水飞蓟素ppt课件
近年来对水飞蓟素的研究较为活跃,归纳 该药的主要作用特点有以下几点: 1 抗自由基活性 2 抗脂质过氧化作用 3 抗脂氧酶作用 4 抗谷胱甘肽（GSH）排空作用 5 抗肿瘤作用 6 抗辐射作用
6
水飞蓟素结构式：
HO
8a O
5 4a
OH
O
16 16a O
13 12a
O
2
OR
23CH2OR 1 10 11
4
2、水飞蓟素的来源 及主要活性成分
（1）来源： 水飞蓟素(Silymarin) 是指从菊科药用 植物水飞蓟种子的种皮中提取所得的一 种黄酮木脂素类化合物。
（2）主要活性成分： 主要的活性成分有水飞蓟宾(Silybin) 、 异水飞蓟宾(Isosilybin) 、水飞蓟亭 (Silychristin) 和水飞蓟宁(Silydianin) 等 四种同分异构体，其中水飞蓟宾含量为 50 % - 70 %。
11
谢谢
12
OMe
17
20
OH
7
HO
O
OH
OH
O
水飞蓟宾A
HO
O
OH
OH
O
O
CH2OH
OH O
HO OCH3
O
O
CH2OH
OH
OH
OH
O
OCH3
O OH
O
CH2OH
水飞蓟亭
OH OCH3
异水飞蓟宾A
8
水飞蓟素及其脱氢衍生物的抗氧 化活性比较
用DPPH·清除法分析水飞蓟素及其脱氢衍生物抗氧化活性： 样品溶液的DPPH自由基清除率对浓度绘制曲线，如图1所示
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后来德国的传统草药师发现了这种草药不只可以解菇毒， 还可以有效的治疗肝病。存在于苦蓟中的有效成分为水 飞蓟素（Silymarin），水飞蓟素其实是存在苦蓟萃取物 中多种黄酮素的总称，其中最主要的三种成分为Silybin、 Silydianin及Silychristin。水飞蓟素已经被FDA作为营养 品和治疗摄入肝脏毒性的药物收录。
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结论：该实验表明，水飞蓟素及其衍生物均具有一定的体外抗氧化活性。且几乎所有 脱氢化合物的抗氧化活性指标均明显大于脱氢前的药物。表明水飞蓟素的脱氢衍生物 具有较强的脱氢氧化活性，值得进一步研究开发。
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临床常用的水飞蓟素药物
益肝灵、西利宾胺（水飞蓟宾葡甲胺）、复方益肝灵 （为水飞蓟素与五仁醇的复方片剂）等
1
前言
在众多的抗自由基天然产物中,水飞蓟素( si lyma rin)为少数几个在临床上广泛使用的药物之一, 而且经过近30年的临床检验,证明该药的确切疗效 和极低的毒性。
2
1、水飞蓟素的发 现
史料记载 大约在二十世纪初期，德国的采菇工作者发现一种可 以解毒菇之毒的药草。在他们还没有发现这种药草之 前，采菇人经常会误采一种长得和一般无毒菇类很像 的剧毒菇─Amanita phalloides，误食这种剧毒菇会造 成肝衰竭而死亡，后来他们发现一种名为水飞蓟 （Silybum marianum），开着美丽桃红色花朵的草药 可以解毒菇之毒，甚至事先服用了这种草药后，即使 再摄食毒菇也不会中毒（草药的剂量是关键），由于 这种草药的枝干切开会流出类似牛奶般的白色苦味汁 液，所以又被俗称为牛奶蓟或苦蓟（Milk Thistle）。
护肝药ppt课件
青霉胺片（北京嘉林 ）
络合重金属，形成稳 定的水溶性物由尿排 出，用于重金属中毒 及肝豆状核变性（ wilson病）导致的铜 在组织中的沉积。
口服，一日0.5g1.5g（4-12片），
分次服用。治肝豆状 核变性病为每公斤体 重每日20mg，分3
次服用。用于慢性铅 、汞中毒为每日1g（
水飞蓟宾胶囊（水林 佳）
S-腺苷蛋氨酸治疗可以 改善酒精性肝病患者的
均为合成五味子丙素的中间体，对细胞色素P450酶活性
有明显诱导作用，从而加强对四氯化碳及某些致癌物质的 解毒能力。
联苯双酯特出优点是降酶效应迅速，应用方便，罕有不良 反应。因对天冬氨酸氨基转移酶AST作用不明显，有学者 认为无保肝作用。多联合用药。
限制某些肝毒性物质穿 透进入肝细胞内部；刺 激RNA聚合酶I的活性， 促进肝细胞的修复和再 生；清除自由基，减轻 其介导的肝细胞损伤和 肝组织炎症； 间接和 直接的抗纤维化。
用于急、慢性肝炎、初 期肝硬化、脂肪肝、中 毒性肝损伤，
葡醛内酯（肝泰乐）
葡萄糖醛酸，解毒、降 低肝淀粉酶的活性；
调节钙离子通道，保护溶酶体膜及线粒体，减轻细胞的损 伤坏死；
促进上皮细胞产生粘多糖，对治疗和预防呼吸道感染有一 定作用。
甘草酸二铵（甘利欣 强 力宁 美能）
适用于伴有谷丙氨基 转移酶升高的急、慢 性肝炎的治疗。
本类药物口服吸收不 完全，不受食物影响 ，主要经胆汁排出。 常见副作用低钾、水 钠潴留、浮肿；
高能量的必需磷脂分子与肝细胞膜或细胞器膜相结合，能 为患病肝脏提供大量的能量。
多烯磷脂酰胆碱胶囊 （易善复）
辅助改善中毒性肝损伤 ；
口服剂量：›12岁人， 2粒，tid；静脉：2040ml/d，维持量均减 半；
水飞蓟素(利加隆)介绍
（四）利加隆:
刺激肝细胞内蛋白质生物合成，促进肝细胞复原
刺激 rRNA 聚合酶
( RNA-聚合酶 A) 促进蛋白质的生物合成 (功能性蛋白 (酶类) 和结构性蛋白) 刺激肝细胞再生 ( 只作用于受损伤的肝组织)
Nature&Science 德国马博士大药厂
德国高品质水飞蓟素
利加隆：促进蛋白质的生物合成
Nature&Science 德国马博士大药厂
德国高品质水飞蓟素
水飞蓟素延缓酒精诱导的狒狒肝纤维化进程 (2)
实验结果在2002年5月在美国旧金山的“消化疾病会议”上公开 发表。 已经观察确认所有的促进纤维增生过程的典型病理参数都对利加 隆治疗有确切的反应。
结论为 “水飞蓟素延缓酒精诱导的狒狒肝纤维化的进程”。
水飞蓟宾: 作用于细胞膜
阻断受体结合
水飞蓟宾整合于肝细胞膜中 (稳定作用)
Nature&Science 德国马博士大药厂
德国高品质水飞蓟素
（二）利加隆: 抗炎症作用
抑制由酶介导产生的炎症介质
脂氧合酶 (白细胞三烯 - LTB4) 环氧合酶 (前列腺素E2 - PGE2)
Nature&Science 德国马博士大药厂
德国高品质水飞蓟素
利加隆: 抗纤维化作用 (动物实验)
间接抗纤维化作用
——通过清除自由基和阻止炎症反应:
实验模型:
四氯化碳 (CCl4)- 诱导的大鼠肝纤维化
Nature&Science 德国马博士大药厂
德国高品质水飞蓟素
水飞蓟素降低慢性四氯化碳中毒后 的大鼠肝脏胶原蛋白含量
40
*** p < 0.001 与 CCL4对照组相比
最新天然药物化学人卫第5版完整下PPT课件
2.30-2.45 ( 3H, s )
甲氧基
3.45-4.10 ( 3H, s )
四、黄酮类化合物的波谱
3、黄酮类化合物13C-NMR谱
129.0
126.3
131.0
133.7
O 1 1 8 . 1 156.3
131.8 163.2
126.3
129.0
125.2
178.4 124.0 125.7
107.6
O
苄氢:δ6.50-6.70( 1H,s ) δ6.37-6.94( 1H,s, DMSO-d6 )
四、黄酮类化合物的波谱
2、黄酮类化合物1H-NMR谱
化合物
糖 黄酮醇3-O-葡萄糖苷
上 的
黄酮醇7-O-葡萄糖苷
氢 黄酮醇4'-O-葡萄糖苷
黄酮醇5-O-葡萄糖苷
黄酮醇6及8-C-糖苷
黄酮醇3-O-鼠李糖苷
5-O-葡萄糖苷
104.3
7-O-鼠李糖苷
99.0
3'
2'
4'
四、黄酮类化合物的波谱
3、黄酮类化合物13C-NMR谱 3'
2'
4'
2）苷元的苷化位移
O
7
O
苷元糖苷化后，直接与糖相连的C-1向 高场位移，而邻、对位的C则向低场位移
四、黄酮类化合物的波谱
4、黄酮类化合物MS谱
途径I：
O
O
M
途径II：
O
O CO
A1
HC C
B1
+
+ O = C = C+-OH C
MO
B2+
四、黄酮类化合物的波谱
天然药物化学第六章黄酮类化合物PPT课件
2. 抗肝脏毒作用
从水飞蓟种子中得到的 水飞蓟素具有保肝作用，用 于治疗急、慢性肝炎、肝硬 化及多种中毒性肝损伤。
（ + ） - 儿 茶 素 (catergen) 也可抗肝脏毒作用，治疗脂 肪肝及因半乳糖胺或四氯化
水 碳等引起的中毒性肝损伤。 飞 蓟
3. 抗炎 芦丁及其衍生物羟乙基芦丁、二氢 槲皮素等具抗炎作用。
芦丁(rutin)是槲皮素的３－O芸香糖苷。用于 治疗毛细管脆弱引起的出血病，并用作高血压及动 脉硬化的辅助治疗剂。
HO
O
OH
OH
HO
O
OH OH
O OH O rutinose
RUTIN
芦丁
OH OH O
QU 槲ER 皮C素ETIN
豆科植物 槐中药槐
米中含有芦丁和槲 皮素。
３．二氢黄酮类
rutinose O
天然药物化学第六章黄酮类化合物 PPT课件
知识要求：
掌握黄酮类化合物的基本构造、结构类型、理化性 质、提取分离的方法 熟悉黄酮类化合物的性状和鉴定的基本知识 了解紫外光谱、核磁共振谱在黄酮类化合物结构鉴 定中的应用。
能力要求;
熟练掌握槐米中黄酮类化合物的提取技术 学会应用化学方法、色谱鉴定黄酮类化合物的操作 技术
O
OH OCH3
O 橙皮苷(hesperidin),具有Vp样作用
4．二氢黄酮醇类
OH
HO
O
O OCH3
O CH2OH
OH O
OH
水飞蓟素(SILYBIN)
水飞蓟素是二氢黄酮醇与苯丙素衍生物缩合成的黄 酮木脂素类成分。具有保肝作用，用于治疗急、慢性 肝炎及肝硬化，代谢中毒性肝损伤。
5．查尔酮类
水飞蓟素
中文名水飞蓟素英文名silymarin别名益肝灵水飞蓟宾西利马林2,3-二氢-3-(4-羟基-3-甲氧基苯基)-2-羟甲基-6-(3,5,7-三羟基-4-氧代苯并吡喃-2-基)苯并二氧六环英文别名SilibininSilybinsilymarin group2,3-Dihydro-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-6-(3,5,7-trihydroxy-4-oxobenzo pyran-2-yl)benzodioxinSilybum marianumSilybum Extract(2R,3R)-3,5,7-trihydroxy-2-[(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dih ydro-1,4-benzodioxin-6-yl]-2,3-dihydro-4H-chromen-4-one(2R,3R)-3,5,7-trihydroxy-2-[(2S,3S)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dih ydro-1,4-benzodioxin-6-yl]-2,3-dihydro-4H-chromen-4-oneCAS 22888-70-665666-07-1EINECS 245-302-5化学式C25H22O10分子量482.436inchiInChI=1/C25H22O10/c1-32-17-6-11(2-4-14(17)28)24-20(10-26)33-16-5-3-12(7-18(16)34-2 4)25-23(31)22(30)21-15(29)8-13(27)9-19(21)35-25/h2-9,20,23-29,31H,10H2,1H3/t20-,23-,24-,25 +/m0/s1密度 1.527g/cm3沸点793°C at 760 mmHg闪点274.4°C蒸汽压 1.63E-26mmHg at 25°C折射率 1.684物化性质产品用途具有明显的保肝作用，适用于急慢性肝炎、早期肝硬化等危险品标志Xi - 刺激性物品风险术语R36/37/38 - 刺激眼睛、呼吸系统和皮肤。
