Fenugreek seeds attenuate thioacetamide induced liver damage.

The intention to conduct this study was to evaluate the hepatoprotective effects of Fenugreek seeds' extract supplementation in thioacetamide induced liver damage in male Sprague Dawley rats. For this study, 24 male Sprague Dawley rats (200-264gm) were distributed randomly into four groups. Group I remained untreated as control rats, group II received thioacetamide (200mg/Kg b.w i.p, administered on alternative days for 8 weeks), group III received thioacetamide (200mg/Kg b.w i.p administered on alternative days for 8 weeks) as well as 2ml of 2% extract of fenugreek seeds (orally administered daily from 4th week till 8th week of the experiment. Group IV only received 2ml of 2% extract of Fenugreek seeds daily for 4 weeks respectively. At the end of the experiment, blood was sampled to obtain plasma that was used for the analysis of liver markers and liver was used for analysis of antioxidant enzymes (catalase and SOD). Increase in total bilirubin, direct bilirubin, ALT and ALP levels, catalase activity and decrease in SOD activity was found in TAA-treated groups which assured liver damage. Whereas, treatment with Fenugreek seeds extract restored the altered levels of total bilirubin, direct bilirubin, ALT, ALP, catalase and SOD activities in the Test + Supp group. The results of this study confirmed the hepatoprotective role of Fenugreek seeds extract in thioacetamide induced liver damage.

Protective effect of Phaeoporus obliquus polysaccharide against acute liver injury induced by carbon tetrachloride and alcohol in mice.

Studied the optimum extraction process of polysaccharide from Phaeoporus obliquus and the effect of Phaeoporus obliquus polysaccharide on carbon tetrachloride (CCl4)- or alcohol-induced acute liver injury in mice. The main factor in influencing the extraction rate of Phaeoporus obliquus polysaccharide were extraction power and time, which was a kind of pyran glucose by infrared spectroscopy. CCl4 and alcohol were employed respectively to establish CCl4 and alcohol-induced acute liver injury mouse models. Compared with model groups mice, Phaeoporus obliquus polysaccharide treatment at the doses of 100mg/kg and 200mg/kg exhibited an obvious reduction liver index, ALP, ALT, AST levels, MDA content and TNF-α level (p<0.01) and SOD activity was increased, which was in a dose-dependent manner. Compared with the model group, the necrosis degree of hepatocytes was obviously reduced and the small fat droplets were formed in some cytoplasm, especially in high dose group, which the liver cells recovered to the level of normal group. Rt-PCR results showed that the expression of CYP2E1 mRNA in liver tissues of Phaeoporus obliquus polysaccharide groups were significantly reduced, and the difference were statistically significant compared with the model group (p<0.05). These results demonstrated that Phaeoporus obliquus polysaccharide has significantly hepatoprotective effect on CCl4 and alcohol-induced acute liver injury in mice.

EPA plus DHA improves survival related to a decrease of injury after extended liver ischemia in Sprague-Dawley rats.

INTRODUCTION AND OBJECTIVES: The omega-3 fatty acids (ω3), EPA and DHA, have been described for their beneficial effects on metabolism and inflammation. In addition, they are interesting tools in the treatment of acute liver disease. This investigation was conducted to assess the effect of EPA+DHA administration before partial ischemia (IR) on survival and liver injury. MATERIALS AND METHODS: Male Sprague-Dawley rats were supplemented for 7 days with ω3 [EPA (270mg/kg) and DHA (180mg/kg)]; controls received saline solution. After EPA+DHA supplementation, liver IR was induced by temporarily occluding the blood supply for 1h, followed up by 48h of reperfusion. Control animals were subjected to sham laparotomy. RESULTS: Previous to IR, the EPA+DHA administration improved the rate and prolonged the survival time by decreasing the AST and ALT levels and improving liver degenerative changes generated by the IR, which decreased TNF-α and IL-1ß. In addition, IL-10 increased at 20h with a tendency to normalize at 48h. The IR group had no differences in the IL-10 levels compared to controls. CONCLUSIONS: The ω3 supplementation could prevent and promote the restoration of the liver tissue and significantly improve the survival rate in rats at 48h.

The effects of chronic oxytocin administration on body weight and food intake in DHT-induced PCOS model rats.

