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水飞蓟宾Legasil®其适应症和组分是什么？
根据提供的证据，Legasil®是一种含有水飞蓟宾的口服营养产品。水飞蓟宾（silibinin）是水飞蓟（milk thistle，学名Silybum marianum）提取物水飞蓟素（silymarin）的主要活性成分 。水飞蓟素是水飞蓟果实中一种类黄酮木脂素（flavonolignans）的混合物，其中水飞蓟宾是其主要成分 。Legasil®被描述为一种具有增强生物利用度的新型水飞蓟宾制剂 。
以下是关于Legasil®适应症和其活性成分水飞蓟宾（silibinin）作用的详细信息：
适应症及潜在应用：
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脑转移瘤（Brain Metastases, BM）：
- Legasil®作为一种口服营养产品，已被报道用于非小细胞肺癌（NSCLC）脑转移患者，并在临床和放射学上带来了显著改善，即使这些患者在全脑放疗和化疗后病情仍在进展且体能状况较差 。
- 水飞蓟宾对进展性脑转移瘤具有抑制作用，包括显著减少瘤周脑水肿，但对原发性肺肿瘤的生长没有影响 。
- 由于脑转移瘤患者预后不佳且需要即时肿瘤控制，将脑放疗与水飞蓟宾基营养品结合使用，不仅可能减轻脑水肿，还可能提供局部控制，并为化疗或新型免疫疗法（如检查点阻滞剂）充分发挥治疗潜力争取时间 。
- 研究发现水飞蓟宾制剂在血脑屏障（BBB）渗透性方面存在差异，这对于水飞蓟宾能否到达靶向癌组织并发挥其中枢神经系统活性至关重要 。Legasil®是一种具有增强生物利用度的水飞蓟宾制剂 。
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乳腺癌肝脏浸润引起的肝功能衰竭：
- 一项病例报告描述了水飞蓟宾（通过Legasil®给药）在一名晚期乳腺癌患者中带来的临床益处。该患者在多次化疗后仍出现广泛肝脏浸润导致的进行性肝功能衰竭。在开始使用Legasil®后，患者的临床症状和肝脏功能得到改善，使其能够继续姑息性化疗 。
- 水飞蓟宾被证实具有肝脏保护、抗炎和抗纤维化作用 。多项临床前研究也表明水飞蓟宾在乳腺癌细胞系中具有抗肿瘤活性 。
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慢性肝病、肝硬化和肝细胞癌：
- 水飞蓟素及其主要活性化合物水飞蓟宾在多种肝脏疾病中均有应用，特别是慢性肝病、肝硬化和肝细胞癌，因其具有抗氧化、抗炎和抗纤维化作用 。
- 水飞蓟素/水飞蓟宾能够通过软化炎症级联反应和调节免疫系统来减轻病毒相关的肝损伤，并对丙型肝炎病毒感染具有直接的抗病毒作用（静脉给药） 。
- 对于酒精滥用，水飞蓟素能够提高细胞活力，减少脂质过氧化和细胞坏死 。
- 在非酒精性脂肪肝病（NAFLD）中，水飞蓟素/水飞蓟宾通过干预氧化应激、胰岛素抵抗、肝脂肪堆积和线粒体功能障碍等多个治疗靶点，对抗疾病进展 。
- 在肝硬化和肝细胞癌（多种肝病的常见终末阶段）中，水飞蓟素通过调节不同的分子模式发挥作用 。
- 尽管有令人鼓舞的临床前数据，但仍需要进一步设计良好的随机临床试验来充分证实水飞蓟素制剂在肝病中的真正价值 。
- 一项针对非酒精性脂肪性肝炎（NASH）患者的随机、双盲、安慰剂对照试验显示，水飞蓟素（700 mg，每日3次，持续48周）未能显著增加实现NAS评分降低30%或更多患者的比例。然而，水飞蓟素组在肝组织学和肝脏硬度测量方面，肝纤维化减少的患者比例显著高于安慰剂组，提示水飞蓟素可能减轻肝纤维化，但仍需更大规模的试验确认 。
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肿瘤治疗抵抗：
- 水飞蓟宾具有天然下调信号转导和转录激活因子3（STAT3）活性的能力 。STAT3在介导对常规化疗/放疗和现代靶向药物的抵抗中起着重要作用 。
- 通过抑制STAT3，水飞蓟宾可能减少癌症治疗的毒性并逆转肿瘤细胞抵抗 。
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皮肤保护和美容（Cosmeceuticals）：
- 水飞蓟宾具有强大的抗氧化活性，能够调节由外源性物质和紫外线辐射引起的多种分子变化，从而保护皮肤 。
- 氧化应激是皮肤老化和多种皮肤病的主要机制之一，因此具有抗氧化活性的植物化学物质（如水飞蓟宾）可用于治疗多种皮肤病和皮肤老化问题 。
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库欣病（Cushing disease, CD）：
- 水飞蓟宾在库欣病（一种严重的内源性皮质醇增多症，常伴有垂体促肾上腺皮质激素瘤）的临床前研究中被提出作为潜在的肿瘤靶向药物，但其疗效和安全性仍有待确定 。
Legasil®的组分（活性成分）：