水飞蓟提取物 2019.06.29
6. 功效、应用
6.1 功效: 本品具有对脂肪氧合酶、过氧化酶的抑制作用。临床上用于肝中毒，肝功能障碍的治疗，抗辐射及降血脂作用。 大量的研究表明水飞蓟素及水飞蓟宾化合物具有广泛的药理活性主要活性归纳为以下几点： 1.清除活性氧 直接清除活性氧，对抗脂质过氧化，维持细胞膜的流动性； 2.保肝作用 水飞蓟素对于由四氯化碳、半乳糖胺，醇类和其他肝毒素造成的肝损害具有保护作用； 3.抗肿瘤作用 各种活性氧能氧化鸟嘌呤形成8一羚基鸟嘌呤，造成DNA损伤，进而引起肿瘤，应用抗氧化剂，特别是自由基清除剂可以防 止这一过程的发生； 4.抗心血管疾病作用 ksoottva等研究了水飞蓟提取物对小鼠杭高胆固醇和低密度脂蛋白氧化作用，用含水飞蓟素提取物的多不饱和脂肪酸和少 量饱和脂肪酸食物喂养小鼠，对照于喂养多不饱和脂肪酸和少量饱和脂肪酸食物的小鼠，前者血清中的胆固醇含量明显降 低，VLDL毛有所降低，HDL一C增加，说明水飞蓟素提高了抗LDL的能力； 5.保护脑缺血损伤作用 冯泉等采用四血管阻断法造成大鼠全脑缺血模型探讨水飞蓟素对脑缺血性损伤保护作用的机制，通过观察水飞蓟素对脑匀 浆液一氧化氮和一氧化氮合成酶的表达量，显示水飞蓟素在显著降低缺血大鼠脑组织中NO、NOS含量的同时，明显缩小了梗 死面积。因而得出结论水飞蓟素能提高机体抗氧化能力，对脑缺血损伤有显著的保护作用
水飞蓟籽油属于新资源食品原料
2.水飞蓟素
中文名称：水飞蓟素
外文名称：Silymarin
别称：益肝灵、利肝泰、西利马灵、利肝隆
简介：水飞蓟素是天然的黄酮木脂素类化合物，系从菊科植 物水飞蓟的干燥果实中提取而得到的天然活性物质，其主要 成分为水飞蓟宾(silybin)、异水飞蓟宾(isosilybim)、水飞蓟宁 (silydianin) 和水飞蓟亭(silychristin)
健康体检讲座ppt课件
2022/2/1
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第11页，共120页。
三、空腹血糖检查
血液中所含的葡萄糖称为血糖。正常人血糖浓度相对稳定，饭后血糖可
以暂时升高，但不超过180mg/dl（ 餐后２小时不超过11.１mmol/L ）， 空腹血液浓度比较恒定，正常为70-110mg/dl（3.9-6.1mmol/L），两
在我们体内有一定尿酸的时候是没有任何问题的，但 是由于客观原因或者遗传原因，在体内尿酸比正常人 的尿酸高出很多的时候，就像是一杯水里放了太多的 盐一样，盐就会形成结晶，同样尿酸也会形成结晶， 沉积在身体各个部位就会形成结石，这种结晶体就会 引起疼痛，特别是结晶在关节周围的时候就会非常疼
痛，这时候就叫痛风。
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二、关于脂肪肝
脂肪肝是良性疾病，如果发现早，治疗及时，一般是可 逆的，一旦发展到肝硬化，就不可逆了。已经查出是脂 肪肝的病人，应立即对症治疗。
由于脂肪肝是不良生活方式引起的疾病，因此，在治 疗原则上一般以纠正不良生活方式为主，使脂肪肝逐 步逆转，对于症状较重者，必要时药物进行治疗。
中毒性肝炎等。 直接胆红素增高为主： 肝内及肝外阻塞性黄疸，胰头癌，毛细胆管型
肝炎及其他胆汁瘀滞综合征等。
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肝功能检查
前白蛋白异常结果分析
血清前蛋白是肝脏功能试验的一个特异、灵敏的指标。 PA还是
评价营养状况的良好指标。200mg/l-400mg/l 前白蛋白降低： 1．肝癌，肝硬化，慢性活动性肝炎，阻塞性黄疸患者均显著降低。是早
水飞蓟素
药品简介
相关信息
安全术语
相关信息
英文别名：Silibinin；Silybin；silymarin group；2,3-Dihydro-3-（4-hydroxy-3-methoxyphenyl） -2-（hydroxymethyl）-6-（3,5,7-trihydroxy-4-oxobenzopyran-2-yl）benzodioxin；Silybum marianum； Silybum Extract
功能
功能
本品具有对脂肪氧合酶、过氧化酶的抑制作用。临床上用于肝中毒，肝功能障碍的治疗，抗辐射及降血脂作 用。
大量的研究表明水飞蓟素及水飞蓟宾化合物具有广泛的药理活性主要活性归纳为以下几点： 1、清除活性氧 直接清除活性氧，对抗脂质过氧化，维持细胞膜的流动性。 2、保肝作用 水飞蓟素对于由四氯化碳、半乳糖胺，醇类和其他肝毒素造成的肝损害具有保护作用。 3、抗肿瘤作用 各种活性氧能氧化鸟嘌呤形成8一羚基鸟嘌呤，造成DNA损伤，进而引起肿瘤，应用抗氧化剂，特别是自由基 清除剂可以防止这一过程的发生。 4、抗心血管疾病作用 ksoottva等研究了水飞蓟提取物对小鼠杭高胆固醇和低密度脂蛋白氧化作用，用含水飞蓟素提取物的多不 饱和
总之，水飞蓟素最大的贡献是对肝细胞膜有稳定作用，它阻止或避免溶解性细胞成分（例如转氨酶）的流失。 水飞蓟素可限制某些肝毒性物质（如α－鹅膏菌素）穿透进入细胞内部。蛋白质合成能力的增强是由于水飞蓟素 刺激细胞核中RNA聚合酶I的活性，因此帮助肝细胞中核糖体RNA的合成，同时导致结构和功能蛋白质（酶）的大 量合成。因此，水飞蓟素可增强肝细胞的修复能力和再生能力。
毒性
毒性
水飞蓟素毒性低，偏琥珀酸钠盐一次静脉注射LD50（mg/kg）：雌性小鼠1050，雄性小鼠970；雌性大鼠825， 雄性大鼠920；家兔最低致死量（MLD）约300；犬最大耐受量300。
关于水飞蓟素
Journal of Chromatography B,945–946 (2014) 1–9Contents lists available at ScienceDirectJournal of ChromatographyBj o u r n a l h o m e p a g e :w w w.e l s e v i e r.c o m /l o c a t e /c h r o mbDevelopment and validation of two liquid chromatography–tandem mass spectrometry methods for the determination of silibinin and silibinin hemisuccinate in human plasmaFederica Sala a ,Pablo Albares b ,Milena Colovic a ,Stefano Persiani a ,∗,Lucio C.Rovati aa Rottapharm|Madaus,R&D Division,Monza,Italy bEurofins|ADME BIOANALYSES,Vergeze,Francea r t i c l ei n f oArticle history:Received 9July 2013Accepted 17November 2013Available online 25 November 2013Keywords:SilibininSilibinin hemisuccinate HPLC–MS/MS ValidationPharmacokineticsa b s t r a c tTo investigate the pharmacokinetics of silibinin and silibinin hemisuccinate in human plasma,two high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS)methods were developed and validated.The methods require a small volume of sample (100L),and the recovery of the analytes was complete with a good reproducibility (CV%1.7–9.5),after a simple protein precipitation.Naringenin was used as internal standard.The chromatographic methods provided a good separation of diastereoisomers A and B of both silibinin and silibinin hemisuccinate onto a Chromolith Performance RP18e 100mm ×3mm column,with a resolution of peaks from plasma matrix in less than 6min.The methods precision values expressed as CV%were always ≤6.2%and the accuracy was always well within the acceptable 15%range.Quantification was performed on a triple-quadrupole tandem mass spectrome-ter by Selected Reaction Monitoring (SRM)mode,in a negative ion mode,via electrospray ionization (ESI).The lower limit of quantitation was set at 5.0ng/mL (silibinin)and 25.0ng/mL (silibinin hemisuccinate),and the linearity was validated up to 1000.0and 12,500.0ng/mL,for silibinin and silibinin hemisucci-nate,respectively,with correlation coefficients (R 2)of 0.991or better.The methods were suitable for pharmacokinetic studies and were successfully applied to human plasma samples from subjects treated intravenously with Legalon ®SIL at the dose of 20mg/kg,expressed as silibinin.