飞蓟宾与卵磷脂之间是以共价键还是以其他次级键结合。方法；应用红外光谱、磷核磁共振波谱方法对本室合成的水飞蓟宾－卵磷脂复合物进行检测分析。结果：水飞蓟宾－卵脂复合物具有水飞蓟宾和卵磷脂的红外光谱特征，其磷核磁共振波谱显示水飞蓟宾和卵磷脂间以非共价键结合。结论：水飞蓟宾－卵磷脂是以非共价键结合，未形成新的化合物，二者自身化学性质在体内不会改变。     

水飞蓟宾类黄酮木质素衍生物的研究进展

水飞蓟是多国药典收载的天然药物,具有抗氧化、抗纤维化、抗炎、免疫调节以及肝细胞再生作用,临床用于治疗肝炎、脂肪肝、肝硬化、缺血性损伤、辐射损伤等。近期随着水飞蓟宾以抗肿瘤新药进入Ⅱ期临床试验,对其衍生物、构效关系以及抗氧化机制等的研究进入加速阶段。本文综述了近年来水飞蓟宾和脱氢水飞蓟宾的近百种衍生物及其活性研究结果 ,并对该类黄酮木质素类化合物今后的发展和设计研究状况做一概述。     

胶束电动毛细管色谱法测定水飞蓟素及其制剂中主要有效成分含量

目的　建立一种胶束电动毛细管色谱分离测定水飞蓟素及其制剂Legalon胶囊、益肝灵片中水飞蓟宾、异水飞蓟宾、水飞蓟亭、水飞蓟宁含量的方法。方法　选用缓冲液为30 mmol.L^-1硼砂-50 mmol.L^-1去氧牛磺胆酸-20 mmol.L^-1 β-环糊精,pH为9.2,运行电压20 kV,压差进样,进样时间3 s,检测波长为288 nm,温度为室温。内标为芦丁。结果　样品中各组分的平均回收率分别为水飞蓟亭99.9％,水飞蓟宁98.3％,水飞蓟宾99.0％,异水飞蓟宾98.2％。结论　此法准确、灵敏,且能分离水飞蓟宾、异水飞蓟宾的非对映异构体。     

水飞蓟宾-卵磷脂复合物红外光谱和磷核磁共振波谱特征

目的确定水飞蓟宾-卵磷脂复合物(SLC)中水飞蓟宾与卵磷脂之间是以共价键还是以其他次级键结合.方法应用红外光谱、磷核磁共振波谱方法对本室合成的水飞蓟宾-卵磷脂复合物进行检测分析.结果水飞蓟宾-卵磷脂复合物具有水飞蓟宾和卵磷脂的红外光谱特征,其磷核磁共振波谱显示水飞蓟宾和卵磷脂间以非共价键结合.结论水飞蓟宾-卵磷脂是以非共价键结合,未形成新的化合物,二者自身化学性质在体内不会改变.     

水飞蓟宾合硼酸钠的制备及初步药理试验

水飞蓟宾合硼酸钠是一种新的水飞蓟宾水溶性衍生物,制备容易,原料价格低廉,毒性较小,经试验保肝作用较好。     

TLC-UV测定水飞蓟宾单磷酸酯钠的含量

目的 :为了准确测定水飞蓟宾单磷酸酯钠的含量。方法 :采用薄层层析对水飞蓟宾和水飞蓟宾单磷酸酯钠进行分离 ,用紫外分光光度法测定水飞蓟宾单磷酸酯钠的含量 ,测定波长 2 88nm。结果 :线性范围 5～30 μg/mL ,相关系数为 0 .9996 ,平均回收率为 98.93% ,RSD为 1.12 %。 结论 :本法能有效消除水飞蓟宾对测定的干扰 ,准确测定水飞蓟宾单磷酸酯钠的真实含量     

