Modeling Pharmacokinetics in Individual Patients Using Therapeutic Drug Monitoring and Artificial Population Quasi-Models: A Study with Piperacillin.

Population pharmacokinetic (pop-PK) models constructed for model-informed precision dosing often have limited utility due to the low number of patients recruited. To augment such models, an approach is presented for generating fully artificial quasi-models which can be employed to make individual estimates of pharmacokinetic parameters. Based on 72 concentrations obtained in 12 patients, one- and two-compartment pop-PK models with or without creatinine clearance as a covariate were generated for piperacillin using the nonparametric adaptive grid algorithm. Thirty quasi-models were subsequently generated for each model type, and nonparametric maximum a posteriori probability Bayesian estimates were established for each patient. A significant difference in performance was found between one- and two-compartment models. Acceptable agreement was found between predicted and observed piperacillin concentrations, and between the estimates of the random-effect pharmacokinetic variables obtained using the so-called support points of the pop-PK models or the quasi-models as priors. The mean squared errors of the predictions made using the quasi-models were similar to, or even considerably lower than those obtained when employing the pop-PK models. Conclusion: fully artificial nonparametric quasi-models can efficiently augment pop-PK models containing few support points, to make individual pharmacokinetic estimates in the clinical setting.

The effect of COVID-19 vaccination status on all-cause mortality in patients hospitalised with COVID-19 in Hungary during the delta wave of the pandemic.

The high mortality of patients with coronavirus disease 2019 (COVID-19) is effectively reduced by vaccination. However, the effect of vaccination on mortality among hospitalised patients is under-researched. Thus, we investigated the effect of a full primary or an additional booster vaccination on in-hospital mortality among patients hospitalised with COVID-19 during the delta wave of the pandemic. This retrospective cohort included all patients (n = 430) admitted with COVID-19 at Semmelweis University Department of Medicine and Oncology in 01/OCT/2021-15/DEC/2021. Logistic regression models were built with COVID-19-associated in-hospital/30 day-mortality as outcome with hierarchical entry of predictors of vaccination, vaccination status, measures of disease severity, and chronic comorbidities. Deceased COVID-19 patients were older and presented more frequently with cardiac complications, chronic kidney disease, and active malignancy, as well as higher levels of inflammatory markers, serum creatinine, and lower albumin compared to surviving patients (all p < 0.05). However, the rates of vaccination were similar (52-55%) in both groups. Based on the fully adjusted model, there was a linear decrease of mortality from no/incomplete vaccination (ref) through full primary (OR 0.69, 95% CI: 0.39-1.23) to booster vaccination (OR 0.31, 95% CI 0.13-0.72, p = 0.006). Although unadjusted mortality was similar among vaccinated and unvaccinated patients, this was explained by differences in comorbidities and disease severity. In adjusted models, a full primary and especially a booster vaccination improved survival of patients hospitalised with COVID-19 during the delta wave of the pandemic. Our findings may improve the quality of patient provider discussions at the time of admission.

Assessment of Antibiotic Pharmacokinetics, Molecular Biomarkers and Clinical Status in Critically Ill Adults Diagnosed with Community-Acquired Pneumonia and Receiving Intravenous Piperacillin/Tazobactam and Hydrocortisone over the First Five Days of Intensive Care: An Observational Study (STROBE Compliant).

Severe community-acquired pneumonia (CAP) is a condition that frequently requires intensive care and, eventually, can cause to death. Piperacillin/tazobactam antibiotic therapy is employed as an empiric intravenous regimen, in many cases supplemented with intravenous bolus hydrocortisone treatment. The individual and condition-dependent pharmacokinetic properties of these drugs may lead to therapeutic failure. The impact of systemic inflammation, as well as of hydrocortisone on the altered pharmacokinetics of piperacillin is largely unknown. The protocol of a clinical study aimed at the characterization of the pharmacokinetics of piperacillin and tazobactam and its association with the concentrations of inflammatory markers and adrenal steroids during CAP therapy will be investigated in up to 40 critically ill patients. The serum concentrations of piperacillin and tazobactam, cortisol, cortisone, corticosterone and 11-deoxycortisol and interleukin-6 levels, as well as routine clinical chemistry and hematology parameters will be monitored from the beginning of treatment for up to five days. Nonparametric population pharmacokinetic modeling and Monte-Carlo simulations will be performed to make estimates of the pharmacokinetics of piperacillin and tazobactam and the probability of pharmacokinetic-pharmacodynamic target attainment. The observed individual characteristics and changes will be correlated with clinical and laboratory findings. The protocol of the observational study will be designed following the STROBE guideline.