© 2013 Elsevier B.V. All rights reserved.1.IntroductionThe diastereoisomers silibinin A and B (Fig.1,part A and B),collectively called silibinin,represent the main constituents of sily-marin,extracted from milk thistle (Silybum marianum )fruits,and the first oral drug to treat toxic and chronic non-viral liver dis-ease.Silibinin showed,in both in vitro and in vivo experiments,anti-hepatotoxic,anti-oxidative and anti-fibrotic properties [1–5].Moreover,it was shown that silibinin could surprisingly inhibit death of animals when intoxicated by Amanita mushroom poison-ing [6–8].Based on such extraordinary findings,a hydrosoluble dihydrogen succinate ester of silibinin,silibininin hemisuccinateAbbreviations:ACD,acid citrate dextrose;HCV,hepatitis C virus;IFN,interferon;MF,matrix factor;MP,mobile phase;NMF,normalized matrix factor;SOC,standard of care;SRM,selected reaction monitoring;TNF,tumor necrosis factor;UHQ,ultra high quality.∗Corresponding author at:Rottapharm|Madaus,Via Valosa di Sopra 9,20900Monza,Italy.Tel.:+390397390396.E-mail address:stefano.persiani@ (S.Persiani).(Fig.1,part C and D),was developed for an intravenous infusion therapy of patients who suffered from acute potentially deadly Amanita phalloides mushroom poisoning.Silibinin hemisuccinate for intravenous use is today registered or licensed in several countries under the name Legalon ®SIL (Rottapharm|Madaus,Monza,Italy)for the treatment of acute hepatic failure following Amanita phalloides intoxication.Its first marketing authorization was in 1984and the recommended dose of silibinin hemisuc-cinate for mushroom poisoning is 20mg/kg daily,expressed as silibinin,in four 5mg/kg infusions until resolution of the clinical signs of intoxication [9].The precise mechanism of action of silib-inin hemisuccinate against amatoxins is still not totally elucidated.Silibinin may exert its effects at several levels as it has been shown to:inhibit the binding of amatoxin to hepatocyte membranes [10];compete with amatoxin for trans-membrane transport [11,12];interrupt biliary secretion and thus enterohepatic recirculation of amatoxin [13];inhibit TNF-␣release in damaged hepatocytes [14];stimulate protein synthesis in damaged liver cells [15,16].In recent years,Legalon ®SIL has been shown to be a potent antiviral agent against HCV both in vitro [17,18]and in patients with chronic viral hepatitis C (HCV)infection1570-0232/$–see front matter © 2013 Elsevier B.V. All rights reserved./10.1016/j.jchromb.2013.11.0282 F.Sala et al./J.Chromatogr.B 945–946 (2014) 1–9Fig.1.Chemical structures of silibinin A (part A),silibinin B (part B),silibinin hemisuccinate A (part C)and silibinin hemisuccinate B (part D).who did not respond or were only sub-optimally responding to standard of care (SOC)therapy with pegylated interferon plus ribavirin [19–22].The recommended dose of silibinin hemisuccinate in chronic HCV is 20mg/kg daily,expressed as sili-binin,in a single infusion for up to 40days.The antiviral effects of silibinin hemisuccinate are the result of a dual mode of action.On the one hand antiviral properties of silibinin are due to the host cellular level,mediated partly by induction of Stat 1phosphorylation which activates intracellular IFN-induced pathways,and partly by IFN-independent mechanisms like for instance inhibition of the 5-lipoxygenase pathway [23].On the other hand,data from virologic experiments prove that silibinin can directly inhibit HCV replication and functions [17,24],without selecting for resistance [25,26].At present,silibinin hemisuccinate is being further developed for the treatment of acute liver failure caused by Amanita mush-room intoxication [27]and in reducing the risk of HCV re-infection after orthotopic liver transplantation in chronic hepatitis C patients and for the treatment of patients that do not respond or respond incompletely to SOC [28,29].These newly discovered antiviral properties of silibinin/silibinin hemisuccinate are clinically relevant because they indicate that an intravenous infusion therapy with Legalon ®SIL might fulfill these urgent therapeutic needs.Several clinical studies have been planned and are ongoing to better characterize its therapeutic potential.Therefore,it is fundamental to develop and validate assays that can accurately quantify silibinin and silibinin hemisuc-cinate diastereoisomers in human plasma for proper PK analyses.To the best of our knowledge,no method is yet available to measure silibinin hemisuccinate in human plasma,whereas several methods have been