Administration of silymarin in NAFLD/NASH: A systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with a high prevalence worldwide and poses serious harm to human health. There is growing evidence suggesting that the administration of specific supplements or nutrients may slow NAFLD progression. Silymarin is a hepatoprotective extract of milk thistle, but its efficacy in NAFLD remains unclear. MATERIALS AND METHODS: Relevant studies were searched in PubMed, Embase, the Cochrane Library, Web of Science, clinicaltrails.gov, and China National Knowledge Infrastructure and were screened according to the eligibility criteria. Data were analyzed using Revman 5.3. Continuous values and dichotomous values were pooled using the standard mean difference (SMD) and odds ratio (OR). Heterogeneity was evaluated using the Cochran's Q test (I2 statistic). A P<0.05 was considered statistically significant. RESULTS: A total of 26 randomized controlled trials involving 2,375 patients were included in this study. Administration of silymarin significantly reduced the levels of TC (SMD[95%CI]=-0.85[-1.23, -0.47]), TG (SMD[95%CI]=-0.62[-1.14, -0.10]), LDL-C (SMD[95%CI]=-0.81[-1.31, -0.31]), FI (SMD[95%CI]=-0.59[-0.91, -0.28]) and HOMA-IR (SMD[95%CI]=-0.37[-0.77, 0.04]), and increased the level of HDL-C (SMD[95%CI]=0.46[0.03, 0.89]). In addition, silymarin attenuated liver injury as indicated by the decreased levels of ALT (SMD[95%CI]=-12.39[-19.69, -5.08]) and AST (SMD[95% CI]=-10.97[-15.51, -6.43]). The levels of fatty liver index (SMD[95%CI]=-6.64[-10.59, -2.69]) and fatty liver score (SMD[95%CI]=-0.51[-0.69, -0.33]) were also decreased. Liver histology of the intervention group revealed significantly improved hepatic steatosis (OR[95%CI]=3.25[1.80, 5.87]). CONCLUSIONS: Silymarin can regulate energy metabolism, attenuate liver damage, and improve liver histology in NAFLD patients. However, the effects of silymarin will need to be confirmed by further research.

Silymarin prevents endothelial dysfunction by upregulating Erk-5 in oxidized LDL exposed endothelial cells.

Extracellular signal-regulated kinase (Erk)-5 is a key mediator of endothelial cell homeostasis, and its inhibition causes loss of critical endothelial markers leading to endothelial dysfunction (ED). Circulating oxidized low-density lipoprotein (oxLDL) has been identified as an underlying cause of ED and atherosclerosis in metabolic disorders. Silymarin (Sym), a flavonolignan, possesses various pharmacological activities however its preventive mechanism in ED warrants further investigation. Here, we have examined the effects of Sym in regulating the expression of Erk-5 and ameliorating ED using in vitro and in vivo models. Primary human umbilical vein endothelial cells (pHUVECs) viability was measured by MTT assay; mRNA and protein expression by RT-qPCR and Western blotting; tube-formation assay was performed to examine endothelialness. In in-vivo experiments, normal chow-fed mice (control) or high-fat diet (HFD)-fed mice were administered Sym or Erk-5 inhibitor (BIX02189) and body weight, blood glucose, plasma-LDL, oxLDL levels, and expression of EC markers in the aorta were examined. Sym (5 µg/ml) maintained the viability and tube-formation ability of oxLDL exposed pHUVECs. Sym increased the expression of Erk-5, vWF, and eNOS and decreased ICAM-1 at transcription and translation levels in oxLDL-exposed pHUVECs. In HFD-fed mice, Sym reduced the body weight, blood glucose, LDL-cholesterol, and oxLDL levels, and increased the levels of vWF and eNOS along with Erk-5 and decreased the level of ICAM-1 in the aorta. These data suggest that Sym could be a potent anti-atherosclerotic agent that could elevate Erk-5 level in the ECs and prevent ED caused by oxidized LDL during HFD-induced obesity in mice.