The potential role of organic and conventional yoghurt consumption in the treatment of non-alcoholic fatty liver disease / Az ökológiai és a konvencionális joghurtfogyasztás lehetséges szerepe a nem alkoholos zsírmájbetegség kezelésében.

INTRODUCTION: Health is an important motivation for the consumption of both organic and functional foods. Organic food contains fewer pesticide residues and statistically more selected health-related compounds such as polyphenols in plant products and polyunsaturated fatty acids in milk and meat products. Recent studies suggest that the gut-liver axis plays an important role in the pathogenesis of non-alcoholic fatty liver disease, so probiotics could be a therapeutic tool. Comparing the health effects of yoghurt from organic origin with so-called conventional yoghurt is difficult, because there is no biomarker that would signal the difference with good specificity and sensitivity. AIM: The aim of this study was to investigate numerous biomarkers to evaluate the difference between yoghurt from conventional and organic origin and their health effects in NAFLD. PATIENTS AND METHOD: We performed a prospective, cohort study consisting of 37 (age = 51.73 ± 11.82, male = 21, female = 16) patients with NAFLD at the 2nd Department of Internal Medicine of the Semmelweis University, Budapest. Diagnosis of NAFLD was based on ultrasonography and the exclusion of other etiololgy. The patients were examined also with shear wave elastography to evaluate the hepatic fibrosis stage. We divided the patients randomly into two groups. The patients consumed individually daily 300 grams of yoghurt from organic (n = 21) or conventional (n = 16) origin for 8 weeks. We collected 37 routine laboratory data, measured 4 cytokines, 3 markers of the redox-homeostasis and 14 body composition values before, after, and 12 weeks after the yoghurt consumption. RESULTS: We found a mild elevation of vitamin D and a minimal reduction of LDL after the yoghurt consumption, but in the other 35 routine laboratory data there was no statistical difference. Adiponectin and leptin levels were elevated after the yoghurt consumption in the "conventional group". In contrast, we found significant decrease of adiponectin levels in the "organic group" after the treatment. Only the adiponectin tendency was different in the two groups. The induced free radical content was also statistically lower after the yoghurt consumption. In the body composition measurements, there were no significant differences. CONCLUSION: These data suggest that adiponectin could be a possible biomarker to evaluate the effectiveness of probiotic treatment in non-alcoholic fatty liver disease. Our work can serve as a basis for future studies investigating relationships between organic yoghurt consumption and health outcomes. Orv Hetil. 2020; 161(35): 1466-1474.

Fat rich diet-induced steatosis and changes in the gut­liver axis / A zsírdús étrend indukálta steatosis és a bél-máj tengely változásai.

INTRODUCTION: Fatty liver can develop as a result of diseases, surgical procedures, medicaments, malnutrition or excessive alcohol consumption, however, fat and poor fiber feeding can be attributed as the primary cause. Non-alcoholic fatty liver can be found in 20-30% of the population. Generally, alimentary-induced fatty liver in early state is described as uncomplicated liver injury. AIM: The aim of our research was to study the effect of fat rich nutrition on the gut-liver axis by routine laboratory, analytical and histological methods in rats. METHODS: We also examined the redox parameters of the liver and of the bowel. Fatty acid composition and element content of liver were measured. RESULTS: Significant changes were found in parameters of redox homeostasis as well as alterations in liver enzymes and metabolites. The changes could be detected in the liver, blood and bowel parts. The development of fatty liver is associated with the decrease of transmethylation capacity. Fatty acid composition and metal ion homeostasis were also altered in liver. Histological examinations showed that hepatocytes were swollen in the central part of the liver lobules, showed droplets and pycnotic nuclei, which were characterized by fatty degeneration. Small and large bowel enterocytes were damaged, sometimes pushed from the surface, and sometimes inflammatory reactions in the mucous membrane were observed. CONCLUSION: Our results suggest that alimentary fatty liver in early state is not considered simply as a reversible alteration because it alters the entire body's redox homeostasis and establishes heart and serious metabolic diseases as well as hasten the development of gastrointestinal tumors. Orv Hetil. 2020; 161(35): 1456-1465.