Polycystic ovary syndrome (PCOS) is commonly associated with metabolic disorders, which are exacerbated by obesity. Recent studies have revealed that oxytocin contributes to metabolic, appetite, and body weight regulation. In the present study, we evaluated the effects of chronic administration of oxytocin on body weight, food intake, and fat mass in a dihydrotestosterone-induced rat model of PCOS. Body weight, body weight change, and relative cumulative food intake were significantly lower in the oxytocin-treated PCOS rats than in the vehicle-treated control PCOS rats. Similarly, visceral adipocyte size was significantly smaller in the oxytocin-treated PCOS rats than in the vehicle-treated control PCOS rats. On the other hand, the numbers of cystic follicles in the ovary did not differ between the two groups. The chronic administration of oxytocin did not affect the rats' serum aspartate aminotransferase, alanine aminotransferase, or lactate dehydrogenase levels, indicating that it does not have adverse effects on hepatic function. These findings suggest that oxytocin could be a candidate drug for preventing the onset of obesity-related metabolic disorders in PCOS patients.

Effects of garlic supplementation on liver enzymes: A systematic review and meta-analysis of randomized controlled trials.

Current evidence on the beneficial effects of garlic on liver enzymes is contradictory. Therefore, the aim of this systematic review and meta-analysis is to evaluate the effect of garlic supplementation on human liver enzymes, such as Alanine Transaminase (ALT/SGPT) and Aspartate Transaminase (AST/SGOT). To collect the required data, PubMed, Scopus, ISI Web of Science, and Google scholar databases were systematically searched from inception to June 2019. A meta-analysis was conducted using the random-effects model to evaluate the effects of garlic supplementation on ALT and AST levels. The Cochran's Q-test and inconsistency index were also used to evaluate heterogeneity among the studies. Among a total of 15,514 identified articles, six studies (containing 301 participants) met the inclusion criteria. Results of the meta-analysis showed that garlic supplementation significantly decreased AST level (Hedges' g = -0.36, 95% confidence interval [CI]: -0.72, -0.004, p = .047); whereas, it had no significant effect on ALT level (Hedges' g = -0.22, 95% CI: -0.64, 0.20, p = .310). Results showed that garlic supplementation reduced AST levels significantly; however, had no significant effect on ALT levels. Further studies are still needed to confirm the results.

Effects of green tea or green tea catechin on liver enzymes in healthy individuals and people with nonalcoholic fatty liver disease: A systematic review and meta-analysis of randomized clinical trials.

The therapeutic potential of green tea as a rich source of antioxidants and anti-inflammatory compounds has been investigated by several studies. The present study aimed to systematically review and analyze randomized clinical trials (RCTs) assessing the effects of green tea, catechin, and other forms of green tea supplementation on levels of liver enzymes. PubMed, SCOPUS, EMBASE, and Cochrane databases were searched until February 2019. All RCTs investigating the effect of green tea or its catechin on liver enzymes including alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and bilirubin were included. A total of 15 RCTs were included. The overall effect of green tea on liver enzymes was nonsignificant (ALT [Standardized mean difference (SMD)= -0.17, CI -0.42 to 0.08, p = .19], AST [SMD = -0.07, CI -0.43 to 0.29, p = .69], and ALP [SMD = -0.17, CI -0.45 to 0.1, p = .22]). However, subgroup analyses showed that green tea reduced the levels of liver enzymes in participants with nonalcoholic fatty liver disease (NAFLD) but in healthy subjects, a small significant increase in liver enzymes was observed. In conclusion, the results of this study suggest that the effect of green tea on liver enzymes is dependent on the health status of individuals. While a moderate reducing effect was observed in patients with NAFLD, in healthy subjects, a small increasing effect was found.

Histological improvement in chronic hepatitis B patients treated with bicyclol: real world experience.

