A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients.
01 Nov 2006-Investigational New Drugs (Kluwer Academic Publishers-Plenum Publishers)-Vol. 25, Iss: 2, pp 139-146
TL;DR: It is concluded that 13 g of oral silybin-phytosome daily, in 3 divided doses, appears to be well tolerated in patients with advanced prostate cancer and is the recommended phase II dose.
Abstract: Silibinin is a polyphenolic flavonoid isolated from milk thistle with anti-neoplastic activity in several in vitro and in vivo models of cancer, including prostate cancer Silybin-phytosome is a commercially available formulation containing silibinin This trial was designed to assess the toxicity of high-dose silybin-phytosome and recommend a phase II dose Silybin-phytosome was administered orally to prostate cancer patients, giving 25-20 g daily, in three divided doses Each course was 4 weeks in duration Thirteen patients received a total of 91 courses of silybin-phytosome Baseline patient characteristics included: median age of 70 years, median baseline prostate specific antigen (PSA) of 43 ng/ml, and a median ECOG performance status of 0 The most prominent adverse event was hyperbilirubinemia, with grade 1-2 bilirubin elevations in 9 of the 13 patients The only grade 3 toxicity observed was elevation of alanine aminotransferase (ALT) in one patient; no grade 4 toxicity was noted No objective PSA responses were observed We conclude that 13 g of oral silybin-phytosome daily, in 3 divided doses, appears to be well tolerated in patients with advanced prostate cancer and is the recommended phase II dose Asymptomatic liver toxicity is the most commonly seen adverse event
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TL;DR: The present review highlights the current status of the development of novel herbal formulations and summarizes their method of preparation, type of active ingredients, size, entrapment efficiency, route of administration, biological activity and applications of novel formulations.
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TL;DR: This review addresses in a comprehensive manner the main molecular events accounting for high-rate glycolysis in cancer, and highlights the key role exerted by the hypoxia-inducible transcription factor HIF-1 in long-term adaptation to Hypoxia.
Abstract: Cancer is a metabolic disease and the solution of two metabolic equations: to produce energy with limited resources and to fulfill the biosynthetic needs of proliferating cells. Both equations are solved when glycolysis is uncoupled from oxidative phosphorylation in the tricarboxylic acid cycle, a process known as the glycolytic switch. This review addresses in a comprehensive manner the main molecular events accounting for high-rate glycolysis in cancer. It starts from modulation of the Pasteur Effect allowing short-term adaptation to hypoxia, highlights the key role exerted by the hypoxia-inducible transcription factor HIF-1 in long-term adaptation to hypoxia, and summarizes the current knowledge concerning the necessary involvement of aerobic glycolysis (the Warburg effect) in cancer cell proliferation. Based on the many observations positioning glycolysis as a central player in malignancy, the most advanced anticancer treatments targeting tumor glycolysis are briefly reviewed.
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TL;DR: The protective effects of silymarin and its major active constituent, silibinin, studied in various tissues, suggest a clinical application in cancer patients as an adjunct to established therapies, to prevent or reduce chemotherapy as well as radiotherapy-induced toxicity.
369 citations
TL;DR: A review of available studies on the effects of the purified product silybin on liver cells or on experimentally induced liver damage, and in patients with liver disease indicates that the bioavailability of slybin phytosome is higher than that of silymarin and is less influenced by liver damage.
Abstract: Herbal products are increasingly used, mainly in chronic liver disease. Extracts of milk thistle, Silymarin and silybin, are the most prescribed natural compounds, with different indications, but with no definitive results in terms of clinical efficacy. This review analyzes the available studies on the effects of the purified product silybin, both as a free and a conjugated molecule, on liver cells or on experimentally induced liver damage, and in patients with liver disease. We searched PUBMED for articles pertaining to the in vitro and in vivo effects of silybin, its antifibrotic, anti-inflammatory, and antioxidant properties, as well as its metabolic effects, combined with the authors' own knowledge of the literature. Results indicate that the bioavailability of silybin phytosome is higher than that of silymarin and is less influenced by liver damage; silybin does not show significant interactions with other drugs and at doses < 10 g/d has no significant side effects. Experimental studies have clearly demonstrated the antifibrotic, antioxidant and metabolic effects of silybin; previous human studies were insufficient for confirming the clinical efficacy in chronic liver disease, while ongoing clinical trials are promising. On the basis of literature data, silybin seems a promising drug for chronic liver disease.
295 citations
Journal Article•
TL;DR: This review covers four polyphenol preparations with poor bioavailability and their complexation into phytosomes to bypass this problem and improves the clinical applicabilities of polyphenols and other poorly absorbed plant medicinals.