The comprehensive characterization of adrenocortical steroidogenesis using two-dimensional ultra-performance liquid chromatography - electrospray ionization tandem mass spectrometry.

The perturbation of the homeostasis of adrenocortical steroids plays a fundamental role in several pathological conditions. Currently, only a few of the substances involved in steroidogenesis are routinely analysed in clinical laboratories for the diagnosis of these conditions. Recently, interest has grown over the development of clinical assays of endogenous steroids using liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, no approaches have assessed the adrenocortical steroidogenesis comprehensively. Here, a novel LC-MS/MS assay is presented for evaluating the serum levels of all respective major substances (aldosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, 11-deoxycorticosterone, 11-deoxycortisol, 21-deoxycortisol, dihydrotestosterone, 17α-hydroxypregnenolone, 17α-hydroxyprogesterone, corticosterone, cortisol, cortisone, pregnenolone, progesterone and testosterone). The analysis time was 5.5 min following highly efficient solid phase extraction conducted on a novel polymer phase with N-polyvinylpyrrolidine branches. The method was validated in accordance with the respective guideline of the European Medicines Agency. The cross-validation of 8 analytes with immunoassays was also accomplished. Two-dimensional chromatography allowed the elution of the 16 analytes between 2.3-4.6 min and with a sufficient resolution of isobaric compounds. Quantitation was performed throughout the clinically relevant concentration ranges. Within-run accuracy was 87.1-115%, 90.0-109%, 87.2-111% and 87.6-107% at spiking levels 1 thru 4, while the precision was 4.7-27.9%, 2.9-17.7%, 5.6-13.9% and 1.9-15.0%, respectively. Between-run accuracy was 81.0-119.5, 85.2-113, 87.4-113 and 93.1-113%, respectively, while the precision was 3.4-13.5%, 2.0-10.2%, 2.1-15.0%, and 1.5-6.6%, respectively. In cross-validation studies, the mean percentage differences ranged between -51.4% (dehydroepiandrosterone sulfate) and 17.5% (dehydroepiandrosterone). The approach allows the comprehensive characterization of the adrenocortical steroid homeostasis in clinical diagnostics.

Antihyperlipidemic Effects of Sour Cherries Characterized by Different In Vitro Antioxidant Power and Polyphenolic Composition.

The aims of the present study were to clarify in vivo effects of three sour cherry cultivars characterized by different polyphenolic composition in hyperlipidemic animals in a short term experiment. The three different sour cherry cultivars were chosen based on their total in vitro antioxidant capacity, total polyphenolic, monomeric anthocyanin and flavonoid content. Male Wistar rats were divided randomly into eight groups: rats kept on normal diet (control) and normal diet supplied with sour cherry powder of one of the three cultivars; others were kept on fat-rich diet and fat-rich diet supplied with sour cherry powder prepared from one of the three cultivars. The treatment lasted 10 days. Lyophilized sour cherry administered in the diet decreased both total cholesterol and LDL cholesterol levels, and increased the HDL cholesterol concentration in sera of hyperlipidemic animals. Significant differences were found in the efficacy of different sour cherry cultivars in case of hyperlipidemia. Sour cherries characterized by higher polyphenol content seem to have a more pronounced effect on serum cholesterol levels. Our results suggest that besides anthocyanins, colourless polyphenols also have lipid lowering effect.

[Automated measurement of biomarkers for the diagnosis of acute myocardial infarction]. / Automatizáltan mérheto biomarkerek az akut myocardialis infarctus diagnosztikájában.