水飞蓟宾-磷脂酰胆碱复合物与水飞蓟宾对四氯化碳所致小鼠急性肝损伤保护作用的对比

目的比较水飞蓟宾 磷脂酰胆碱复合物 (SPC)与水飞蓟宾对四氯化碳所致的小鼠肝损伤的保护作用。方法 5 0只小鼠随机分成 5组 ,通过对对照组、给药组小鼠血清中天冬氨酸氨基转移酶 (AST)、丙氨酸氨基转移酶(ALT)及肝组织学观察 ,比较SPC与水飞蓟宾对四氯化碳所致小鼠肝损伤之预防作用的效果。结果水飞蓟宾和SPC均能降低小鼠血清ALT、AST活性 ,能减轻肝脏病理学变化 ,但以SPC作用最为明显。结论SPC对四氯化碳造成的急性肝损伤有明显的保护作用 ,SPC的作用强于水飞蓟宾。     

水飞蓟宾磷酸单酯钠盐的制备及质量考察

制备了新的具良好水溶性的水飞蓟宾衍生物--水飞蓟宾磷酸单酯钠盐,其水溶液pH约为4,其0.04%水溶液在45℃至少5d保持稳定.     

水飞蓟宾葡甲胺的制备与精制

目的:研究水飞蓟宾葡甲胺的制备与精制.方法:先用无水乙醇溶解水飞蓟宾粗品进行重结晶精制,用精制的水飞蓟宾和葡甲胺结合成复盐.结果:实验中合成的产物经紫外分光度计检测水飞蓟宾葡甲胺含量高于96%,HPLC检测水飞蓟宾葡甲胺含量80%,总质量得率约为72.1%.结论:实验证明此水飞蓟宾葡甲胺的制备工艺稳定,各步工艺操作条件易控,产品质量可靠,适宜于工业化生产.     

Preparation and effects of 2,3-dehydrosilymarin, a promising and potent antioxidant and free radical scavenger

Objectives Silymarin or silybin has been effectively used for treating liver diseases and acute liver injury partly due to its antioxidant activity. In this study, 2,3‐dehydrosilymarin, a compound exhibiting remarkable antiradical/antioxidant activity, was prepared from silymarin for the first time. The solubility, radical scavenging capacity and liver protecting activity of 2,3‐dehydrosilymarin were studied and compared with silybin, dehydrosilybin and silymarin. Methods The structures of its main components were verified by ultra‐performance liquid chromatography/mass spectrometry (UPLC‐MS) and other spectral analysis. In addition, a rapid screening method, online high‐performance liquid chromatography/1,1‐dipheny1‐2‐picrylhydrazyl (HPLC‐DPPH) system, was developed for identifying the individual antioxidants in 2,3‐dehydrosilymarin. Key findings Both in‐vitro and in‐vivo results markedly proved that dehydrosilymarin has decent aqueous solubility and remarkable antiradical/antioxidation capacity. Moreover, 2,3‐dehydrosilybin and 2,3‐dehydrosilychristin were identified to be the two major active compounds contained in 2,3‐dehydrosilymarin. Conclusions Our results suggest that 2,3‐dehydrosilymarin may be a promising and potent alternative for inhibition of free radical and prevention of oxidation.     

水飞蓟果实中的黄酮类化合物

从菊科水飞蓟属植物水飞蓟(Silybum marianum L.Gaertn)的干燥成熟果实中分离鉴定了9个化合物,分别为黄酮木质素类化合物:水飞蓟宾(1),2,3-脱氢水飞蓟宾(2),水飞蓟亭(3),2,3-脱氢水飞蓟亭(4);黄酮类化合物:4’-甲氧基紫杉叶素(5),紫杉叶素(6),二氢山奈酚(7),槲皮素(8)以及酚酸类化合物:3,4-二羟基苯甲酸(9)。其中化合物5,7,9为首次从该属植物中分得。     

水飞蓟宾口服亚微乳剂的制备及大鼠体内药动学研究

目的:制备水飞蓟宾口服亚微乳并研究其在大鼠体内的药动学。方法:采用薄膜分散-探头超声法制备水飞蓟宾亚微乳。大鼠分别灌服水林佳(市售水飞蓟宾磷脂复合物胶囊)和水飞蓟宾亚微乳,于不同时间点取血,HPLC法测定血药浓度,采用DAS(Date Acquisition System)软件求算药动学参数。结果:水飞蓟宾亚微乳制剂的平均粒径为(155.9±2.2)nm,Zeta电位为-(29.62±0.03)mV,体外释放动力学符合Weibull方程;大鼠灌服水林佳和水飞蓟宾亚微乳后MRT分别为(1.73±0.03)h和(3.44±0.08)h,AUC0-∞分别为(1.83±0.38)mg·h·L-1和(4.72±0.48)mg·h·L-1。水飞蓟宾亚微乳的相对生物利用度为257.9%。结论:水飞蓟宾制成亚微乳制剂后延长了药物在体内的滞留时间,提高了药物的口服生物利用度。     

水飞蓟宾脂质微球的制备及在大鼠体内的药物动力学考察

目的制备水飞蓟宾脂质微球并对其理化性质及大鼠体内药物动力学特征进行考察,为水飞蓟宾的临床应用提供理论依据。方法采用高压均质法制备水飞蓟宾脂质微球;分别采用动态光散射法、超速离心法考察制剂的粒径、zeta电位及药物的相分布;以自制水飞蓟宾溶液剂作为参比制剂,采用HPLC法考察大鼠体内药物动力学。结果制剂平均粒径约为192.4 nm,zeta电位为-24.56 mV,约77.5%的药物分布在油水界面膜上;40℃加速实验10 d,药物的相分布无变化;4℃留样观察6个月内稳定;水飞蓟宾脂质微球和溶液剂的药时过程均符合双隔室模型;非隔室模型分析结果表明,脂质微球和溶液剂的AUC0-t分别为(1.90±0.29)、(2.07±0.44)mg.h.L-1,两制剂药-时曲线相似。结论所制备的水飞蓟宾脂质微球性质稳定,大部分药物分布在油水界面膜上;脂质微球未改变药物在大鼠体内的药物动力学特征。     

Comparative bioavailability of Silipide, a new flavanolignan complex, in rats.

The comparative pharmacokinetics of Silipide (IdB 1016, a silybin-phosphatidylcholine complex) and silybin were investigated by measuring unconjugated and total plasma silybin levels as well as total biliary and urinary silybin excretion in rats following administration of a single oral dose (200 mg/kg as silybin). Mean peak levels of unconjugated and total silybin after IdB 1016 were 8.17 and 74.23 micrograms/ml respectively. Mean AUC (0-6 h) values were 9.78 and 232.15 h.micrograms.ml-1 indicating that about 94% of the plasma silybin is present in a conjugated form. After administration of silybin, plasma levels of both unconjugated and total compound were under the analytical detection limit. Cumulative biliary (0-24 h) and urinary (0-72 h) excretion values after administration of IdB 1016 accounted for 3.73% and 3.26% of the administered dose, respectively. After silybin administration, the biliary and urinary excretion accounted for only 0.001% and 0.032% of the dose respectively. Our results indicate a superior bioavailability of silybin administered orally as IdB 1016. This was due mainly to an impressive increase in gastrointestinal absorption.     

Studies of the metabolism and excretion of silybin in the rat]

The metabolism and excretion of silybin (as N-methyl-glucamine salt) was investigated after intravenous and oral administration to rats. In the urine, silybin was excreted mostly in the unchanged form after intravenous as well as oral application, whilst in the bile it appeared above all in the form of metabolites. By hydrolysis with arylsulfatase/beta-glucuronidase, the metabolites were identified as sulfate and glucuronide conjugates of silybin and dehyrosilybin; the latter appeared in small quantities as a dehydrated product of silybin. After intravenous injection of 20 mg silybin per kg body weight, the excreted amount of silybin after 48 h was 8%, whereas 76% was eliminated in the bile within the same period of time. After oral application of 2--20 mg silybin/kg body weight 20% after 40 mg/kg 35% and after 120 mg/kg 20% of the administered silybin was excreted in the bile during 48 h. The maximum excretion rate was achieved at application of 20 mg/kg p.o. after 1 h. At this dosage, 2--5% was eliminated within the same time in the urine. The excretion of silybin mainly took place (more than 80% of the total of excreted bilybin) in the bile, both after oral and intravenous administration.     