Legasil®的活性成分是水飞蓟宾（silibinin） 。水飞蓟宾是水飞蓟素（silymarin）的主要活性化合物 。水飞蓟素是从水飞蓟（Silybum marianum）的提取物，而水飞蓟宾是其中生物活性最高的成分，通常占水飞蓟素的50%到70% 。Legasil®被描述为一种新型的、具有增强生物利用度的水飞蓟宾制剂，这对于其能够到达靶向组织并发挥作用至关重要 。
总结：
Legasil®是一种含有水飞蓟宾的口服营养产品，其活性成分水飞蓟宾是从水飞蓟中提取的类黄酮木脂素。水飞蓟宾具有显著的生物学效应，包括抗氧化、抗炎、抗纤维化、免疫调节和抗肿瘤活性 。Legasil®的具体适应症在文献中主要包括治疗非小细胞肺癌脑转移瘤 和改善乳腺癌患者因肝脏广泛浸润引起的肝功能衰竭 。此外，水飞蓟宾广泛用于治疗各种慢性肝病（如非酒精性脂肪肝病、病毒性肝炎、酒精性肝病）、肝硬化和肝细胞癌 ，并被研究用于皮肤保护 、作为肿瘤治疗抵抗的辅助策略（通过靶向STAT3） 以及在库欣病中作为潜在的肿瘤靶向药物 。Legasil®所采用的水飞蓟宾制剂旨在提高其生物利用度，以期更好地发挥其治疗潜力 。
References
1Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years.PubMed
Alessandro Federico, Marcello Dallio, Carmelina Loguercio
Silymarin is the extract of , or milk thistle, and its major active compound is silybin, which has a remarkable biological effect. It is used in different liver disorders, particularly chronic liver diseases, cirrhosis and hepatocellular carcinoma, because of its antioxidant, anti-inflammatory and antifibrotic power. Indeed, the anti-oxidant and anti-inflammatory effect of silymarin is oriented towards the reduction of virus-related liver damages through inflammatory cascade softening and immune system modulation. It also has a direct antiviral effect associated with its intravenous administration in hepatitis C virus infection. With respect to alcohol abuse, silymarin is able to increase cellular vitality and to reduce both lipid peroxidation and cellular necrosis. Furthermore, silymarin/silybin use has important biological effects in non-alcoholic fatty liver disease. These substances antagonize the progression of non-alcoholic fatty liver disease, by intervening in various therapeutic targets: oxidative stress, insulin resistance, liver fat accumulation and mitochondrial dysfunction. Silymarin is also used in liver cirrhosis and hepatocellular carcinoma that represent common end stages of different hepatopathies by modulating different molecular patterns. Therefore, the aim of this review is to examine scientific studies concerning the effects derived from silymarin/silybin use in chronic liver diseases, cirrhosis and hepatocellular carcinoma.
2Intestinal Permeability Study of Clinically Relevant Formulations of Silibinin in Caco-2 Cell Monolayers.PubMed
Almudena Pérez-Sánchez, Elisabet Cuyàs, Verónica Ruiz-Torres, et al.