developed for silibinin analysis,but they were not fully validated [30,31]or they were not able to individually quantify the two diastereoisomers [32,33]or they are based on demanding sam-ples’preparation [34].Consequently,two new,precise and simple HPLC–MS/MS methods were validated to investigate the pharma-cokinetics of silibinin and silibinin hemisuccinate in human plasma.The methods require a small volume of sample (100L)and offer a complete recovery of the analytes after a simple protein precip-itation.High selectivity and sensitivity are guaranteed by working in the Selected Reaction Monitoring (SRM)mode.The methods were successfully applied to samples collected during a pharma-cokinetic study conducted in healthy male volunteers receiving anintravenous single administration of Legalon ®SIL infused within 4h at the dose of 20mg/kg expressed as silibinin.2.Materials and methods2.1.Standards and chemicalsAnalytical reference standard of silibinin (isomer A and B),as well as the internal standard naringenin,was supplied by Sigma–Aldrich (St.Louis,MO).Whereas analytical reference standard of trans silibinin hemisuccinate (isomer A and B)was obtain from Euromed (Mollet del Vallès,Spain).Analytical grade methanol and acetonitrile were purchased from SDS (Carlo Erba Reactifs,Val de Reuil,Cedex,France).Formic and acetic acids were obtained from Merck (New Jersey,USA).Ammonium acetate was supplied by Fisher Scientific (Loughborough,UK)and sodium acetate was purchased from Sigma–Aldrich.Ultra High Quality (UHQ)water was obtain from Eurofins|ADME Bioanalyses (Vergèze,France).Control human plasma from sodium citrate blood,used to prepare daily standard calibration curves and quality control sam-ples (QCs),was obtained from volunteers.2.2.Standard and quality control solutionsSilibinin,silibinin hemisuccinate and naringenin standard solu-tions were prepared at the concentration of 1.0mg/mL in methanol,in a dark flask and taking into account the respective corrective fac-tors.The isomer A concentration was expressed according to the ratio between the two isomers A and B contained in the reference standard.Working solutions necessary to prepare the standard points of the calibration curve and those necessary to prepare the plasma quality control samples were obtained by diluting different amounts of stock solution with methanol to obtain silibinin and silibinin hemisuccinate at the final concentrations reported below:Silibinin concentration (g/mL)=0.05,0.15,0.5,1,1.25,2.5,5,8,10,50and 100.Silibinin hemisuccinate concentration (g/mL)=0.25,0.75,6.25,12.5,25,62.5,100,125and 200.F.Sala et al./J.Chromatogr.B945–946 (2014) 1–93The internal standard(IS)working solution was prepared at0.02 and at0.04g/mL by diluting the stock solution with0.1%acetic acid in acetonitrile.All these solutions were freshly prepared daily.2.3.Preparation of standards and quality control samplesIn a1.5mL polypropylene tube,10L of the appropriate diluted solution of silibinin and silibinin hemisuccinate were added to 100L of control human plasma to obtain eight calibration stan-dards in the range5.0–1000.0ng/mL and25.0–12,500.0ng/mL, respectively.To prepare QC samples,control human plasma was mixed with an appropriate amount of QC solutions obtaining QC plasma samples at thefinal concentration of5.0,15.0,125.0,500.0and 800.0ng/mL for silibinin,and25.0,75.0,6250.0and10,000.0ng/mL for silibinin hemisuccinate.Aliquots were frozen at−80◦C and were used to check the stability under storage conditions and after freeze/thaw cycles.2.3.1.Samples preparationPlasma samples(110L QC and standards,100L study sam-ples+10L MeOH)were mixed with20L of sodium acetate1.5M (pH5)and were added with600L of the internal standard solution at0.02g/mL for silibinin analysis and at0.04g/mL for silibinin hemisuccinate analysis.After vortexing for1min,the plasma sam-ples were centrifuged for5min at14,000rpm between0and9◦C. Then,600L of the supernatant was transferred in a polypropylene tube and dried under a nitrogen stream at approximately45◦C.The dried residue was reconstituted with200L of42:58ammonium acetate(pH3.5,5mM):methanol/0.1%formic acid in UHQ water (90/10),vortexed for30s and transferred in a96-well plate.Before the injection onto the LC–MS/MS system,samples were centrifuged for5min at3500rpm between0and9◦C.2.4.Chromatographic conditionsThe HPLC system consisted of a LC-20AD,which included an automatic sampler(SIL-20AC)and a column oven(CTO-20AC),Shi-madzu(Kyoto,Japan).Silibinin and silibinin hemisuccinate A and B were separated onto a Chromolith Performance RP18e100mm×3mm(Merck, Billerica,MA,USA)maintained at40◦C.The mobile phases(MP) consisted of0.1%formic acid in UHQ water(MP A)and in methanol (MP B)and an