INTRODUCTION: Cardiac biomarkers have a prominent role in the diagnosis of acute myocardial infarction. AIM: The aim of the authors was to study the diagnostic effectiveness of automated measurement of cardiac biomarkers. METHOD: Myeloperoxidase, high-sensitivity C-reactive protein, myoglobin, heart-type fatty acid binding protein, creatine kinase, creatine kinase MB, high-sensitivity troponin I and T were measured. RESULTS: The high-sensitivity troponin I was the most effective (area under curve: 0.86; 95% confidence interval: 0.77-0.95; p<0.001) for the diagnosis of acute myocardial infarction. Considering a critical value of 0.35 ng/mL, its sensitivity and specificity were 81%, and 74%, respectively. Combined evaluation of the high-sensitivity troponin T and I, chest pain, and the electrocardiogram gave the best results for separation of acute myocardial infarction from other diseases (correct classification in 62.5% and 98.9% of patients, respectively). CONCLUSIONS: Until a more sensitive and specific cardiac biomarker becomes available, the best method for the diagnosis of acute myocardial infarction is to evaluate electrocardiogram and biomarker concentration and to repeat them after 3-6 hours.

[Effects of magnesium supplementation on calcium and magnesium levels, and redox homeostasis in normolipidemic and food-induced hyperlipidemic rats]. / Magnéziumpótlás hatása a kalcium- és magnéziumszintekre, valamint a redox-homeosztázisra normolipidaemiás és alimentárisan eloidézett hyperlipidaemiás patkányokban.

UNLABELLED: Magnesium supplementation is quite popular because of intention of health and healthy lifestyle. However, there is no information on the metabolic effects of magnesium supplementation in healthy people and in different diseases. AIMS: Authors examined the effects of magnesium-malate on calcium, magnesium levels, and antioxidant parameters in normolipidemic and hyperlipidemic rats. METHODS: Male Wistar rats (n = 40; 150-200 g) were divided into 4 groups (control, control-treated, hyperlipidemic, hyperlipidemic-treated). Rats in the control and control-treated groups were fed with normal diet, while hyperlipidemic and hyperlipidemic-treated groups were fed with fat rich diet (2% cholesterol, 20% sunflower oil, 0.5% cholic acid). After the 9-day-long diet the following parameters were measured: routine laboratory parameters with automatic analysator, metal content using ICP-OES, and redox-parameters using spectrophotometric and luminometric methods. RESULTS: Magnesium-malate failed to produce significant changes in the measured parameters in control animals in most cases. Magnesium-malate decreased significantly serum glucose concentration, alkaline phosphatase and amylase activities in the hyperlipidemic group. Significantly low induced chemiluminescent activity was measured in the plasma and erythrocytes of hyperlipidemic group. The magnesium supplementation did not increase significantly magnesium concentration in different organs although the calcium/magnesium concentration ratio was decreased. CONCLUSIONS: In control animals there was no significant change in the measured parameters in most cases after dietary supplementation with a large amount of magnesium for a short period of time, but magnesium supplementation affected the metal homeostasis, routine laboratory parameters and redox system in hyperlipidemic animals. Although several changes were favorable, it should be emphasized that magnesium supplementation must be applied watchfully particularly in metabolic diseases.

Alterations in the content of metal elements and fatty acids in hepatic ischaemia-reperfusion: induction of apoptotic and necrotic cell death.

Ischaemia and reperfusion are related to oxidative stress, which alters with the redox-homeostasis of the liver cells. Our aim was to reveal the correlations between changes of metal element and fatty acid concentration (two main components of redox-balance) and apoptotic and necrotic processes of hepatic ischaemia-reperfusion. Wistar rats were divided into three groups: control, sham-operated and reperfusion. Hepatic ischaemia was induced for 45 min in the left lateral, left medial and right medial lobes followed by 24 h of reperfusion. Global redox parameters and glutathione peroxidase and superoxide dismutase activity were detected by luminometry and spectrophotometry. Routine laboratory measurements, fatty acid composition (with gas chromatography) as well as metal ion concentration of liver (with ICP-OES) were determined. Metallothionein activity was measured by atomic absorption spectrometry. Immunohistochemical and histological examinations were carried out to investigate apoptotic and necrotic changes in the liver. During reperfusion, global antioxidant parameters decreased and superoxide dismutase level of the liver was significantly lower than in the sham-operated group. Changes in the metal element concentration are essential for cellular biochemical pathways, and significant correlations were found between decrease in Cu and Zn content and decreased superoxide dismutase activity. Necrotic lesions along with increased number of apoptotic cells were found in the liver after 24 h of reperfusion. Alterations in the metal element and fatty acid content was found in the liver tissue during 24 h of ischaemia-reperfusion along with increase in the number of apoptotic cells and significant disturbance of the antioxidant balance. Study of the metal element content of the liver during hepatic ischaemia-reperfusion may provide new supportive strategies for liver surgery and transplantation.