BACKGROUND: Bicyclol, the most commonly-used liver hepatoprotective drug in China, is often selected to control disease progression in CHB patients who refuse anti-viral treatment. However, data on histological changes after bicyclol treatment in these patients are scarce. Therefore, this study has been conducted to find out whether bicyclol has good benefits of histological improvement in CHB patients who refuse anti-viral agents. METHODS: The demographic, clinical and pathological data were collected from CHB patients who received bicyclol from January 2010 to June 2016. Improvement in liver inflammation or fibrosis is defined as at least one-grade or one-stage decrease as measured by the Scheuer scoring system. Thirty patients treated with ETV for 48 weeks were chosen as a control group to compare the histological improvement between bicyclol and entecavir (ETV) after 48-week treatment. RESULTS: A total of 123 patients with CHB treated with bicyclol were included in this study. Paired liver biopsies were performed in 70 patients. Inter-biopsy interval was 17.44 ± 8.90 months (12-60 months). As shown by facts, 41.4% patients achieved liver inflammation improvement, while only 10.0% patients showed liver inflammation progression after bicyclol treatment. In regarding to liver fibrosis, as shown by facts, 28.6% patients achieved fibrosis improvement. More importantly, It was found that the proportions of patients with liver inflammation and fibrosis improvement were both not significantly lower than those in ETV group (53.3% vs 63.3 and 36.7% vs 43.4%). Most of patients (82.4%) with elevated baseline ALT became normal after bicyclol treatment. More importantly, as shown by the multi-variate analysis, the treatment course of bicyclol was an independent factor for liver inflammation improvement. With the HBeAg status adjusted, ALT and HBV-DNA quantity, the odds ratio (95% confidence interval) of patients with ≥48-week treatment was 5.756 (1.893,17.500) when compared with patients via < 48-week treatment. CONCLUSION: Bicyclol can improve liver inflammation and the ALT normalization rate of CHB patients, especially when the treatment course is prolonged. This has confirmed that bicyclol could control hepatitis activity, which might be a good choice for CHB patients who refuse anti-viral treatments.

Sufentanil Preconditioning Protects Against Hepatic Ischemia-Reperfusion Injury by Suppressing Inflammation.

BACKGROUND Inflammation is one of the most significant mechanisms of hepatic ischemia-reperfusion injury (IRI). Sufentanil has a protective effect against liver injury by reducing inflammatory response. In this study, we used a cellular hepatic ischemic/reoxygenated (IR) model to determine whether sufentanil preconditioning protects against hepatic IRI. MATERIAL AND METHODS The human normal liver cells line L-O2 was studied. The levels of glutamic oxaloacetic transaminase (AST), lactate dehydrogenase (LDH), malonaldehyde (MDA), and superoxide dismutase (SOD) were measured using corresponding assay kits. The protein levels of total and phosphorylated ERK1/2, JNK, and p38, and the expression of p65 and COX2 genes, were measured by Western blotting. The levels of inflammatory factors were examined by ELISA. The Cell Counting Kit-8 (CCK-8) was used to determine if the viability of L-O2 cells was affected by sufentanil. The effects of sufentanil on IR-induced cell apoptosis were examined by flow cytometry. RESULTS IR-induced caused L-O2 cells to become rounded and to have a lower adhesive rate than normal cells. The levels of AST, LDH, and MDA were higher but the level of SOD was lower in the IR group than in the control group. The phosphorylated protein levels of ERK1/2, JNK, and p38, along with the expression of p65 and COX2, were upregulated in the IR group compared to the normal group. In addition, a variety of inflammatory factors were secreted in L-O2 cells after IR. The viability of L-O2 cells decreased and cell apoptosis increased significantly after IR treatment. All indexes of cell injury were reversed by sufentanil in a concentration-dependent manner. CONCLUSIONS Sufentanil stimulation triggers downregulation of inflammatory factors such as HIF-1alpha, TNF-alpha, IL-1ß, and IL-6, possibly through suppressing the p38/ERK/JNK/NF-kappaB-p65/COX2 pathways, and thereby reduces the damage to IR hepatic cells.

The GLP-1 analog liraglutide attenuates acute liver injury in mice.