isocratic program was applied to silibinin analyses. In particular,the separation of silibinin A and B was obtained with 62%MP A and38%MP B at aflow rate of1mL/min,whereas the separation of silibinin hemisuccinate A and B was reached at aflow rate of0.8mL/min.The analysis of silibinin hemisuccinate was in isocratic mode at50%MP A,but with the addition of a gradient wash step to clean the column between every injection.The chro-matographic conditions were:step1–50%MP A for7min;step 2–from50%MP A to2%in0.1min;step3–constant conditions for2.9min;step4–from2%MP A to the initial conditions over 0.1min;initial condition kept for3min.The total run time was7min for silibinin isomers and13min for silibinin hemisuccinate isomers.The samples,kept at4◦C,were injected onto the column and were then introduced into the mass spectrometer.2.5.Mass spectrometryThe HPLC system was coupled with an API4000(AB Sciex, Framingham,MA,USA)triple quadrupole mass spectrometer equipped with an electrospray ionization(ESI)interface,operating in negative ion mode.Detection was optimized setting an ion-spray voltage of−4200V and a source temperature of600and450◦C for silibinin and silibinin hemisuccinate,respectively.Collision acti-vated dissociation gas(CAD)was set at4,the curtain gas(CUR)at 25and nebulizer and heater gas(GS1and GS2)werefixed,respec-tively,at50and60for both analytes.For the analysis of samples, the mass spectrometer operated in the Selected Reaction Moni-toring mode(SRM),allowing the[M−H]−of silibinin and silibinin hemisuccinate(m/z481and681,respectively)to pass through the first quadrupole into the collision cell.After fragmentation,the characteristic product ions of the two compounds were monitored in the third quadrupole at m/z301for silibinin and at m/z463for silibinin hemisuccinate.The transitions monitored for the internal standard naringenin were m/z271>151and271>119.For each transition,the declustering and entrance potential(DP and EP),the collision energy(CE)and the collision cell exit potential(CXP)were optimized.SRM captures and integrations of chromatographic peak area were performed using Analyst software,version1.5.1(AB Sciex, Framingham,MA,USA),whereas concentrations calculation and data analysis were performed using Watson7.2.0.03(Thermo Elec-tron Corporation,Waltham,MA,USA).2.6.Validation study2.6.1.Recovery and matrix effectThe recovery of silibinin and silibinin hemisuccinate was eval-uated in six replicates at three different plasma concentrations: 3×LLOQ,0.5×ULOQ and0.8×ULOQ.The results obtained from the extracted samples and from pure solutions were compared.The recovery of internal standard was evaluated in the same way.The influence of the matrix effect on silibinin and silibinin hemisuccinate was assessed on six different batches of human plasma.Dry plasma extracts were reconstituted with200L of pure standard solutions,corresponding tofinal concentrations at3×LLOQ,0.5×ULOQ and0.8×ULOQ for silibinin and silibinin hemisuccinate.The signal obtained was compared to that obtained with pure standard solutions injected six times onto the chromato-graphic system.The mean area obtained was used for calculation. The quantitative measure of matrix effect(matrix factor,MF)is defined as the ratio of the analyte peak area in the presence of matrix ions to the analyte peak area in the absence of matrix ions.A MF of1corresponds to a lack of matrix effect;a value of less than 1suggests ionization suppression and a MF greater than1may be due to an ionization enhancement.The normalized matrix factor (NMF)was calculated as following:NMF=(analyte peak area/IS)in matrix/(analyte peak area/IS)in pure solution.2.6.2.Calibration curvesThe linearity of calibration curves was validated on three differ-ent occasions.Each curve comprised a blank human plasma,a blank human plasma spiked with IS(zero standard plasma sample,not included in the calibration calculation)and eight calibration stan-dards.The concentration–response relationship was determined through standard curves performed with a least squared linear regression and1/X2weighting.2.6.3.Precision,accuracy and LLOQThe intra-and inter-run precision and accuracy were evaluated on three different days by determining in sextuplet silibinin and silibinin hemisuccinate at the nominal QC concentrations of LLOQ, 3×LLOQ,0.5×ULOQ and0.8×ULOQ.The precision of the method at each concentration was reported as a coefficient of variation (CV%),expressing the standard deviation as a percentage of the mean calculated concentration;the accuracy of the measure was determined by expressing the percentage ratio of the absolute4 F.Sala et al./J.Chromatogr.B945–946 (2014) 1–9difference of the determined concentration from the theoretical