CPT11 with P-glycoprotein/CYP 3A4 dual-function inhibitor by self-nanoemulsifying nanoemulsion combined with gastroretentive technology to enhance the oral bioavailability and therapeutic efficacy against pancreatic adenocarcinomas

Therapeutic efficacies of orally administrated hydrophobic chemodrugs are decreased by poor water solubilities and reduced oral bioavailabilities by P-glycoprotein (P-gp) and CYP450. In this study, CPT11 alone or combined with dual-function inhibitors (baicalein (BA) silymarin (SM), glycyrrhizic acid (GA), and glycyrrhetinic acid (GLA)) of P-gp and CYP450 loaded in a lecithin-based self-nanoemulsifying nanoemulsion preconcentrate (LBSNENP) to improve the solubility and inhibit the elimination by P-gp and CYP450. Results revealed that the LBSNENP composed of Capryol 90, lecithin/Tween 80/Cremophor EL, and propylene glycol at a weight ratio of 18:58:24 (designated PC90C10P0) was optimally selected. Encapsulating CPT11 with PEO-7000K in PC90C10P10/30 further enhanced the resultant hydrogel to be gastro-retainable and to release CPT11 in a sustained manner. Pharmacokinetic study of CPT11-loaded PC90C10P0 administered orally revealed an absolute bioavailability (FAB, vs. intravenous CPT11) of 7.8 ± 1.01% and a relative bioavailability (FRB1, vs. oral solution of CPT11) of 70.7 ± 8.6% with a longer half-life (T_1/2) and mean residence time (MRT). Among the dual-function inhibitors, SM was shown to be the most influential in increasing the oral bioavailability of CPT11. SM also increased the plasma concentration of the SN-38 active metabolite, which formed from the enhanced plasma concentration of CPT11. It is concluded that treatment with CPT11 loaded in PC90C10P0 with or without solubilization with SM could expose tumors to higher plasma concentrations of both CPT11 and SN-38 leading to enhancement of tumor growth inhibition with no signs of adverse effects.     

Chronic treatment of silymarin improves hyperalgesia and motor nerve conduction velocity in diabetic neuropathic rat

The effect of chronic silymarin (SM) treatment on hyperalgesia, sciatic motor nerve conduction velocity (MNCV) and oxidative stress in streptozotocin (STZ)‐diabetic neuropathic rat was evaluated. Rats were divided into control, diabetic, SM‐treated control and diabetic, and sodium salisylate (SS)‐treated control and diabetic. SM was administered daily at a dose of 100 mg/kg for two months. Finally, hyperalgesia and sciatic MNCV and oxidative stress markers were assessed. Diabetic rats showed a significant deficit in MNCV and markedly exhibited chemical and thermal hyperalgesia, indicating development of diabetic neuropathy. Antioxidant enzyme superoxide dismutase (SOD) level significantly reduced and malondialdehyde (MDA) level significantly increased in diabetic rats compared to control rats; SM treatment significantly ameliorated the alteration in MNCV, hyperalgesia, MDA level and antioxidant enzyme SOD in diabetic rats. These results clearly suggest the potential effect of SM in prevention and treatment of diabetic neuropathy. Copyright © 2009 John Wiley & Sons, Ltd.     

Protective effects of silymarin on testis histopathology,oxidative stress indicators,antioxidant defence enzymes and serum testosterone in cadmium‐treated mice

Cadmium is known as an oxidative stress‐inducing factor. Silymarin extracted from Silybum marianum is regarded as a potent antioxidant. The present study investigated the preventing effects of silymarin on cadmium chloride‐induced toxicity in terms of testis histopathology and serum testosterone level as well as oxidative stress indicators in mice. In addition, the activities of antioxidant defence enzymes was evaluated. Adult male mice were divided into four groups (n = 6 in each group): (a) control; (b) cadmium chloride; (c) silymarin + cadmium chloride and (d) Silymarin. In this study, cadmium chloride significantly decreased the diameter and wall thickness of the seminiferous tubule, diameter of the spermatogonia nucleus and serum testosterone levels compared to the control group. Furthermore, in mice treated with this pollutant, a significant increase in malondialdehyde was observed while ferric reducing antioxidant power level, and the activity of catalase, superoxide dismutase and glutathione peroxidase were significantly reduced in the testis. In the silymarin + cadmium chloride group, silymarin could significantly reverse the toxic effects of cadmium chloride. The findings of this study showed that silymarin, as a potent antioxidant, can compensate the adverse effects of cadmium chloride on testis histopathology, testosterone level, oxidative stress indicators and antioxidant defence enzymes in mice.     