Abstract: Plant-derived polyphenols are increasingly receiving attention as dietary supplements for the homeostatic management of inflammation, to support detoxification, and for anticancer, weight loss, and other benefits. Their pro-homeostatic effects on genes, transcription factors, enzymes, and cell signaling pathways are being intensively explored, but the poor bioavailability of some polyphenols likely contributes to poor clinical trial outcomes. This review covers four polyphenol preparations with poor bioavailability and their complexation into phytosomes to bypass this problem. Silybin and the other silymarin flavonolignans from milk thistle conserve tissue glutathione, are liver-protective, and have anticancer potential. Curcumin and its related diphenolic curcuminoids have potent antioxidant, anti-inflammatory, and anti-carcinogenic properties. The green tea flavan-3-ol catechins have antioxidant, anti-inflammatory, cardio- and neuro-protective effects, and anti-carcinogenic benefits, with fat oxidation effects coupled to weight loss. The complex grape seed proanthocyanidin mix (including catechin and epicatechin monomers and oligomers) counters oxidative stress and protects the circulatory system. For each of these preparations, conversion into phytosomes has improved efficacy without compromising safety. The phytosome technology creates intermolecular bonding between individual polyphenol molecules and one or more molecules of the phospholipid, phosphatidylcholine (PC). Molecular imaging suggests that PC molecule(s) enwrap each polyphenol; upon oral intake the amphipathic PC molecules likely “usher” the polyphenol through the intestinal epithelial cell outer membrane, subsequently accessing the bloodstream. PC itself has proven clinical efficacy that contributes to phytosome in vivo actions. As a molecular delivery vehicle, phytosome technology substantially improves the clinical applicabilities of polyphenols and other poorly absorbed plant medicinals. (Altern Med Rev 2009;14(3):226-246)
284 citations
References
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TL;DR: A strong positive association was observed between IGF-I levels and prostate cancer risk, independent of baseline prostate-specific antigen levels, which may have implications for risk reduction and treatment.
Abstract: Insulin-like growth factor-I (IGF-I) is a mitogen for prostate epithelial cells. To investigate associations between plasma IGF levels and prostate cancer risk, a nested case-control study within the Physicians' Health Study was conducted on prospectively collected plasma from 152 cases and 152 controls. A strong positive association was observed between IGF-I levels and prostate cancer risk. Men in the highest quartile of IGF-I levels had a relative risk of 4.3 (95 percent confidence interval 1.8 to 10.6) compared with men in the lowest quartile. This association was independent of baseline prostate-specific antigen levels. Identification of plasma IGF-I as a predictor of prostate cancer risk may have implications for risk reduction and treatment.
1,977 citations
"A phase I and pharmacokinetic study..." refers background in this paper
...The insulin-like growth factor (IGF) pathway appears to be an important actor in prostate cancer, with epidemiologic evidence associating an increased IGF level with increased prostate cancer risk [12]....
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TL;DR: Silymarin and its active constituent, silybin, have been reported to work as antioxidants scavenging free radicals and inhibiting lipid peroxidation, and to protect against genomic injury and stabilize mast cells, chelate iron, and slow calcium metabolism.
709 citations
TL;DR: Analysis of subgroups indicated that treatment was effective in patients with alcoholic cirrhosis and in patients initially rated 'Child A' (P = 0.01) and in customers initially rated "Child A" (P= 0.03).
458 citations
TL;DR: The results of this study indicate that silymarin has no effect on survival and the clinical course in alcoholics with liver cirrhosis.
303 citations
TL;DR: Results suggest that silibinin could be a useful agent for the intervention of hormone-refractory human prostate cancer.
Abstract: Reduction in serum prostate-specific antigen (PSA) levels has been proposed as an endpoint biomarker for hormone-refractory human prostate cancer intervention. We examined whether a flavonoid antioxidant silibinin (an active constituent of milk thistle) decreases PSA levels in hormone-refractory human prostate carcinoma LNCaP cells and whether this effect has biological relevance. Silibinin treatment of cells grown in serum resulted in a significant decrease in both intracellular and secreted forms of PSA concomitant with a highly significant to complete inhibition of cell growth via a G1 arrest in cell cycle progression. Treatment of cells grown in charcoal-stripped serum and 5alpha-dihydrotestosterone showed that the observed effects of silibinin are those involving androgen-stimulated PSA expression and cell growth. Silibinin-induced G1 arrest was associated with a marked decrease in the kinase activity of cyclin-dependent kinases (CDKs) and associated cyclins because of a highly significant decrease in cyclin D1, CDK4, and CDK6 levels and an induction of Cip1/p21 and Kip1/p27 followed by their increased binding with CDK2. Silibinin treatment of cells did not result in apoptosis and changes in p53 and bcl2, suggesting that the observed increase in Cip1/p21 is a p53-independent effect that does not lead to an apoptotic cell death pathway. Conversely, silibinin treatment resulted in a significant neuroendocrine differentiation of LNCaP cells as an alternative pathway after Cip1/p21 induction and G1 arrest. Together, these results suggest that silibinin could be a useful agent for the intervention of hormone-refractory human prostate cancer.
233 citations
"A phase I and pharmacokinetic study..." refers background in this paper
...Using the human prostate cancer cells LNCaP, silibinin treatment decreases cell growth with selective G1 arrest [10]....
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