one,and the theoretical value(deviation of accuracy%).The lower limit of quantitation(LLOQ)was defined as the low-est amount of the analyte that can be determined in a sample with sufficient degree of precision and accuracy(within20%for both parameters).The silibinin and silibinin hemisuccinate methods were developed and validated to investigate their pharmacoki-netic profile in human plasma;therefore appropriate concentration ranges were chosen andfixed at their lowest end as the LLOQ.2.6.4.StabilityThe stability of silibinin and silibinin hemisuccinate was assessed by analyzing QC samples at concentrations of3×LLOQ and 0.8×ULOQ.The stability of silibinin and silibinin hemisuccinate in human plasma extracts,kept between0and9◦C(autosampler sta-bility),was checked by re-analyzing,respectively,the processed samples74and82h after thefirst injection.The bench top plasma stability was determined after2h(silibinin)and1.5h(silibinin hemisuccinate)at room temperature and unprotected from light, and the freeze/thaw stability was measured after three freeze and thaw cycles.For each QC level,a series of six plasma samples had been stored at−80◦C for at least24h and left unattended for thaw-ing at room temperature.When completely thawed,the samples were frozen again for more than12h.The freeze and thaw cycle was repeated two more times and then the samples were analyzed. In addition,long term stability of silibinin and silibinin hemisucci-nate was assessed in plasma after storage at−80◦C and in stock solution at4◦C.The compounds were considered stable when the differences between the freshly prepared samples and the stability testing samples were found to be not exceeding15%deviation.Furthermore,in order to evaluate the stability of silibinin and silibinin hemisuccinate ex vivo in samples,several human plasma samples collected during the clinical study were reanalyzed in a separate analytical session.2.6.5.Dilution testingIn anticipation of the need to dilute samples falling outside the concentration range of the calibration curve,diluted QC sam-ples were prepared and analyzed.Six human plasma samples were spiked with silibinin and silibinin hemisuccinate at one concen-tration level above the ULOQ concentration(5000.0ng/mL and 12,500.0ng/mL,respectively)and they were diluted approximately 10-fold and50-fold with blank matrix before analysis.2.7.Clinical studyThe analytical methods were developed and validated to assess the pharmacokinetics of silibinin and silibinin hemisuccinate after a single intravenous administration of Legalon®SIL(Rot-tapharm|Madaus,Monza,Italy)infused within4h in six healthy male volunteers at the therapeutic dose of20mg/kg expressed as silibinin,and participating in a randomized,open-label,crossover study performed at Eurofins|Optimed Clinical Research(Gières, France).The study was approved by the local ethics committee and was conducted in accordance with the current revision of the Decla-ration of Helsinki concerning medical research in human.Written informed consent to participate was obtained by each participant.To determine the plasma concentrations of silibinin and silib-inin hemisuccinate and to study the pharmacokinetic profile,blood samples were collected into polypropylene tubes containing ACD (acid citrate dextrose)solution.The time points for4h intravenous infusion were:pre-dose,0.08,0.25,0.5,1,1.5,2,2.5,3,3.5,4,4.08, 4.25,4.5,5,7,10,13,16,20and24h.Within30min following blood collection,each blood sample was centrifuged at1500×g for 10min at4◦C.Immediately after the centrifugation,the top layer of human plasma was transferred into three different polypropylene tubes and frozen at−80◦C until analysis.Silibinin A and B and silibinin hemisuccinate A and B con-centrations were calculated using Watson7.2.0.03directly from chromatograms after integration by Analyst 1.5.1.The phar-macokinetic analysis was carried out using Kinetica®,version 4.3(Thermo Electron Corporation,Philadelphia,USA).The maxi-mum plasma concentration(C max)was obtained directly from the plasma concentration–time data and the area under the plasma concentration–time curve from time0to the last time point(AUC t) was calculated according to the linear trapezoidal rule.3.Results and discussion3.1.HPLC–MS/MSRepresentative SRM chromatograms of a blank plasma sample, a zero standard plasma sample(blank plasma spiked with IS)and a LLOQ sample both for silibinin and silibinin hemisuccinate are shown in Fig.2.No interfering peaks from endogenous substances appeared in the chromatograms.The developed methods allowed the separation of the two diastereoisomers of silibinin(A and B)and silibinin hemisuccinate (A and B).The retention times were3.6and4.2min for silibinin A and