INTRODUCTION AND OBJECTIVES: Acute liver injury is a current health problem with few effective treatments. The present study investigated the hepatoprotective and curative potential of the glucagon-like peptide-1 analog liraglutide against carbon tetrachloride (CCl4)-induced hepatotoxicity. MATERIALS AND METHODS: Male Swiss mice were subjected to two protocols. The first protocol (Pretreatment) consisted of intraperitoneal (i.p.) treatment with liraglutide (0.057 and 0.118mgkg-1) or vehicle (distilled water) once daily for 7 days. On days 6 and 7, the animals were challenged with 2% CCl4 (5mgkg-1, i.p.). The second protocol (Late treatment) began with an injection of 5% CCl4 (5mgkg-1, i.p.) and subsequent treatment with liraglutide (0.057mgkg-1) or vehicle (distilled water) for 1 day. In both protocols, 24h after the last administration, blood and bile were collected from anesthetized animals, followed by euthanasia and liver collection. Plasma and bile underwent biochemical analyses, and histological, oxidative stress, and metabolic parameters were evaluated in the liver. RESULTS: Both liraglutide treatment protocols attenuated hepatotoxicity that was induced by CCl4, decreasing plasma levels of hepatic enzymes, stimulating the hepatic antioxidant system, and decreasing centrilobular necrosis, hepatic glycogen, and lipid accumulation. CCl4 tended to reduce bile lipid excretion, but liraglutide did not influence this parameter. CONCLUSIONS: The present results demonstrated the hepatoprotective and therapeutic effects of liraglutide, which may be attributable to a decrease in liver oxidative stress and the preservation of metabolism. Liraglutide may have potential as a complementary therapy for acute liver injury.

Drug rechallenge following drug-induced liver injury.

Drug-induced hepatocellular injury is identified internationally by alanine aminotransferase (ALT) levels equal to or exceeding 5× the upper limit of normal (ULN) appearing within 3 months of drug initiation, after alternative causes are excluded. Upon withdrawing the suspect drug, ALT generally decrease by 50% or more. With drug readministration, a positive rechallenge has recently been defined by an ALT level of 3-5× ULN or greater. Nearly 50 drugs are associated with positive rechallenge after drug-induced liver injury (DILI): antimicrobials; and central nervous system, cardiovascular and oncology therapeutics. Drugs associated with high rates of positive rechallenge exhibit multiple risk factors: daily dose >50 mg, an increased incidence of ALT elevations in clinical trials, immunoallergic clinical injury, and mitochondrial impairment in vitro. These drug factors interact with personal genetic, immune, and metabolic factors to influence positive rechallenge rates and outcomes. Drug rechallenge following drug-induced liver injury is associated with up to 13% mortality in prospective series of all prescribed drugs. In recent oncology trials, standardized systems have enabled safer drug rechallenge with weekly liver chemistry monitoring during the high-risk period and exclusion of patients with hypersensitivity. However, high positive rechallenge rates with other innovative therapeutics suggest that caution should be taken with rechallenge of high-risk drugs. CONCLUSION: For critical medicines, drug rechallenge may be appropriate when 1) no safer alternatives are available, 2) the objective benefit exceeds the risk, and 3) patients are fully informed and consent, can adhere to follow-up, and alert providers to hepatitis symptoms. To better understand rechallenge outcomes and identify key risk factors for positive rechallenge, additional data are needed from controlled clinical trials, prospective registries, and large health care databases. (Hepatology 2017;66:646-654).

Unanticipated increases in hepatic steatosis among human immunodeficiency virus patients receiving mineralocorticoid receptor antagonist eplerenone for non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease is common in human immunodeficiency virus, but there are no approved therapies. The aim of this open-label proof-of-concept study was to determine the effect of the mineralocorticoid receptor antagonist eplerenone on hepatic fat in human immunodeficiency virus-infected patients with hepatic fat ≥5% by magnetic resonance spectroscopy. METHODS: Five subjects received eplerenone (25 mg daily × 1 week followed by 50 mg daily × 23 weeks). Laboratory tests were done at each visit, and the primary endpoint, change in hepatic fat content, was determined by MRI spectroscopy at baseline and week 24. RESULTS: The study was stopped early after observing unexpected significant increases in hepatic fat at week 24 (mean increase 13.0 ± 7.3%, P = .02). The increases in steatosis were accompanied by a tendency for transaminase values to decrease (alanine aminotransferase mean change -14 ± 16 IU/L, P = .14). There were no consistent changes in other metabolic parameters or blood pressure. Repeat assessment of hepatic steatosis 1-2 months after stopping study medication revealed improvements in steatosis towards baseline values. CONCLUSIONS: The unexpected observation of increased hepatic steatosis with the administration of eplerenone led to early termination of the investigation. While limited because of the small number of participants and the open-label design, this study provides data to suggest that mineralocorticoid receptor antagonism with eplerenone may not be an effective approach to treat hepatic steatosis in human immunodeficiency virus or the general population. Additional research is needed to determine the pathophysiological mechanism behind these unanticipated observations.