Liver-protecting effects of table beet (Beta vulgaris var. rubra) during ischemia-reperfusion.

OBJECTIVE: Table beet (Beta vulgaris var. rubra) contains important bioactive agents (betaine and polyphenols), which have a wide range of physiologic effects. Because nutritive antioxidants may reduce the occurrence of complications and postoperative mortality, dietary intake of polyphenols and vitamins before surgery may greatly contribute to the survival of patients. Our aim was to determine the liver-protecting properties of bioactive substances of table beet in a model of ischemia-reperfusion injury of the rat. METHODS: Wistar rats were divided into two groups: non-treated (n = 24) and fed with table beet (n = 8). For 10 days the second group was treated with lyophilized table beet (2 g/kg body weight daily) mixed into the rat chow. Hepatic ischemia was maintained for 45 min, followed by 15 min of reperfusion. Ischemia-reperfusion was carried out on animals from both groups. Chemiluminescent intensity, H-donating ability, reducing power, free SH group concentration, Randox-total antioxidant status, glutathione peroxidase, and superoxide dismutase activities were determined by luminometry and spectrophotometry. Fatty acid (Shimadzu GC) and metal ion (inductively coupled plasma optical emission spectrometry) concentrations were observed in the liver. RESULTS: As a result of feeding, global parameters (H-donating ability, reducing power, free SH group concentration) and enzymatic antioxidants (glutathione peroxidase and superoxide dismutase) of the liver were found to increase significantly, which indicated that the treatment had a positive effect on its redox state. The increase found in zinc and copper content may protect the hepatocytes against oxidative stress because these elements are required for the function of superoxide dismutase enzymes. In the table beet group the concentration of short-chain fatty acids decreased, whereas that of long-chain fatty acids increased. The changes in metal element and fatty acid concentrations confirmed that these elements have an essential function in cellular pathways. CONCLUSION: It may be stated that a natural antioxidant-rich diet has a positive effect on redox homeostasis during hepatic ischemia-reperfusion.

Antioxidant effect of squeezed juice from black radish (Raphanus sativus L. var niger) in alimentary hyperlipidaemia in rats.

Black radish (Raphanus sativus L. var. niger) root has been used in folk medicine since antiquity as a natural drug for the stimulation of bile function. According to in vitro studies the squeezed juice from black radish root exhibited significant antioxidant properties. In the present study, the beneficial effect of the black radish juice on some free radical reactions in rats fed with a diet rich in lipids (20% sunflower oil, 2% cholesterol, 0.5% cholic acid in normal chow) was examined. Thiobarbituric acid reactive substances and conjugated diene concentrations were significantly higher, while the antioxidant enzyme activities and the free radical scavenging capacity were lower in hyperlipidaemic rats compared with normal controls. Supplementation of the lipid-rich diet with black radish juice resulted in a significant improvement of the parameters mentioned above. Although the exact mechanism of the biologically active compounds in black radish on the lipid metabolism and lipid peroxidation is not clear yet, a beneficial effect of the drug was evident in alimentary hyperlipidaemia.

[Effect of vitamin E supplementation on the vitamin content of lipoprotein in young men and women]. / Az E-vitamin-pótlás hatása fiatal férfiak és nok lipoproteinjének vitamintartalmára.

UNLABELLED: The effect of supplementary Vitamin E on the vitamin content of lipoproteins in young men and women. Inappropriate vitamin and trace element supplementation may facilitate the development of atherosclerosis. It is known that Vitamin E protects lipids from oxidative stress, while clinical signs of atherosclerosis appear later in women compared to men. AIMS: (1) The increase of vitamin E in plasma and plasma lipoproteins after 4 weeks of supplementation vitamin E was investigated, (2) furthermore it was tested whether a proportion shift occurs in alpha-tocopherol content of lipoproteins, (3) and checked for gender-related differences in plasma and plasma lipoprotein vitamin E levels before, during and after treatment, (4) plasma CRP levels as a marker of lipid peroxidation were also followed. METHODS: 5-5 young healthy men and women took part in the study, receiving 700 IU/day Vitamin E for one month. