Combined amiodarone and silymarin treatment,but not amiodarone alone,prevents sustained atrial flutter in dogs

Amiodarone/Silymarin Treatment for Sustained Atrial Flutter. INTRODUCTION: Because amiodarone generates free radicals that may mediate amiodarone's toxicity, simultaneous therapy with an antioxidant might be beneficial if the antioxidant did not impair amiodarone's antiarrhythmic action. We tested whether simultaneous administration of a flavonoid antioxidant, silymarin, altered the electrophysiologic (EP) actions of amiodarone in 62 open chest dogs with electrically induced atrial flutter created by a Y-shaped right atrial incision. METHODS AND RESULTS: Fifteen dogs received oral amiodarone (600 mg/day); 15 dogs received amiodarone (600 mg/day) and silymarin (70 mg bid); and 8 dogs received silymarin (70 mg bid) alone. All dosing was for 8 weeks; 24 control dogs received no drugs prior to induction of atrial flutter. Atrial flutter was induced by rapid right atrial pacing, and EP measurements were made before (presurgical) and after (postsurgical) creation of a Y-shaped right atrial incision. There was no difference in the frequency of induction of atrial flutter lasting >30 minutes among amiodarone-treated (8/15 [53%]), silymarin-treated (4/6 [67%]), and control (15/21 [71%]) groups, whereas the frequency of induction in the amiodarone+silymarin dogs (2/15 [13%]) was significantly reduced (P = 0.008) compared with the other three groups. Both amiodarone and amiodarone+silymarin treatment prolonged the presurgical and postsurgical right atrial effective refractory period (P = 0.012) compared with control; however, there was no significant difference in either parameter between the amiodarone+silymarin-treated and amiodarone-treated groups. The increase in atrial flutter mean cycle length (postsurgical minus presurgical) was significantly (P = 0.005) less in the amiodarone+silymarin-treated and control dogs compared with the amiodarone-treated dogs (16 +/- 11 msec for amiodarone+silymarin; 24 +/- 8 msec for control; and 42 +/- 14 msec for amiodarone treatment). Amiodarone+silymarin treatment resulted in a longer postsurgical right atrial refractory period (155 +/- 13 msec) than atrial flutter mean cycle length (154 +/- 19 msec), consistent with reduction and/or elimination of the excitable gap. Silymarin alone did not exert significant EP or antiarrhythmic action. CONCLUSION: Amiodarone exerted no preventative antiarrhythmic action in this atrial flutter model, probably because it could not reduce the excitable gap of atrial flutter. However, an antioxidant, silymarin, without a direct antiarrhythmic action, when administered together with amiodarone, potentiated amiodarone's antiarrhythmic actions and prevented sustained atrial flutter by reduction and/or elimination of the excitable gap.     

水飞蓟素磷脂复合物对化学性肝损伤的保护作用

目的探讨水飞蓟素磷脂复合物对小鼠急性肝损伤的保护作用.方法昆明种小鼠连续灌胃0.09、0.28、0.84g/kg bw水飞蓟素磷脂复合物30 d,以四氯化碳造成急性化学性肝损伤后,分别测定血清ALT、AST,并做肝脏病理组织学检查.结果水飞蓟素磷脂复合物0.28、0.84g/kg bw剂量能降低ALT、AST活性,减轻肝脏病理损伤(P＜0.05).结论水飞蓟素磷脂复合物对CCI4造成的急性肝损伤有明显的保护作用.     

Preventive effect of silymarin against taurolithocholate-induced cholestasis in the rat

Increased amounts of monohydroxylated bile salts (BS) have been found in neonatal cholestasis, parenteral nutrition-induced cholestasis and Byler's disease, among others. We analyzed whether the hepatoprotector silymarin (SIL), administered i.p. at the dose of 100mg/kg/day for 5 days, prevents the cholestatic effect induced by a single injection of the model monohydroxylated BS taurolithocholate (TLC, 30 micromol/kg, i.v.) in male Wistar rats. TLC, administered alone, reduced bile flow, total BS output, and biliary output of glutathione and HCO(3)(-) during the peak of cholestasis (-75, -67, -81, and -80%, respectively, P<0.05). SIL prevented partially these alterations, so that the drops of these parameters induced by TLC were of only -41, -25, -60, and -64%, respectively (P<0.05 vs. TLC alone); these differences between control and SIL-treated animals were maintained throughout the whole (120 min) experimental period. Pharmacokinetic studies showed that TLC decreased the intrinsic fractional constant rate for the canalicular transport of both sulfobromophthalein and the radioactive BS [14C]taurocholate by 60 and 68%, respectively (P<0.05), and these decreases were fully and partially prevented by SIL, respectively. SIL increased the hepatic capability to clear out exogenously administered TLC by improving its own biliary excretion (+104%, P<0.01), and by accelerating the formation of its non-cholestatic metabolite, tauromurideoxycholate (+70%, P<0.05). We conclude that SIL counteracts TLC-induced cholestasis by preventing the impairment in both the BS-dependent and -independent fractions of the bile flow. The possible mechanism/s involved in this beneficial effect will be discussed.     