复方水飞蓟素-丹参素滴丸的制备工艺研究

目的：筛选固体分散体技术制备水飞蓟素-丹参素复方滴丸的最佳工艺条件。方法：采用聚乙二醇4000、聚乙二醇6000和Poloxamer188为固体分散体载体材料,熔融法制备复方水飞蓟素-丹参素滴丸,考察了基质组成、药物与基质配比、药液温度、滴距、滴速、冷却剂与冷却温度等因素对滴丸成型的影响,以丸重差异、圆整度、溶出度为指标进行工艺条件的优化。结果：最佳工艺条件为：基质组成为PEG4000∶PEG6000∶Poloxamer188为5∶5∶1,药物与基质配比为1∶2,滴制时药液温度为90℃,滴距为5cm,滴速40滴?min-1,二甲基硅油为冷却剂,冷却温度在10~15℃。结论：优选的复方水飞蓟素-丹参素滴丸制备工艺合理、可行,对主药有良好的增溶效果。     

Iron‐chelating effect of silymarin in patients with β‐thalassemia major: A crossover randomised control trial

This study aimed to determine the potential iron‐chelating effects of silymarin in patients with β‐thalassemia major receiving standard iron‐chelation therapy. We evaluated whether addition of silymarin to standard iron‐chelation therapy could improve iron burden markers and liver and cardiac function in these patients, via a placebo‐controlled, crossover clinical study. Silymarin (140 mg) or placebo were administered thrice daily to all patients (n = 82) for 12 weeks, and after a 2‐week washout period, patients were crossed over to the other groups. Silymarin efficacy was assessed by measuring serum iron level, ferritin level, total iron‐binding capacity and liver and cardiac function on magnetic resonance imaging. Silymarin treatment resulted in a negative change in the serum iron and ferritin levels and a positive change in the total iron‐binding capacity levels (treatment effect, p < .001, p = .06, and p = .05, respectively). Silymarin treatment led to positive changes in cardiac and liver function in both treatment sequences of study; however, this was not statistically significant. There was a negative change in liver iron concentration in both treatment sequences (treatment effect, p = .02). In conclusion, combined iron‐chelation and silymarin therapy was effective for improving the iron‐burden status in patients with β‐thalassemia major.     

Effects of Silymarin on Diabetes Mellitus Complications: A Review

Diabetes mellitus is a common metabolic disorder that is caused by a deficit in the production of (type 1) or response to (type 2) insulin. Diabetes mellitus is characterized by a state of chronic hyperglycemia and such symptoms as weight loss, thirst, polyuria, and blurred vision. These disturbances represent one of the major causes of morbidity and mortality nowadays, despite available treatments, such as insulin, insulin secretagogues, insulin sensitizers, and oral hypoglycemic agents. However, many efforts have been made to discover new drugs for diabetes treatment, including medicinal plant extracts. Silymarin is a powder extract of the seeds from Silybum marianum, a plant from the Asteraceae family. The major active ingredients include four isomers: silybin, isosilybin, silychristin, and silydianin. Silymarin is indicated for the treatment of hepatic disorders, such as cirrhosis, chronic hepatitis, and gallstones. Moreover, several studies of other pathologies, including diabetes, sepsis, osteoporosis, arthritis, hypercholesterolemia, cancer, viral infections, and Alzheimer's and Parkinson's diseases, have tested the effects of silymarin and reported promising results. This article reviews data from clinical, in vivo, and in vitro studies on the use of silymarin, with a focus on the complications of diabetes, including nephropathy, neuropathy, healing delays, oxidative stress, hepatotoxicity, and cardiomyopathy. Copyright © 2017 John Wiley & Sons, Ltd.     