Efficacy of silymarin in patients with non-alcoholic fatty liver disease - the Siliver trial: a study protocol for a randomized controlled clinical trial.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases globally. Pharmacological treatments for NAFLD are still limited. Silymarin, a compound extracted from Silybum marianum, is an herbal supplement traditionally used in folk medicine for liver disorders. It has been proposed that silymarin may possess hepatoprotective and anti-inflammatory properties. The present trial aims to assess the efficacy of silymarin supplementation in the adjuvant treatment of NAFLD in adult patients. METHOD: This is a randomized double-blind placebo-controlled clinical trial recruiting adult NAFLD patients in therapy on an outpatient basis. Participants are randomized to an intervention (I) or control (C) group. Both groups receive identical capsules and are followed for 12 weeks. I receives 700mg of silymarin + 8mg vitamin E + 50mg phosphatidylcholine daily, while C receives 700mg maltodextrin + 8mg vitamin E + 50mg phosphatidylcholine daily. Patients undergo a computerized tomography (CT) scan and blood tests at the beginning and end of the study. Monthly face-to-face consultations and weekly telephone contact are carried out for all participants. The primary outcome assessed will be change in NAFLD stage, if any, assessed by the difference in attenuation coefficient between liver and spleen, obtained by upper abdomen CT. DISCUSSION: The results of this study may provide a valuable opinion on whether silymarin can be used as adjuvant therapy for the management or treatment of NAFLD. The data presented on the efficacy and safety of silymarin may provide more foundation for further trials and for a possible use in clinical practice. TRIAL REGISTRATION: This study has been approved by the Research Ethics Committee of the Professor Edgard Santos University Hospital Complex, Salvador BA, Brazil, under protocol 2.635.954. The study is carried out according to guidelines and regulatory standards for research involving humans, as set out in Brazilian legislation. Trial registration - ClinicalTrials.gov : NCT03749070. November 21, 2018.

Efficacy and safety of silymarin containing antioxidant serum as an adjuvant treatment of mild-to-moderate acne vulgaris: A prospective, open-label pilot study.

BACKGROUND: Silymarin is the active component of milk thistle, which has antioxidant properties by scavenging free radicals and potential comedolytic properties. AIMS: This study aimed to assess the efficacy and safety of 0.5% silymarin-loaded antioxidant serum (SAS) used to treat mild-to-moderate acne. PATIENTS AND METHODS: A prospective, open-label pilot study was conducted. We enrolled 22 Korean acne patients who applied the 0.5% SAS on the whole face twice daily while continuing the current anti-acne medications. Grade of acne severity, individual lesion counts, sebum output levels, skin erythema, and melanin pigmentation were assessed. RESULTS: After a 4-week application, the modified Global Acne Grading Score (mGAGS), Global Evaluation Acne (GEA) scale, and the acne lesion counts were significantly decreased. Sebum secretion, skin pigmentation, and erythema were also reduced during the study period, yet only the melanin pigmentation index reached statistical significance. Subgroup analysis revealed that the patients who took the low-dose oral isotretinoin during the study period showed more noticeable improvements in skin sebum output and melanin pigmentation. Additionally, no adverse event was associated with using the 0.5% SAS. CONCLUSION: The 0.5% silymarin-containing antioxidant formulation improved acne's clinical severity and related skin biophysical parameters.

A Randomized, Double-Blind, Split-Face Study of Topical Silymarin vs 2% Hydroquinone Cream in Melasmas.

BACKGROUND: Hydroquinone is effective in melasma treatment, but side effects may limit its use. Silymarin cream may be a safer alternative. OBJECTIVE: To compare the efficacy of 1.4% silymarin with 2% hydroquinone for melasma treatment in Asians. METHODS: In a randomized, double-blind, split-face study of 25 patients with epidermal or mixed-type melasma, the facial sides were randomized for the application of silymarin cream on one side and hydroquinone on the contralateral side for 3 months. Results were evaluated using a colorimeter, modified Melasma Area and Severity Index (mMASI) score, and patient self-assessment. RESULTS: Twenty-three patients completed the study. Colorimetric measurements calculated as relative lightness index (RL*I) showed no statistical difference between the 2 treatments (P=0.715). Compared with baseline, both treatments showed statistically significant improvements of RL*I, with 14.56% and 12.82% improvement in silymarin and hydroquinone, respectively. Modified MASI scores decreased after both treatments but were only statistically significant on the hydroquinone side, achieving 17.97% reduction (P=0.02) vs 7.11% (P=0.32) on the silymarin side. There was no statistically significant difference of the RL*I and modified MASI between the 2 treatments (P>0.05). Patients' assessment of hydroquinone treatment showed a 69.6% good-excellent improvement with a visual analog scale (VAS) satisfaction score of 7.82, compared with silymarin showing a 73.9 % good-excellent improvement and VAS score of 7.65 (P=0.50). More adverse effects occurred with the hydroquinone. CONCLUSION: Although hydroquinone showed a better response, topical silymarin was effective in the treatment of epidermal and mixed-type melasma with fewer side effects. J Drugs Dermatol. 2022;21(12):1304-1310. doi:10.36849/JDD.6491.