护肝宁片联合水飞蓟宾对脂肪肝患者血脂及血管内皮素-1的影响

目的观察护肝宁片联合水飞蓟宾治疗脂肪肝的疗效,探讨其对血管内皮素-1(ET-1)的影响。方法将我院收治的脂肪肝患者随机分为2组,即水飞蓟宾组及护肝宁片联合水飞蓟宾治疗组(联合治疗组),分别给予水飞蓟宾、护肝宁片联合水飞蓟宾治疗。检测两组治疗前后TC、TG、LDL、ALT、AST、γ-GT、ET-1水平。另选20例健康成年人作为健康对照组,检测其血清ET-1水平。结果治疗后,水飞蓟宾组、联合治疗组血清TC、TG、LDL、ALT、AST、γ-GT水平明显降低(P<0.05),但联合治疗组减低更明显(P<0.05)。与健康人群相比,联合治疗组血清内皮素-1水平明显增高,治疗后,水飞蓟宾组、联合治疗组血清内皮素-1水平均明显降低(P均<0.05)。水飞蓟宾组总有效率为87.5%,联合治疗组总有效率为96.12%,两组比较差异有统计学意义(P<0.05)。结论护肝宁联合水飞蓟宾治疗脂肪肝疗效显著,脂肪肝患者ET-1明显增高,ET-1可能参与脂肪肝的病理生理过程。     

Untersuchungen zur Elimination von Silymarin bei cholezystektomierten Patienten

The biliary elimination of silybin, the main component of Silymarin, was examined in 11 cholecystectomized patients with T-drainage after a 3 to 5 day-administration of 140 mg of silymarin (Legalon(R), sugarcoated tablets) t. i. d. The elimination of silybin was measured in 12- or 24-h-intervals. Six of these 11 patients received in addition one day before and one day after the repeated dose-period a single dose of 140 mg silymarin, in order to test the influence of repeated application on the biliary elimination kinetic. After repeated intake the steady state of silybin elimination was reached by the second day at the latest. The daily silybin quantities lay between 10 and 40 mg and were nearly independent of bile flow, which was subject to no great intraindividual variations. Kinetic studies showed that after repeated intake of silymarin the elimination of silybin was approx. twice as high as that following the first single intake. This increased elimination, however, stopped after 12 h. 48 h after the last silymarin intake silybin excretion was very low and after 72 h silybin was no longer detectable in the bile. All these observation show, that silybin does not accumulate. The silybin concentrations lay between 20 and 70 microg/ml of the day and the night bile (collecting intervals of 12 h) and correspond to the pharmacologically effective concentrations of 10 (-5) and 10 (-4) mol/l obtained in animal experiments. The intraindividual differences between the silybin concentrations in the day and night bile were relatively small, so that with the recommended doses therapeutically effective silybin concentrations can always be expected in the bile.     

Pharmacokinetic studies on IdB 1016, a silybin- phosphatidylcholine complex, in healthy human subjects

IdB 1016 is a complex of silybin (the main active component of silymarin) and phosphatidylcholine, which in animal models shows greater oral bioavailability and therefore greater pharmacological activity compared with pure silybin and silymarin. In order to assess its pharmacokinetic profile in man, plasma silybin levels were determined after administration of single oral doses of IdB 1016 and silymarin (equivalent to 360 mg silybin) to 9 healthy volunteers. Although absorption was rapid with both preparations, the bioavailability of IdB 1016 was much greater than that of silymarin, as indicated by higher plasma silybin levels at all sampling times after intake of the complex. Regardless of the preparation used, the terminal half-life was relatively short (generally less than 4 h). In a subsequent study, 9 healthy volunteers received IdB 1016 (120 mg b.i.d., expressed as silybin equivalents) for 8 consecutive days. The plasma silybin level profiles and kinetic parameters on day 1 were similar to those determined on day 8. Most of the silybin present in the systemic circulation was in conjugated form. Less than 3% of the administered dose was accounted for by urinary recovery of free plus conjugated silybin, a significant proportion of the dose probably being excreted in the bile. It is concluded that complexation with phosphatidylcholine in IdB 1016 greatly increases the oral bioavailability of silybin, probably by facilitating its passage across the gastrointestinal mucosa.