[Efficacy of probiotics on the treatment of non-alcoholic fatty liver disease].

Objective: To study the clinical effect of probiotics in the treatment of non-alcoholic fatty liver disease (NAFLD). Methods: A total of 200 patients with NAFLD were randomly divided into 4 groups: control group (routine treatment group) and combined treatment group A, B and C. Each group had equal patients. The control group received orally polyene phosphatidylcholine capsules; whereas combined group A, B and C were given orally the live "combined Bifidobacterium Lactobacillus and Enterococcus powder" , "two live combined Bacillus subtilis and Enterococcus" , and the both probiotics respectively. The duration of treatment was 1 month. Laboratory parameters were evaluated before treatment and thirtieth day after treatment, including cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol(LDL-C), alanine aminotransferase(ALT), aspartate aminotransferase (AST), fasting blood glucose (FPG), serum high molecular weight adiponectin (HMW-APN) and serum TNFα. Meanwhile the faece sample was collected for routine test and bacterial culture. Liver ultrasound scan was done in all patients. Results: In terms of blood lipids and blood glucose, each group improved after treatment with significant differences (P<0.05) except for HDL-C. As for liver function, serum ALT and AST decreased after treatment in each group; especially in combined group C which were lower than those of control group [(33.7±7.6) U/L vs. (45.0±8.5) U/L; (22.0±1.6) U/L vs. (29.4±3.7) U/L; P<0.05]. TNFα levels decreased after treatment in each group, in addition the values in combined group C was significantly lower than that of control group[(0.51±0.27) µg/L vs. (0.82±0.28) µg/L, P<0.05]. Serum HMW-APN increased after treatment in each group, and the HMW-APN in combined C group was significantly higher than that of control group[(9.28±3.72) µg/L vs. (7.87±3.96)µg/L, P<0.05]. (5) After treatment, all groups showed improvement of fatty liver by ultrasound, but the difference between groups was not statistically significant. (6) Compared with before treatment, fecal flora in combined groups was all reduced (P<0.01), but it was comparable before and after treatment in control group. Conclusions: Probiotics improve intestinal microecological system in NAFLD patients via inhibiting TNFα and enhancing adiponectin, possibly resulting in regulating blood glucose, lipid metabolism, and protecting liver injury from NAFLD.

Effects of metformin on compensatory pancreatic ß-cell hyperplasia in mice fed a high-fat diet.

Metformin has been widely used for the treatment of type 2 diabetes. However, the effect of metformin on pancreatic ß-cells remains controversial. In this study, we investigated the impacts of treatment with metformin on pancreatic ß-cells in a mouse model fed a high-fat diet (HFD), which triggers adaptive ß-cell replication. An 8-wk treatment with metformin improved insulin resistance and suppressed the compensatory ß-cell hyperplasia induced by HFD-feeding. In contrast, the increment in ß-cell mass arising from 60 wk of HFD feeding was similar in mice treated with and those treated without metformin. Interestingly, metformin suppressed ß-cell proliferation induced by 1 wk of HFD feeding without any changes in insulin resistance. Metformin directly suppressed glucose-induced ß-cell proliferation in islets and INS-1 cells in accordance with a reduction in mammalian target of rapamycin phosphorylation. Taken together, metformin suppressed HFD-induced ß-cell proliferation independent of the improvement of insulin resistance, partly via direct actions.

Sasa veitchii extracts suppress acetaminophen-induced hepatotoxicity in mice.

BACKGROUND: The aim of this study was to investigate the therapeutic effects of a Sasa veitchii leaf extract (SE) on acetaminophen (APAP)-induced hepatotoxicity. METHODS: Seven-week-old male ddY mice were orally administered SE or saline (0.2 mL) once a day for a week. Twenty-four hours after the last pretreatment, the mice were intraperitoneally injected with 550 mg/kg APAP or saline under fasting conditions. The mice from each group were euthanized and bled for plasma analysis 2, 6, 24, and 72 h after the injection. RESULTS: We found that pretreatment with SE significantly decreased hepatic injury markers (i.e., alanine aminotransferase and aspartate aminotransferase), oxidative stress (malondialdehyde and glutathione level), inflammatory cytokines, histological damage, c-jun N-terminal kinase activation, and receptor-interacting protein-1 activation. Further, SE pretreatment decreased Cyp2e1 expression and increased total antioxidant capacity in the liver. CONCLUSION: Our findings demonstrate that prophylactic SE treatment protects mice from APAP-induced hepatotoxicity through modulation of Cyp2e1 expression and antioxidant capacity.