The effects of silymarin plus glutathione on the prevention of liver ischemia-reperfusion injury

Abstract Liver ischemia-reperfusion (IR) injury is a major clinical trouble encountered in clinical practice. This study aimed to examine the therapeutic effects of silymarin (SM) plus glutathione (GSH) on hepatic IR injury using a rat model of liver IR. Fifty male rats were randomly divided into five groups, each consisting of 10 rats as follows: Sham, IR, SM-IR, GSH-IR and SM plus GSH-IR. All groups except sham were subjected to 30-min ischemia and 24-h reperfusion. The treated groups received 100 mg/kg of SM, GSH and a mixture of SM plus GSH, 60 min prior to the IR. After a period of 24 h, blood and liver samples were collected for biochemical and histopathological evaluations. Pretreatment with SM, GSH and SM plus GSH before hepatic IR significantly decreased IR-induced elevations of aminotransferases, and significantly reduced the histopathological damage scores of the liver in the late phase of IR injury. Moreover, SM plus GSH treatment prior to liver IR significantly suppressed inflammatory process and oxidative stress as demonstrated by attenuations in tumor necrosis factor-α, myeloperoxidase and the thiobarbituric acid-reactive substances. These findings suggest that administration of SM plus GSH prior to liver IR may protect the liver parenchyma from the effects of an IR injury

The therapeutic effects of silymarin for patients with glucose/lipid metabolic dysfunction: A meta-analysis.

BACKGROUND: To comprehensively evaluate the treatment efficacy and safety of silymarin for patients with glucose/lipid metabolic dysfunction using a meta-analysis. METHODS: A systematic literature search in PubMed, EMBASE and Cochrane Library databases was performed up to October 1, 2019. STATA 13.0 software was used to estimate pooled standardized mean difference (SMD) and 95% confidence interval (95% CI). RESULTS: Sixteen studies involving 1358 patients were identified. Overall meta-analysis showed that compared with control, silymarin significantly reduced levels of fasting blood glucose (SMD: -1.27, 95% CI = [-1.78, -0.76]; P < .001), homeostatic model assessment for insulin resistance (SMD: -0.41, 95% CI = [-0.70, -0.12]; P = .005), hemoglobin A1c (SMD: -1.88, 95% CI = [-2.57, -1.20]; P < .001), total cholesterol (SMD: -1.13, 95% CI = [-1.82, -0.77]; P < .001), triglyceride (SMD: -0.37, 95% CI = [-0.69, -0.05]; P = .025), low-density lipoprotein-cholesterol (SMD: -1.30, 95% CI = [-1.93, -0.67]; P < .001), C-reactive protein (SMD: -0.63, 95% CI = [-1.01, -0.27]; P = .001), and increased high-density lipoprotein-cholesterol (SMD: 0.17, 95% CI = [0.05, 0.29]; P = .005), but had no impacts on function indicators of liver and kidney (alanine transaminase, aspartate aminotransferase, creatinine phosphokinase, creatinine) and the complication rate. Subgroup analyses indicated that insulin (which was negative in overall analysis) was significantly decreased in patients undergoing silymarin monotherapy (SMD: -2.03, 95% CI = [-3.03, -1.04]; P = .044) for more than 3 months (SMD: -0.01, 95% CI = [-0.25, -0.24]; P = .035). CONCLUSION: Supplementation of silymarin may be effective and safe for the management of diabetes mellitus and hyperlipidemia.

Rosa brunonii Lindely fruit as a new protective agent evaluated against Rif/INH induced toxicity in rats.