Inhibitory effect of silibinin on ligand binding to erbB1 and associated mitogenic signaling, growth, and DNA synthesis in advanced human prostate carcinoma cells

We recently showed the inhibitory effect of a flavonoid antioxidant, silymarin, on erbB1-Shc activation in prostate cancer (PCA) DU145 cells. In the present study, we performed more detailed mechanistic and molecular modeling studies with pure silibinin to assess and define its effect on membrane signaling related to erbB1 activation in human PCA LNCaP and DU145 cells. Studies also were performed to establish the biologic responses toward extracellular signal-regulated protein kinase 1/2 (ERK1/2) activation, cell growth, and DNA synthesis. Treatment of serum-starved cells with various doses of silibinin for 2 h followed by (125)I-epidermal growth factor (EGF) showed 30-75% inhibition in ligand binding and 55-95% inhibition in its internalization in LNCaP cells and 20-64% and 12-27% inhibition in these two events in DU145 cells. Time-response studies showed similar effects. In further studies, treatment of serum-starved cultures with silibinin followed by EGF showed strong inhibitory effects on membrane and cytoplasmic signaling molecules. In the case of erbB1 activation, silibinin showed a 58-75% decrease in LNCaP and a 40-100% decrease in DU145 cells at 50, 75, and 100-microg/mL doses. Inhibitory effects of silibinin also were evident on ERK1/2 activation (20-80% inhibition) in both cell lines. Treatment of serum-starved cultures with silibinin resulted in 20-40% and 30-55% inhibition of LNCaP and DU145 cell growth, respectively, at similar doses after 1-3 d of treatment, and 10-50% cell death in both cell lines. Under 10% serum conditions, identical silibinin treatments resulted in 20-65% inhibition of cell growth in LNCaP and DU145 cells but did not cause any cell death. Similar doses of silibinin treatments for 24 h also resulted in 25-60%, 35-40%, and 36-50% inhibition of DNA synthesis when cells were cultured in 10% serum, totally serum starved, and serum starved plus stimulated with EGF, respectively. Molecular modeling of silibinin showed that it is a highly lipophilic compound, suggesting that it interacts with lipid-rich plasma membrane, including binding with erbB1, thereby competing with the EGF-erbB1 interaction. Because the ligand-erbB1 autocrine-loop is causally involved in advanced and androgen-independent PCA, the observed effects of silibinin and its strong lipophilic nature could be useful in developing this agent for the prevention and therapy of PCA.     

Radioprotective effect of silymarin against radiation induced hepatotoxicity

The radioprotective effect of silymarin using different modes of treatment against radiation (3 or 6 Gy) induced hepatotoxicity 1, 3 and 7 days post-irradiation was studied. Whole-body gamma-irradiation revealed an increase in serum alkaline phosphatase (AP) activity as well as liver glutathione reductase (GR) and glutathione peroxidase (GSH-PX) activities on the first post-exposure day with respect to the control value. However, 3 days after radiation exposure, these parameters showed a significant decrease below the control level which persisted till the end of the experimental time except for serum AP activity that showed another increase on the seventh post-exposure day at 3 Gy dose of radiation. A gradual increase in serum alanine and aspartate aminotransferase (ALT&AST) as well as gamma glutamyl transpeptidase activities were observed due to irradiation throughout the experimental time. Administration of silymarin as single (70 mg kg (-1)), fractionated (490 mg kg (-1)) oral doses or as intravenous (i.v.) injection (50 mg kg (-1)), caused significant protection. Intravenous treatment showed the most pronounced protection. The protective effect of silymarin was attributed to its antioxidant and free radicals scavenging properties.     