Medicinal role of papaya seeds on thrombocyte count tested on healthy rabbits.

The main objective of the current study is to evaluate the medicinal role of Papaya seeds on thrombocyte count and hepatic parameter on healthy rabbits. Experimental and Interventional study, at the Department of pharmacology Baqai Medical University Karachi. Rabbits (18 in number different age and both sex) were included, subsequently subdivided into three group (n=6). Group A (Control), B and C (sample fed dose 250 & 500mg OD, oral route). Blood were drawn 0 time, subsequently samples were drawn at 15, 30, 45 days. Data was analyzed by using SPSS 19.0. Analysis of results showed increase in the Platelet level 19.2%, 65.5%. No significant change seen in the SGPT, Alkaline Phosphatase, WBC, Neutrophil, Lymphocytes, Eosinophils and Monocytes as compared with the controls. It can be concluded that the administration of Papaya seeds powder dose rapidly increase platelet count and may play an important therapeutic role in thrombocytopenia.

The effect of sulforaphane on oxidative stress and inflammation in rats with toxic hepatitis induced by acetaminophene.

OBJECTIVE: The aim of the present study was to reveal the possible effect of sulforaphane on oxidative stress and inflammation in rats liver with toxic hepatitis induced by acetaminophene. BACKGROUND: Sulforaphane is a compound with high antioxidant properties. Acetaminophen, which is a para-aminophenol derivative, can lead to fatal hepatic necrosis with direct hepatotoxic effects at high doses. METHODS: Thirty six male Sprague-Dawley rats were randomly divided into four groups. Control group (n = 9) was fed with standard rat chow and water for 3 days. Group APAP (n = 9) received a single dose acetaminophen 1 g/kg by oral gavage in addition to standard chow and water. Group SFN (n = 9) received sulforaphane 500 µg/kg by oral gavage in addition to standard chow and water for 3 days. Group APAP+SFN (n = 9) received sulforaphane 500 µg/kg and a single dose acetaminophen 1 g/kg by oral gavage in addition to standard chow and water. Acetaminophen was administered three hours after SFN administration. RESULTS: Neopterin, MDA, AST, ALT and CRP levels of group APAP were significantly increased compared to control group. GSH level of group APAP was significantly lower than in the control group. CONCLUSION: Sulforaphane is a protective agent against acetaminophen-induced liver damage and it can be added in the treatment protocol (Tab. 1, Fig. 5, Ref. 51).

The protective effect of thymoquinone over olanzapine-induced side effects in liver, and metabolic side effects.

OBJECTIVES: The aim of the study was to investigate the possible protective qualities of thymoquinone (TQ) against the side-effects of olanzapine (OLZ) in an experimental model in rat liver with histologic and biochemical assessments. METHODS: Experimental procedures were performed on 35 female Sprague Dawley rats. Rats were randomly divided into five groups as: group 1: control; group 2: OLZ; group 3: OLZ+TQ-1; group 4: OLZ+TQ-2; and group 5: OLZ+TQ-3. RESULTS: The results showed that a 2­week administration of OLZ (4 mg/kg, once a day for the first week, 8 mg/kg once a day for the second week, p.o.) and treatment with TQ (25, 50, 100 mg/kg, once daily, p.o.) significantly reduced weight gain induced by OLZ. In addition, TQ increased the total antioxidant status (TAS), high-density lipoprotein cholesterol (HDL), insulin levels and decreased serum oxidative stress index (OSI), total oxidant status (TOS), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), low density lipoprotein cholesterol (LDL), glucose, triglycerides (TG) and total cholesterol (CH) levels significantly (p < 0.05). CONCLUSION: This study revealed that treatment with TQ might protect liver tissue against the side-effects of OLZ. TQ could be an effective course of therapy to enhance therapeutic efficacy (Tab. 4, Fig. 4, Ref. 47).

Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial.

BACKGROUND: Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. METHODS: In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18-70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10,000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01685203. FINDINGS: Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91·6-100]) in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3-97·5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference -9·16% [95% CI -19·61 to 1·29]; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92·7-100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia. INTERPRETATION: An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection. FUNDING: AbbVie.