Rosa brunonii L., a less investigated plant contains flavonoid glycosides and is used to treat stomach ailments, heart problems, and diabetes in folk. The crude extract of the plant possesses antioxidant activity. The current work was aimed to investigate the presence of phytochemicals, antioxidative stress and protective potential of chloroform extract of the Rosa brunonii L. fruits (RBFCE) against liver and kidney toxicity induced by anti-tuberculosis drugs, rifampicin/isoniazid (Rif/INH) in Wistar albino rats. Animals were divided into six groups, each comprising 6 rats and fed with a standard pelleted diet. Normal control group was given only a standard pelleted diet. The vehicle control group received 0.5% carboxymethylcellulose (CMC) aqueous solution (vehicle). Negative and positive control groups were given Rif/INH (50+50 mg/kg, p.o) and silymarin (SILM) (200 mg/kg, p.o) in 0.5% vehicle for 30 days, respectively. Extract treated groups received low and high doses of RBFCE (500 mg/kg, p.o and 1000 mg/kg, p.o respectively) in 0.5% vehicle for 30 days. At a higher dose, animals showed significantly reduced Rif/INH induced toxicity in liver and kidney tissues as indicated by the normalized serum biochemical markers and histopathological investigations. The present exploration reveals the presence of strong antioxidant phytochemical constituents, antioxidative stress and protective potential of RBFCE against Rif/INH induced hepatic and renal damage.

The effect of silymarin on liver enzymes in patients taking isotretinoin: A randomized clinical trial.

The aim of the present study was to investigate the effect of silymarin (Livergol) on liver enzymes in patients taking isotretinoin (Roaccutane). In this double-blind clinical trial, 74 patients with acne and taking isotretinoin were randomly assigned into intervention (N = 37) and control (N = 37) groups. The intervention group received a 140 mg Livergol capsule per day for 30 days. The control group received a starch-containing capsule as a placebo once a day for 30 days. Liver enzyme levels were measured before and after the intervention. The data were analyzed using chi-square test, Independent t test, paired sample t test and analysis of covariance (ANCOVA). The results showed no statistically significant difference between the intervention and control groups at the beginning of study in levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) (p > .05). At the end of the study, a statistically significant difference was observed between the two groups in levels of AST and ALT (p < .05). Livergol prevented liver enzymes from increasing, so it can be used as an effective, low-cost, and low-complication treatment for the problem of increased levels of liver enzymes following the use of isotretinoin.

Efficacy and safety of oral silymarin in comparison with oral doxycycline and their combination therapy in the treatment of acne vulgaris.

Two factors of oxidative stress and inflammatory processes are implicated in pathogenesis of acne vulgaris. Silymarin has antioxidant and anti-inflammatory activities. This study was done to evaluate the effect of oral silymarin in the treatment of acne vulgaris compared to doxycycline and also their combination therapy. This randomized controlled trial was performed on 60 patients with acne vulgaris were divided into three groups of 20 patients, including: Silymarin (Group 1), Doxycycline (Group 2), and both compounds (Group 3). The patients' response was monitored every month and the lesions were evaluated using photography and two methods of Global Acne Grading system (GAGS) and Acne Severity Index (ASI). According to the results, the response to silymarin was not significantly different with doxycycline in the GAGS index (p = .260), but was lower in the ASI (p = .021). In this study, the synergistic effects of silymarin and doxycycline combination have been investigated in comparison with doxycycline. Although the improvement was more favorable in combination group, there was no statistically significant difference (p = .9 in ASI and p = .5 in GAGS). The results of our study suggest that although the silymarin monotherapy is not as effective as doxycycline for the treatment of acne vulgaris, it can be a therapeutic option.

Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial.

The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease and may be a treatment for NASH due to its antioxidant properties. We aimed to assess the safety and efficacy of higher than customary doses of silymarin in non-cirrhotic patients with NASH. This exploratory randomized double-blind placebo controlled multicenter Phase II trial tested a proprietary standardized silymarin preparation (Legalon®, Rottapharm|Madaus, Mylan) and was conducted at 5 medical centers in the United States. Eligible adult patients had liver biopsy within 12 months showing NASH without cirrhosis with NAFLD Activity Score (NAS) ≥4 per site pathologist's assessment. Participants were randomized to Legalon® 420 mg, 700 mg, or placebo t.i.d. for 48 weeks. The primary endpoint was histological improvement ≥2 points in NAS. Of 116 patients screened, 78 were randomized. There were no significant differences in adverse events among the treatment groups. After 48-50 weeks, 4/27 (15%) in the 700 mg dose, 5/26 (19%) participants randomized to 420 mg, and 3/25 (12%) of placebo recipients reached the primary endpoint (p = 0.79) among all randomized participants, indicating no benefit from silymarin in the intention to treat analysis Review by a central pathologist demonstrated that a substantial number of participants (49, 63%) did not meet histological entry criteria and that fibrosis stage improved most in the placebo treated group, although not significantly different from other groups. Silymarin (Legalon®) at the higher than customary doses tested in this study is safe and well tolerated. The effect of silymarin in patients with NASH remains inconclusive due to the substantial number of patients who entered the study but did not meet entry histological criteria, the lack of a statistically significant improvement in NAS of silymarin treated patients, and the unanticipated effect of placebo on fibrosis indicate the need for additional clinical trials. Trial Registration: clinicaltrials.gov, Identifier: NCT00680407.

Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review.

Milk thistle (Silybum marianum) is a medicinal plant from the Asteraceae family. Silymarin is the major constituent of milk thistle extract and is a mixture of some flavonolignans such as silybin, which is the most active component of silymarin. It is most commonly known for its hepatoprotective effect. Also, studies have shown other therapeutic effects such as anticancer, anti-Alzheimer, anti-Parkinson, and anti-diabetic, so its safety is very important. It has no major toxicity in animals. Silymarin was mutagen in Salmonella typhimurium strains in the presence of metabolic enzymes. Silybin, silydianin, and silychristin were not cytotoxic and genotoxic at concentration of 100 µM. Silymarin is safe in humans at therapeutic doses and is well tolerated even at a high dose of 700 mg three times a day for 24 weeks. Some gastrointestinal discomforts occurred like nausea and diarrhea. One clinical trial showed silymarin is safe in pregnancy, and there were no anomalies. Consequently, caution should be exercised during pregnancy, and more studies are needed especially in humans. Silymarin has low-drug interactions, and it does not have major effects on cytochromes P-450. Some studies demonstrated that the use of silymarin must be with caution when co-administered with narrow therapeutic window drugs.

Treatment options for nonalcoholic fatty liver disease: a double-blinded randomized placebo-controlled trial.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and is becoming the most frequent indication of liver transplantation. Cardiovascular disease is the main cause of death in these patients. There is no Food and Drug Association-approved medication for NAFLD patients. We aimed to provide more robust evidence on the use of medications that are inexpensive and available, namely, metformin, silymarin, pioglitazone, and vitamin E, for treating NAFLD. MATERIALS AND METHODS: We conducted a randomized double-blinded, placebo-controlled trial on 150 consecutive patients with NAFLD who were assigned to five groups: lifestyle plus placebo, metformin 500 mg/day, silymarin 140 mg/day, pioglithasone 15 mg/day, and vitamin E 400 IU/day, all for 3 months. Anthropometric and biochemical variables were measured at baseline and 3 months later. RESULTS: The mean age of the patients was 47.0±9.1 (range: 18-65) years and the sex distribution was 73 (48.7%) women and 77 (51.3%) men. Patients in all groups showed a significant improvement in anthropometric parameters such as waist circumference and BMI. There was no statistically significant difference in alanine transaminase and aspartate transaminase in the control group after treatment (P=0.51, 0.18, respectively); however, both liver enzymes decreased significantly in the other groups. DISCUSSION AND CONCLUSION: This randomized double-blinded placebo-controlled clinical trial suggested a significant benefit of silymarin, pioglitazone, and vitamin E in improving liver aminotransferases in patients with NAFLD after only 3 months, without exerting any specific side effects.

Topical silymarin versus hydroquinone in the treatment of melasma: A comparative study.

BACKGROUND: Melasma is a highly prevalent hyperpigmentation disorder with a high relapsing rate and a negative impact on the psychological state of the affected patients. The exact pathogenesis of melasma is not completely elucidated; however, ultraviolet induced oxidative stress has an important role in its pathogenesis. Silymarin, antioxidant drug, reduces the harmful effects of solar ultraviolet radiation such as inflammation, immune responses, DNA damage, and pigmentation. OBJECTIVES: To assess the efficacy and safety of topical silymarin with different concentrations (0.7% and 1.4%) versus hydroquinone 4% in the treatment of melasma. METHODS: Forty-two adult female patients with melasma were assigned to three equal groups each containing 14 patients; group1 was treated by silymarin 0.7% cream, group 2 was treated by silymarin 1.4% cream and group 3 was treated by hydroquinone 4% cream. The duration of treatment was 3 months. RESULTS: MASI score was significantly reduced in all groups at the end of third month; however, there were no significant differences in the therapeutic response between the three studied groups. No side effects were recorded with silymarin, while hydroquinone was associated with significant adverse effects. CONCLUSIONS: Silymarin cream might serve as an effective and safe treatment modality for melasma.