B,respectively;whereas the retention times for silibinin hemisuccinate A and B were,respectively,4.1and4.6min.The importance of this separation is the possibility to integrate and quantify each diastereoisomer,allowing the study of their different pharmacokinetic properties.The optimal conditions for analyte detection were achieved in negative ion mode:silibinin,silibinin hemisuccinate and the internal standard,naringenin,were monitored at the following mass-to-charge ratios(m/z)of[M−H]−:481,681and271,respec-tively.Then,the collision energy was optimized to obtain the product ions with the highest signal(m/z301,463,151,respec-tively).Product ion mass spectra of each analyte and of IS are presented in Fig.3,along with their respective supposed daughter ion chemical structures.3.2.Validation study3.2.1.Recovery and matrix effectThe analytical methods involved a simple protein precipitation that allowed a complete recovery of all analytes:silibinin A and B, silibinin hemisuccinate A and B and naringenin.The results obtained from the extracted samples and from pure solutions,in six replicates at three different concentrations, injected on to the chromatographic system,were compared.The extent of recovery was consistent,precise and reproducible across human plasma batches.As shown in Table1,the recovery was com-plete,with good reproducibility in the range2.5–5.8%(expressed as CV%),for silibinin A and B and in the range5.4–9.5%for sili-binin hemisuccinate A and B.The mean recovery of naringenin was105.9±1.8%during silibinin analysis and109.2±3.0%during silibinin hemisuccinate analysis.As shown in Table2,no significant ion suppression or enhance-ment was observed for the analytes and IS.Precision results of silibinin A and B,silibinin hemisuccinate A and B and IS were always lower than10%and the normalized matrix factor was approxi-mately1,demonstrating that the IS effectively corrects for matrix effect and variability,and is suitable as an IS.3.2.2.Calibration curvesCalibration curves were determined by plotting the concentra-tions versus analyte-to-IS peak area ratio and were found to beF.Sala et al./J.Chromatogr.B945–946 (2014) 1–95Fig.2.Representative SRM chromatograms of human blank plasma during silibinin analysis(part A)and during silibinin hemisuccinate analysis(part B);SRM chromatograms of naringenin at concentration of0.02g/mL(part C)and at concentration of0.04g/mL(part D);representative SRM chromatograms of silibinin(part E)and silibinin hemisuccinate(part F)at LLOQ concentration.linear within the range5.0–1000.0ng/mL for silibinin A and B, and within the range25.0–12,500.0ng/mL for silibinin hemisuc-cinate A and B,with a mean coefficient of determination(R2) of0.9953(range:0.9908–0.9994).The accuracy during silibinin analyses was in the range0.01to−3.69%and the precision was in the range0.39–5.43%when expressed as CV%.The accuracy dur-ing silibinin hemisuccinate analyses was in the range0.09–4.14% and the precision was7.08–10.56%.6 F.Sala et al./J.Chromatogr.B 945–946 (2014) 1–9Fig.3.Product ion spectra in negative ion mode of silibinin hemisuccinate (part A),silibinin (part B)and naringenin (part C)along with the supposed chemical structures of the monitored product ions.3.2.3.Precision,accuracy and LLOQThe repeatability and reproducibility of the analytical methods were demonstrated through the analysis of six replicates at three different concentrations,during a single run analysis for intra-day study and over three consecutive runs for inter-day determination.The precision and accuracy results are summarized in Table 3.Forsilibinin analysis,the intra and inter-day precision were less than 6.2and 5.5%,respectively,whereas for silibinin hemisuccinate anal-ysis the values were,respectively,less than 3.4and 4.8%.The intra and inter-day deviation of accuracy were less than 10.9and 8.9%,and less than 14.2and 8.4%,respectively,for silibinin and silibinin hemisuccinate.F.Sala et al./J.Chromatogr.B945–946 (2014) 1–97Table1Recovery of silibinin(A and B),silibinin hemisuccinate(A and B)and naringenin from human plasma.Analyte concentrations(ng/mL)Recovery%(mean,n=6)±SD CV%Silibinin A13.64113.6±6.0 5.3 454.70106.8±2.7 2.5 727.52101.6±4.7 4.6 Silibinin B15.00107.5±5.9 5.5 500.00105.2±4.2 4.0 800.00100.6±5.8 5.8 Silibinin hemisuccinate A69.30117.6±8.57.2 5775.00112.6±6.1 5.4 9240.00112.9±6.2 5.5 Silibinin hemisuccinate B75.00120.2±11.49.5 6250.00117.2±9.48.0 10,000.00114.1±7.3 6.4 Naringenin20.00105.9±1.8 1.7 40.00109.2±3.0 2.7The LLOQ wasfixed at5.0ng/mL for silibinin and at25.0ng/mL for silibinin hemisuccinate and was validated during three differ-ent runs by six replicates of human plasma spiked with the working solution.The precision and the accuracy for silibinin were,respec-tively,10.8and4.6%(isomer A),and10.2and3.7%(isomer B), whereas the precision for silibinin hemisuccinate was4.1and5.2%, respectively,for isomer A and isomer B.The accuracy for silibinin hemisuccinate A and silibinin hemisuccinate B was,respectively, 4.8and5.3%.3.2.4.StabilityStability data are presented in Tables4and5.The autosampler stability has been demonstrated allowing re-injection of an analyt-ical run up to74(silibinin)and82h(silibinin hemisuccinate)after sample processing.Silibinin(A and B)and silibinin hemisuccinate (A and B)were stable in fresh human plasma at room temperature for,respectively,2and1.5h.Human plasma samples containing silibinin hemisuccinate A and B,and silibinin A were stable afterTable2Normalized matrix factor(NMF)of silibinin(A and B),silibinin hemisuccinate(A and B)and naringenin in human plasma.Analyte concentrations(ng/mL)Mean NMF(n=6)±SD CV%Silibinin A13.64 1.07±0.098.5 454.70 1.01±0.03 3.2 727.52 1.02±0.02 2.1 Silibinin B15.00 1.04±0.05 5.0 500.000.99±0.03 2.9 800.00 1.00±0.03 3.2 Silibinin hemisuccinate A69.300.97±0.07 6.7 5775.00 1.02±0.06 5.9 9240.00 1.08±0.08 6.9 Silibinin hemisuccinate B75.000.97±0.088.6 6250.00 1.03±0.05 5.0 10,000.00 1.10±0.087.5 Naringenin20.00 1.09±0.10a8.940.00 1.15±0.02a 2.1a MF,matrix factor.Table3Intra-and inter-day accuracy and precision of the method for quantitative determi-nation of silibinin(A and B)and silibinin hemisuccinate(A and B).Analyteconcentrations(ng/mL)Intra-day(n=6)Inter-day(n=18)Dev.ofaccuracy%Precision%Dev.ofaccuracy%Precision%Silibinin A13.6410.9 5.58.1 5.5454.70−0.3 1.0−1.0 3.4727.52 2.4 4.3−1.0 4.7Silibinin B15.0010.3 6.28.9 5.0500.000.6 1.80.5 3.3800.00 3.2 3.80.6 4.3Silibinin hemisuccinate A69.3014.2 2.58.4 4.85775.008.2 1.4 2.7 4.69240.00 1.8 2.6−2.3 4.2Silibinin hemisuccinate B75.00 6.8 3.4 5.7 2.86250.000.1 1.4−0.2 2.610,000.00−4.6 2.1−4.8 3.2three freeze(−80◦C)and thaw(room temperature)cycles,whereas silibinin B was not stable after three freeze/thaw cycles.Therefore, no reanalysis could be performed on the same plasma aliquot for silibinin B.Long term stability of silibinin(A and B)and silibinin hemisuc-cinate(A and B)in human plasma was validated,respectively,up to,34and64days after freezing at−80◦C,whereas the stock solu-tions of silibinin and silibininin hemisuccinate in methanol were demonstrated to be stable upon storage at0–9◦C for,respectively, 18and31days.In addition,the stability of the compounds was also evaluated ex vivo in human plasma samples collected during the clinical study. The reanalysis showed that,whereas silibinin B was not stable, silibinin A,silibinin hemisuccinate A and B were stable in ex vivo samples stored at−80◦C for14months,because,in more than80% of plasma samples,the difference between original concentration and reassay concentration was within20%.3.3.Clinical samplesFig.4shows the plasma concentration–time profiles of silibinin A,silibinin B,silibinin hemisuccinate A and silibinin hemisuc-cinate B determined by the present method in a healthy male volunteer following a4-h infusion of Legalon®SIL at the dose of 20mg/kg(expressed as silibinin).Plasma samples analysis occurred within the validated long-term stability period of all compounds. The mean C max and AUC t values were characterized by low inter-subjects variability(expressed as SD),as shown by the following data(N=6):C max(g/mL):0.4±0.1(silibinin A);0.05±0.02(silibinin B);55.0±7.9(silibinin hemisuccinate A);28.3±3.9(silibinin hemisuccinate B).AUC t(g/mL h): 2.1±0.8(silibinin A);0.3±0.1(silibinin B); 210.7±42.5(silibinin hemisuccinate A);86.2±14.6(silibinin hemisuccinate B).The results showed that Legalon®SIL administered via a4h infusion produced silibinin and silibininin hemisuccinate plasma concentrations that were within the validated analytical ranges。
化疗不良反应处理ppt课件
PPT学习交流
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化疗引起贫血
PPT学习交流
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主要内容
胃肠道反应 骨髓抑制
粒细胞缺乏性发热 血小板减少 贫血
肝肾毒性 心脏毒性 过敏反应
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肝脏毒性
大部分肿瘤药物经过肝脏代谢 CTX、BCNU、CCNU、MTX、5-FU、ADM、DNR、MMC
肝酶升高(BCNU、CCNU、Ara-C) 肝纤维化和肝硬化（MTX） 胆汁淤积、药物性黄疸 脂肪肝 药物性肝炎 肝坏死
血常规/尿常规/粪常规/网织红细胞 凝血功能 肝功能、肝炎系列、肝硬化指标 血小板抗体 骨髓穿刺
PPT学习交流
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血小板减少
轻度血小板减少
➢ 重组人白介素-11：25-50ug/Kg（巨合粒 1.5mg）
•
化疗结束后24-48h或血小板下降开始
•Hale Waihona Puke 血小板升至100×109/L停用
•
注意心脏毒性，特别心律失常（7%）
既往肝功能较差或既往病毒性肝炎，重新评估，用药慎重 化疗禁忌肝酶大于正常值2.5倍，肝转移患者大于5倍
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肝脏毒性
化疗前、中、后监测肝功能 轻度肝功异常化疗同步使用保肝药 化疗过程中出现轻度肝酶升高，同步使用保肝药 严重肝损害（药物性黄疸）停止化疗，积极保肝治疗 保肝药物一般每次可选1-2种 保肝治疗效果不显著，可换用其他保肝药 可供选择保肝药：维生素类、联苯双酯、还原型谷胱甘肽、
化疗相关不良反应处理
PPT学习交流
1
主要内容
胃肠道反应 骨髓抑制
粒细胞缺乏性发热 血小板减少 贫血
肝肾毒性 心脏毒性 过敏反应
PPT学习交流