Safety and efficacy of daclizumab in relapsing-remitting multiple sclerosis: 3-year results from the SELECTED open-label extension study.

BACKGROUND: Daclizumab is a humanized monoclonal antibody against CD25 that modulates interleukin 2 signaling. The SELECT TRILOGY of clinical studies (SELECT/SELECTION/SELECTED) evaluated the safety and efficacy of daclizumab in patients with relapsing-remitting multiple sclerosis (RRMS). We report the long-term safety and efficacy of daclizumab 150 mg subcutaneous every 4 weeks in patients with RRMS in the SELECTED open-label extension study. METHODS: An interim intent-to-treat analysis of all enrolled patients was performed in January 2014 for this ongoing study. RESULTS: The SELECTED study enrolled 90% of patients who completed SELECTION. In the safety and efficacy analysis (N = 410), median treatment time in SELECTED was 25 months (range, <1-45). Adverse events (AEs) were reported in 76% of patients, serious AEs (SAEs) excluding MS relapse in 16%, and treatment discontinuation due to AEs including multiple sclerosis (MS) relapse in 12%. AEs were primarily of mild to moderate severity, and common AEs (≥10%), excluding MS relapse, were nasopharyngitis (12%) and upper respiratory tract infection (12%). Most commonly reported SAEs (in ≥3 patients), excluding MS relapses, were increased serum hepatic enzymes, pneumonia, ulcerative colitis, and urinary tract infection (<1% each). Incidences of AE groups of interest include cutaneous events (28%), cutaneous SAEs (2%), gastrointestinal SAEs (2%), hepatic SAEs, (1%) and malignancies (1%). The incidence of AEs, SAEs, and treatment-related study discontinuations did not increase over time and no deaths were reported. The adjusted annualized relapse rate (95% confidence interval (CI)) analyzed at 6-month intervals was 0.15 (0.10-0.22) for weeks 97-120 and 0.15 (0.10-0.21) for weeks 121-144. In year 3, the adjusted mean (95% CI) number of new/newly enlarging T2 hyperintense lesions was 1.26 (0.93-1.72) and the mean (median) annualized change in brain volume was -0.32% (-0.34%). CONCLUSIONS: The AE incidence did not increase with extension of therapy into year 3 in SELECTED; the safety profile was similar to that previously observed. The clinical efficacy of daclizumab was sustained over the 3 years comprising the SELECT TRILOGY, although potential selection bias cannot be excluded. TRIAL REGISTRATION: Clinicaltrials.gov NCT01051349; first registered January 15, 2010.

Melatonin Upregulates the Activity of AMPK and Attenuates Lipid Accumulation in Alcohol-induced Rats.

AIMS: Melatonin is supposed to be an effective hepatoprotective agent. The effects and mechanisms of melatonin on alcoholic fatty liver (AFL) have not been well explored. The aim of this study was to investigate the preventive and therapeutic effects of melatonin on alcohol-induced fatty liver rats. METHODS: The AFL rats were induced by intragastric infusion of alcohol plus a high-fat diet for 6 weeks, and melatonin (10, 20, 40 mg/kg) was administered by gastric perfusion. We also established fatty acid overload cell model in HepG2 cells to investigate the effect of melatonin on AMP-activated protein kinase (AMPK) activity. RESULTS: The results showed that melatonin (20 and 40 mg/kg) administration significantly reduced alcohol-induced hepatic steatosis with lowering activities of serum alanine aminotransferase, aspartate aminotransferase and levels of serum and hepatic triglyceride. The activity of superoxide dismutase was increased and the content of malondialdehyde was decreased in liver homogenates of rats treated with melatonin. Melatonin increased the phosphorylation of AMPK in the liver tissues of alcohol-induced rats as well. Additionally, in vitro studies showed that melatonin increased the expression of melatonin1A receptor (MT1R), whereas luzindole, a receptor antagonist of melatonin, had no effect on its expression. In addition, melatonin reduced the levels of adenosine 3',5'-cyclic monophosphate (cAMP) and increased the phosphorylation of AMPK, and melatonin treatment could markedly reverse these effects. CONCLUSION: In conclusion, melatonin could protect against liver injury caused by alcohol gastric perfusion. The effect may be related to alleviating lipid peroxidation and upregulating the activity of AMPK mediated by MT1R signaling pathway.