Cisplatin nephrotoxicity and protection by milk thistle extract in rats

The protective effect of methanolic extract of milk thistle seeds and silymarin against cisplatin-induced renal toxicity in male rats after a single intraperitoneal injection of 3 mg kg cisplatin were studied. Over 5 days, cisplatin-treated rats showed tubular necrosis and elevation in blood urea nitrogen (BUN) and serum creatinine (Scr). Pretreatment of animals with silymarin (50 mg kg) or extract (0.6 g kg) 2 h before cisplatin prevented the tubular damage. Rats treated with silymarin or extract 2 h after cisplatin had BUN and Scr significantly lower than those receiving cisplatin, but mild to moderate necrosis was observed. These results suggested that milk thistle may protect against cisplatin-induced renal toxicity and might serve as a novel combination agent with cisplatin to limit renal injury.     

Effects of silymarin on the resolution of liver fibrosis induced by carbon tetrachloride in rats

Summary.  Silymarin, a standardized extract of the milk thistle ( Silybum marianum ), has a long tradition as a herbal remedy, and was introduced as a hepatoprotective agent a few years ago. However, the therapeutic effects of silymarin remain undefined. Carbon tetrachloride (CCl₄) is a xenobiotic used extensively to induce oxidative stress and is one of the most widely used hepatic toxins for experimental induction of liver fibrosis in the laboratory. In this study, we investigated the restoration of the CCl₄-induced hepatic fibrosis by high dose of silymarin in rats. After treatment with oil (as normal group; n  =   6) or CCl₄ [as model ( n  =   7) and therapeutic ( n  =   7) groups] by intragastric delivery for 8 weeks for the induction of liver fibrosis, the rats in the normal and model group were administered orally normal saline four times a week for 3 weeks whilst the therapeutic group received silymarin (200 mg/kg). The histopathological changes were observed with Masson staining. The results showed that the restoration of the CCl₄-induced damage of liver fibrosis in the therapeutic group was significantly increased as compared to that in the model group. Moreover, silymarin significantly decreased the elevation of aspartate aminotransferase (AST), alanine aminotransferase, and alkaline phosphatase in serum, and also reversed the altered expressions of α-smooth muscle actin in liver tissue. Therefore, these findings indicated that silymarin may have the potential to increase the resolution of the CCl₄-induced liver fibrosis in rats.     

共研磨法改善水飞蓟素固体分散体的溶出度

目的:通过共研磨技术改善水飞蓟素固体分散体的体外溶出度。方法:设计单因素试验考察溶出度的影响因素,如共研磨载体材料的种类及与共研磨药物的比例,研磨的时间等因素。结果:以甘露醇与PVP K30为混合亲水性载体材料,与药物的比例为1∶1∶1,研磨6 h,以pH7.4的磷酸盐缓冲溶液为溶出介质。结论:共研磨法制备水飞蓟素固体分散体能显著提高药物的体外溶出度,且制备工艺简单易行。     

水飞蓟素－两亲性壳聚糖胶束的制备及其大鼠在体肠吸收

制备水飞蓟素-两亲性壳聚糖胶束 (SM-OGC), 以提高水飞蓟素口服生物利用度, 并研究其在大鼠小肠各部位的吸收情况。采用透析法制备SM-OGC, 测定载药胶束的粒径、zeta电位等理化参数;并以水飞蓟素混悬液为对照,运用大鼠在体单向灌流模型,考察SM-OGC的口服吸收。结果表明,SM-OGC平均粒径为 (162.4 ± 3.0) nm, zeta电位为 (+32.6 ± 0.98) mV,包封率为 (39.17 ± 0.98) % , 载药量达到 (28.15 ± 0.43) % 。SM-OGC在各个肠段吸收皆显著高于水飞蓟素混悬液对照组 (P < 0.05), 且十二指肠吸收最好,结肠、空肠和回肠吸收相近。OGC胶束对水飞蓟素在大鼠小肠的吸收有明显的促进作用。     

Recent advances in plant hepatoprotectives: a chemical and biological profile of some important leads

Medicinal plants have been traditionally used for treating liver diseases since centuries. Several leads from plant sources have been found as potential hepatoprotective agents with diverse chemical structures. Although, a big list of hepatoprotective phytomolecules was reported in the scientific literature, only a few were potent against various types of liver damages. Of which, silymarin, andrographolide, neoandrographolide, curcumin, picroside, kutkoside, phyllanthin, hypophyllanthin, and glycyrrhizin have largely attracted the scientific community. This review focuses discussion on the chemistry, biological activity, mode of action, toxicity, and future prospects of these leads.