Topical Silymarin Administration for Prevention of Capecitabine‐Induced Hand–Foot Syndrome: A Randomized,Double‐Blinded,Placebo‐Controlled Clinical Trial

Hand–foot syndrome (HFS) is a frequent dose‐limiting adverse reaction of capecitabine in patient with gastrointestinal cancers. Silymarin is a polyphenolic flavonoid extracted from the Silybum marianum that exhibits strong antioxidant and antiinflammatory activities. In this study, we evaluated silymarin efficacy in prevention of capecitabine‐induced HFS in patients with gastrointestinal cancers, as the first human study. During this pilot, randomized, double‐blinded, placebo‐controlled clinical trial, the effect of silymarin gel 1%, which is applied on the palms and soles twice daily starting at the first day of chemotherapy for 9 weeks, on HFS occurrence was assessed. Forty patients fulfilled the inclusion criteria assigned to the silymarin or placebo group. World Health Organization HFS grading scale scores were recorded at baseline and every 3 weeks during these 9 weeks. The median WHO HFS scores were significantly lower in silymarin group at the end of the 9^th week (p < 0.05). The scores increased significantly in both placebo and silymarin groups during chemotherapy, but there was a delay for HFS development and progression in silymarin group. Prophylactic administration of silymarin topical formulation could significantly reduce the severity of capecitabine‐induced HFS and delays its occurrence in patients with gastrointestinal cancer after 9 weeks of application. Copyright © 2017 John Wiley & Sons, Ltd.     

中药防治酒精性肝病作用机制的研究进展

随着人们生活方式的变化,嗜酒者数量逐年增长,导致酒精性肝病的患病率逐渐增加,造成了巨大的社会负担。肝脏是人体负责代谢和消化的重要器官,因此保护肝脏免受损伤以及修复肝脏损伤尤为重要。中药已被广泛用于非酒精性脂肪肝病的长期治疗,但针对酒精性肝病方面的研究仍比较薄弱。综述了酒精性肝病的发病机制以及防治酒精性肝病的中药药理作用及其潜在机制,以期为酒精性肝病的防治工作以及开发新型天然保肝药物提供参考。     

Silymarin and Vitamin E do not Attenuate and Vitamin E Might Even Enhance the Antiarrhythmic Activity of Amiodarone in a Rat Reperfusion Arrhythmia Model

Oxidative stress and lysosomal phospholipoidosis, which also might be partly attributed to free radicals induced by amiodarone (AM), may be involved in AM toxicity, which can be prevented by antioxidants. Our aim was to study if vitamin E (E) or silymarin (S), a lipid and a water-soluble antioxidant, modified the antiarrhythmic efficacy of AM in a rat reperfusion arrhythmia test. The following groups of male Sprague-Dawley rats (15 rats/group) were treated by gavage once a day for 4 weeks: 1. methylcellulose (MC, 0.4%), 2. sunflower seed oil (SSO), 3. AM, suspended in MC (30 mg/kg), 4. E, dissolved in SSO (100 mg/kg), 5. AM + E, 6. S, suspended in MC (80 mg/kg), 7. AM + S. The mean duration of ventricular tachycardia + fibrillation (MDVT + VF) and sinus rhythm (MDSR) the incidence of ventricular fibrillation (VF) and ventricular tachycardia (VT) and mortality were measured during a 10-min reperfusion after a 5-min coronary artery occlusion in anaesthetized rats. An arrhythmia score, representing the combined incidence and duration of different types of ventricular arrhythmia, was calculated. Compared with the MC group, MDSR was longer and MDVT + VF was shorter in all drug treated groups and in the SSO group. In the AM + E treated group MDSR was prolonged more and MDVT + VF was shortened more than in the AM, E or SSO groups. Compared with the MC group, the incidence of VF and mortality was similarly decreased in the SSO group and in most drug treated groups. No significant difference in the incidence of VT was found among all groups. The arrhythmia score was reduced by all drug treatments. Combined treatment with AM + E decreased arrhythmia score more than treatment with AM or SSO alone, but arrhythmia score was similar in the AM + E and E groups. In conclusion, both AM and antioxidant treatments alone or together resulted in a marked reduction of reperfusion arrhythmias in this model. SSO also exerted a moderate antiarrhythmic effect. Antioxidants administered together with AM did not attenuate and E might have even enhanced the antiarrhythmic effect of AM, therefore the combination of antioxidants with AM may be advantageous to reduce AM toxicity.