Role of silibinin in the management of diabetes mellitus and its complications.

Diabetes mellitus is globally approaching epidemic proportions and acts as a major cause of a number of serious health problems diagnosed as diabetic complications. The current oral drugs in the treatment of diabetes and its complications could meet some but not all of the patients' needs, and the development of novel drugs with a hypoglycemic effect is urgently required. Silibinin, a flavonolignan traditionally used for the treatment of gallbladder and hepatic diseases, was reported to improve glycemic homeostasis by improving the activity of pancreatic ß-cells, increasing insulin sensitivity of liver and muscle cells, and decreasing lipid deposition in adipocytes. Researches also indicated the effectiveness of silibinin in controlling several diabetic complications including neuropathy, retinopathy, impaired healing, hepatopathy, cardiomyopathy, nephropathy, and osteoporosis. In this review, we summarize the recent anti-diabetes findings of silibinin and clarify the underlying pharmacological mechanisms, and update the knowledge in understanding the role of silibinin in control of diabetic complications.

Synergistic apoptotic effects of silibinin in enhancing paclitaxel toxicity in human gastric cancer cell lines.

Gastric cancer (GC) is the 3rd leading cause of tumor­associated mortality worldwide. The efficacy of paclitaxel, a frequently used GC chemotherapeutic agent, is hindered due to drug resistance, dose­induced toxicity and adverse side effects. Silibinin, an active compound of a widely consumed dietary supplement, milk thistle extract, has recently been demonstrated to have strong antitumor efficacy in a human GC cell model. Thus, to enhance the efficacy of GC treatment, the present study evaluated whether silibinin exerted a synergistic therapeutic effect with paclitaxel. It was observed that the combination of silibinin­paclitaxel was able to trigger cell cycle arrest and apoptosis. The cell cycle arrest assay indicated that silibinin and paclitaxel alone induced a G2/M phase arrest, and the silibinin­paclitaxel combination strongly inhibited G2/M cells from entering the S phase. The apoptosis assay and western blot analysis of poly­ADP­ribose polymerase, pro­caspase 3 and pro­caspase 8 demonstrated that silibinin synergized with paclitaxel in promoting SGC­7901 GC cell apoptosis. Furthermore, upregulation of the ratio of apoptosis regulator Bcl­2/apoptosis regulator BAX and tumor necrosis factor receptor superfamily member 6 (Fas)/Fas ligand indicated that the silibinin­paclitaxel combination activated the death receptor­mediated pathway in SGC­7901 cells. The results of the present study suggested that silibinin enhanced the therapeutic potential of paclitaxel against human GC SGC­7901 cells.

Efficacy and safety of iron chelators in thalassemia and sickle cell disease: a multiple treatment comparison network meta-analysis and trial sequential analysis.

BACKGROUND: To compare the efficacy and safety of desferrioxamine (DFO), deferiprone (DFP), deferasirox (DFX) and silymarin in patients with either thalassemia or sickle cell disorder through network meta-analysis. METHODS: Electronic databases were searched for appropriate randomized clinical trials comparing iron chelators in patients with iron overload. Random effects model was used to generate direct, indirect and mixed treatment comparison pooled estimates for the following outcomes: serum ferritin, liver iron concentration (LIC), changes in serum ferritin, mortality, urine iron excretion, adverse events, neutropenia, agranulocytosis and number of patients withdrawing the chelating therapy. RESULTS: Thirty-two clinical trials were included in the meta-analysis. DFX/DFO was associated with better serum ferritin levels compared to DFO, DFX, DFO/Silymarin and DFP/DFO. DFX/DFO also lower LIC significantly compared to DFO. DFP/DFO was associated with higher LVEF, low risk of adverse events and reduced end of serum ferritin compared to DFO. Combination of silymarin with either DFP or DFX was observed with reduced end of treatment serum ferritin compared to using either of the drugs alone. DFP was observed with better effects in sickle cell disease. The strength of evidence was very low for most of the comparisons. CONCLUSION: Relative estimates between the individual iron chelators have been established. However, this evidence should be considered preliminary and may change with the results of future head-to-head clinical trials.