An ever-growing number of preclinical studies have investigated the tumoricidal activity of the milk thistle flavonolignan silibinin. The clinical value of silibinin as a bona fide anti-cancer therapy, however, remains uncertain with respect to its bioavailability and blood⁻brain barrier (BBB) permeability. To shed some light on the absorption and bioavailability of silibinin, we utilized the Caco-2 cell monolayer model of human intestinal absorption to evaluate the permeation properties of three different formulations of silibinin: silibinin-meglumine, a water-soluble form of silibinin complexed with the amino-sugar meglumine; silibinin-phosphatidylcholine, the phytolipid delivery system Siliphos; and Eurosil/Euromed, a milk thistle extract that is the active component of the nutraceutical Legasil with enhanced bioavailability. Our approach predicted differential mechanisms of transport and blood⁻brain barrier permeabilities between the silibinin formulations tested. Our assessment might provide valuable information about an idoneous silibinin formulation capable of reaching target cancer tissues and accounting for the observed clinical effects of silibinin, including a recently reported meaningful central nervous system activity against brain metastases.
3Response of brain metastasis from lung cancer patients to an oral nutraceutical product containing silibinin.PubMed
Joaquim Bosch-Barrera, Elia Sais, Noemí Cañete, et al.
Despite multimodal treatment approaches, the prognosis of brain metastases (BM) from non-small cell lung cancer (NSCLC) remains poor. Untreated patients with BM have a median survival of about 1 month, with almost all patients dying from neurological causes. We herein present the first report describing the response of BM from NSCLC patients to an oral nutraceutical product containing silibinin, a flavonoid extracted from the seeds of the milk thistle. We present evidence of how the use of the silibinin-based nutraceutical Legasil® resulted in significant clinical and radiological improvement of BM from NSCLC patients with poor performance status that progressed after whole brain radiotherapy and chemotherapy. The suppressive effects of silibinin on progressive BM, which involved a marked reduction of the peritumoral brain edema, occurred without affecting the primary lung tumor outgrowth in NSCLC patients. Because BM patients have an impaired survival prognosis and are in need for an immediate tumor control, the combination of brain radiotherapy with silibinin-based nutraceuticals might not only alleviate BM edema but also prove local control and time for either classical chemotherapeutics with immunostimulatory effects or new immunotherapeutic agents such as checkpoint blockers to reveal their full therapeutic potential in NSCLC BM patients. New studies aimed to illuminate the mechanistic aspects underlying the regulatory effects of silibinin on the cellular and molecular pathobiology of BM might expedite the entry of new formulations of silibinin into clinical testing for progressive BM from lung cancer patients.
4Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases.PubMed
Ludovico Abenavoli, Angelo A Izzo, Natasa Milić, et al.
Milk thistle (MT; Silybum marianum), a member of the Asteraceae family, is a therapeutic herb with a 2,000-year history of use. MT fruits contain a mixture of flavonolignans collectively known as silymarin, being silybin (also named silibinin) the main component. This article reviews the chemistry of MT, the pharmacokinetics and bioavailability, the pharmacologically relevant actions for liver diseases (e.g., anti-inflammatory, immunomodulating, antifibrotic, antioxidant, and liver-regenerating properties) as well as the clinical potential in patients with alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, drug-induced liver injury, and mushroom poisoning. Overall, literature data suggest that, despite encouraging preclinical data, further well-designed randomized clinical trials are needed to fully substantiate the real value of MT preparations in liver diseases.
5Silybin and silymarin--new and emerging applications in medicine.PubMed
Radek Gazák, Daniela Walterová, Vladimír Kren
This review critically surveys the literature published mainly within this millennium on the new and emerging applications of silybin (pure, chemically defined substance) and silymarin (flavonoid complex from Silybum marianum - milk thistle seeds). These compounds used so far mostly as hepatoprotectants were shown to have other interesting activities, e.g. anticancer and canceroprotective and also hypocholesterolemic activity. These effects were demonstrated in a large variety of illnesses of different organs, e.g. prostate, lungs, CNS, kidneys, pancreas and also in the skin protection. Besides the cytoprotective activity of silybin mediated by its antioxidative and radical-scavenging properties also new functions based on the specific receptor interaction were discovered. These were studied on the molecular level and modulation of various cell-signaling pathways with silybin was disclosed--e.g. NF-kappaB, inhibition of EGFR-MAPK/ERK1/2 signaling, activity upon Rb and E2F proteins, IGF-receptor signaling. Proapoptotic activity of silybin in pre- and/or cancerogenic cells and anti-angiogenic activity of silybin are other important findings that bring silymarin preparations closer to respective application in the cancer treatment. Discovery of the inhibition and modulation of drug transporters, P-glycoproteins, estrogenic receptors, nuclear receptors by silybin and some of its new derivatives contribute further to the better understanding of silybin activity on the molecular level. Silymarin application in veterinary medicine is reviewed as well. Recent works using optically pure silybin diastereomers clearly indicate extreme importance of the use of optically active silybin namely in the receptor studies. Significance of silymarin and its components in the medicine is clearly indicated by an exponential growth of publications on this topic--over 800 papers in the last 5 years.
6Silibinin administration improves hepatic failure due to extensive liver infiltration in a breast cancer patient.PubMed
Joaquim Bosch-Barrera, Bruna Corominas-Faja, Elisabet Cuyàs, et al.
BACKGROUND: Silibinin exerts hepatoprotective, anti-inflammatory and anti-fibrotic effects. Several pre-clinical studies have shown anti-tumoral activity of silibinin in breast cancer cell lines. CASE REPORT: We present the case of a heavily pre-treated breast cancer patient with extensive liver infiltration. The patient presented with progressive liver failure despite several chemotherapy treatments, including paclitaxel, capecitabine and vinorelbine. After four cycles of a fourth-line chemotherapy treatment consisting of carboplatin and gemcitabine, the patient's liver blood test results deteriorated to life-threatening levels. The compassionate use of Legasil®, a new commercially available nutraceutical product containing a new silibinin formulation, was offered to the patient according to article 37 of the 2013 Declaration of Helsinki. After treatment initiation, the patient presented clinical and liver improvement, which permitted the patient to continue palliative chemotherapy. CONCLUSION: This is the first case report of a clinical benefit of silibinin administration in a breast cancer patient.
7Cosmeceuticals and silibinin.PubMed
Rana P Singh, Rajesh Agarwal
Cosmeceuticals are used for nourishing and improving the appearance of the skin and are also documented as effective agents for treating various dermatologic conditions. Cosmeceutical preparations from herbal origin are most popular among consumers because these agents are mostly nontoxic and possess strong antioxidant activity. Because oxidative stress is one of the major mechanisms for skin aging and dermatologic conditions, phytochemicals with proven antioxidant activity, such as silibinin, could be useful for treating many dermatologic conditions as well as skin aging. Silibinin is a flavonolignan compound from Silybum marianum (milk thistle plant) that possesses strong antioxidant activity and also modulates many molecular changes caused by xenobiotics and ultraviolet radiation to protect the skin. This contribution reviews the evidence generated from laboratory studies to support the scientific rationale for the effective use of silibinin in cosmeceutical preparations.
8A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis.PubMed
Chan Wah Kheong, Nik Raihan Nik Mustapha, Sanjiv Mahadeva
BACKGROUND & AIMS: Silymarin is a complex mixture of 6 major flavonolignans and other minor polyphenolic compounds derived from the milk thistle plant Silybum marianum; it has shown antioxidant, anti-inflammatory and antifibrotic effects, and may be useful in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to study the efficacy of silymarin in patients with nonalcoholic steatohepatitis (NASH)-the more severe form of NAFLD. METHODS: We performed a randomized, double-blind, placebo-controlled trial of consecutive adults with biopsy-proven NASH and a NAFLD activity score (NAS) of 4 or more at a tertiary care hospital in Kuala Lumpur, Malaysia, from November 2012 through August 2014. Patients were randomly assigned to groups given silymarin (700 mg; n = 49 patients) or placebo (n = 50 patients) 3 times daily for 48 weeks. After this 48-week period, liver biopsies were repeated. The primary efficacy outcome was a decrease of 30% or more in NAS; findings from 48-week liver biopsies were compared with those from the baseline biopsy. Secondary outcomes included changes in steatosis, lobular inflammation, hepatocyte ballooning, NAS and fibrosis score, and anthropometric measurements, as well as glycemic, lipid, and liver profiles and liver stiffness measurements. RESULTS: The percentage of patients achieving the primary efficacy outcome did not differ significantly between the groups (32.7% in the silymarin group vs 26.0% in the placebo group; P = .467). A significantly higher proportion of patients in the silymarin group had reductions in fibrosis based on histology (reductions of 1 point or more; 22.4%) than did the placebo group (6.0%; P = .023), and based on liver stiffness measurements (decrease of 30% or more; 24.2%) than did the placebo group (2.3%; P = .002). The silymarin group also had significant reductions in mean aspartate aminotransferase to platelet ratio index (reduction of 0.14, P = .011 compared with baseline), fibrosis-4 score (reduction of 0.20, P = .041 compared with baseline), and NAFLD fibrosis score (reduction of 0.30, P < .001 compared with baseline); these changes were not observed in the placebo group (reduction of 0.07, P = .154; increase of 0.18, P = .389; and reduction of 0.05, P = .845, respectively). There was no significant difference between groups in number of adverse events; adverse events that occurred were not attributed to silymarin. CONCLUSIONS: In a randomized trial of 99 patients, we found that silymarin (700 mg, given 3 times daily for 48 weeks) did not reduce NAS scores by 30% or more in a significantly larger proportion of patients with NASH than placebo. Silymarin may reduce liver fibrosis but this remains to be confirmed in a larger trial. It appears to be safe and well tolerated. ClinicalTrials.gov: NCT02006498.
9Targeting STAT3 with silibinin to improve cancer therapeutics.PubMed
Joaquim Bosch-Barrera, Bernardo Queralt, Javier A Menendez
Signal transducer and activator of transcription 3 (STAT3) has a prominent role in mediating resistance to conventional chemo-/radio-therapies and modern targeted drugs. While a number of STAT3 inhibitors have been shown to enhance the efficacy of therapeutic agents in vitro, the majority of them have yet to enter clinical evaluation mostly because of lack of efficacy issues. Silibinin is the main component of the silymarin complex, a standardized extract obtained from the seeds of the milk thistle herb Silybum marianum. This review summarizes current evidence supporting the ability of silibinin to function as a natural down-modulator of STAT3 activity. We examine the reported capacity of silibinin to reduce the toxicity of cancer treatments and to reverse tumor cell resistance via STAT3 inhibition. We also briefly review our clinical data in cancer patients treated with oral nutraceutical products containing silibinin. The beneficial effects of silibinin might accelerate the design of strategies aimed to overcome and prevent the emergence of STAT3-mediated cancer drug resistance in clinical settings.
10Tumor-Directed Therapeutic Targets in Cushing Disease.PubMed
Marily Theodoropoulou, Martin Reincke
CONTEXT: The most frequent cause of endogenous hypercortisolism is Cushing disease (CD), a devastating condition associated with severe comorbidities and high mortality. Effective tumor-targeting therapeutics are limited. DESIGN: Search in PubMed with key words "corticotroph" and "Cushing's disease" plus the name of the mentioned therapeutic agent and in associated references of the obtained papers. Additionally, potential therapeutics were obtained from ClinicalTrials.gov with a search for "Cushing disease." RESULTS: At present, the tumor-targeted pharmacological therapy of CD is concentrated on dopamine agonists (cabergoline) and somatostatin analogs (pasireotide) with varying efficacy, escape from response, and considerable side effects. Preclinical studies on corticotroph pathophysiology have brought forward potential drugs such as retinoic acid, silibinin, and roscovitine, whose efficacy and safety remain to be determined. CONCLUSIONS: For many patients with CD, effective tumor-targeted pharmacological therapy is still lacking. Coordinated efforts are pivotal in establishing efficacy and safety of novel therapeutics in this rare but devastating disease.
11Hepatoprotective effects of silybin in liver fibrosis.PubMed
Xiao-Xin Liu, Waseem Hassan, Hammad Ahmed, et al.
Chronic liver disease results in a response resembling "wound healing", also known as fibrosis, resulting in the progressive accumulation of connective tissue. Excessive fibrogenesis that results in the disruption of intercellular connections, interactions, and extracellular matrix composition are features of the fibrotic process mediated by various cell types and chemical mediators such as transforming growth factor-β. Redox-sensitive processes are major contributors to controlling this inflammatory and pro-fibrogenic cytokine's production and synthesis. Other essential hepatic fibrogenesis activities, such as the activation of stellate cells, the expression of metalloproteinases and their inhibitors can also be linked to generation of reactive oxygen species and lipid peroxidation products, which are implicated in development and progression of fibrosis. The herb , also known as milk thistle, is widely studied for its potential to treat liver illnesses. Silymarin contains 50% to 70% silybin, which has the highest level of biological activity. In comparison, silybin seems to be relatively safer and the available evidence on its potential mechanisms of action is encouraging. The aim of this article is to analyze the increasing evidences linking biochemical oxidative events to excessive fibrogenesis and silybin's inhibitory mechanisms that aid in the reversal of fibrosis and fibrotic lesions.