Protective effects of silymarin on methotrexate-induced damages in rat testes

Abstract The present study aimed to investigate the protective effects of silymarin (SMN), an antioxidant, on methotrexate (MTX)-induced damage in rat testes. Thirty-two Wistar albino rats were divided into four groups (n = 8): control, MTX (20 mg/kg, i.p. on days 1 and 5), SMN (200 mg/kg, orally), and MTX + SMN (20 mg/kg, i.p. on days 1 and 5 and SMN 200 mg/kg orally) groups. At the end of the 6-week trial period, histopathological, immunohistochemical, biochemical, and spermatological analyses were performed on testes tissues. Histopathologically, MTX-induced damage, including depletion of germ cell and loos of spermatozoa, was significantly improved with SMN treatment. Immunohistochemically, the immunoreactivity of glutathione peroxidase 1 (GPx1) and manganese superoxide dismutase 2 (SOD2) were detected more intensely in the MTX + SMN group than in the MTX group. Biochemical examinations revealed that SMN supplementation decreased the lipid peroxidation and increased enzymatic antioxidants in the SMN-treated rats. Spermatologically, significant differences were found in the density, motility, dead-to-live sperm ratio, and abnormal sperm rate in the MTX + SMN group compared to the MTX group. In conclusion, SMN seems to have protective effects as an antioxidant against MTX-induced damage in rat testes.

High Dose of Silymarin in Patients with Decompensated Liver Disease: A Randomized Controlled Trial.

Hepatitis C virus (HCV) is a major public health problem being the most common cause of chronic liver disease in Egypt. HCV-induced decompensated liver cirrhosis patients have a median survival of 2 years even with currently used new treatments. Silymarin is the most commonly used herbal product in chronic liver disease for its anti-inflammatory, antiviral, antioxidant, and antifibrotic effects. The aim of this study was to assess the effects of silymarin in high dose on the clinical and biochemical status of chronic HCV-associated decompensated liver cirrhosis. The study was conducted on 62 chronic HCV-decompensated cirrhotic patients. Patients were randomized according to treatment plans: group A, included 31 patients who received silymarin in dose of 1,050 mg/day, and group B, included 31 patients who received silymarin in dose of 420 mg/day. Patients were subjected to baseline history taking, laboratory evaluation, abdominal ultrasound, Child scoring, and quality-of-life (QoL) questionnaire. Follow-up was done every 2 weeks for 12 weeks. Silymarin in high dose had an effect on reducing alanine transaminase, aspartate aminotransferase levels (P ≤ 0.01), as well as improving albumin (P = 0.04), bilirubin (P = 0.02), and international normalized ratio (P = 0.03), thus resulted in improvement in Child score (P = 0.048), however, regular silymarin regimen (420 mg/day) failed to achieve the previous biochemical changes. High-dose regimen of silymarin also had a positive impact on improving QoL. No serious adverse events were reported. Silymarin in high dose is a good choice for improvement of liver biochemical profile and QoL in chronic HCV cirrhotic patients.

Comparison of efficacy of folic acid and silymarin in the management of antiepileptic drug induced liver injury: a randomized clinical trial.

BACKGROUND: Liver injury associated with antiepileptic drugs accounts for a large proportion of drug-induced liver injuries (DILI) in children. Although withdrawal of the causative agent is the only proved treatment for DILI, in some clinical situations it is not possible. Recent studies have reported promising results of using hepatoprotective drugs with antioxidant actions for the management of DILI. This study aimed to evaluate the efficacy of folic acid versus silymarin treatment in relation to decreasing liver enzymes in patients with DILI due to antiepileptic therapy. METHODS: This randomized, open-label, clinical trial evaluated 55 children with epilepsy who were on antiepileptic treatment and experienced DILI. The children were randomized to receive either silymarin (5 mg/kg per day) or folic acid (1 mg per day) for one month and were followed up for three months. RESULTS: Liver enzymes significantly decreased in both groups. The decrease trend in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were stronger in the folic acid group compared to silymarin group (P=0.04 and P=0.007, respectively). At the end of the study patients in the folic acid group had significantly lower ALT (P=0.04), AST (P=0.02), and gamma-glutamyl transferase (GGT) (P<0.001) levels and also higher percentage of normal ALT (30.7% vs 3.4%, P=0.009) and AST (42.3% vs 0%, P<0.001), and GGT (23.1% vs 0%, P=0.008) values compared to the patients in the silymarin group. No rebound elevations in ALT, AST and GGT levels or adverse reactions were noted in neither of the study groups. CONCLUSION: Although both treatments were safe and effective in decreasing liver enzymes, folic acid seems to be superior to silymarin in the management of DILI.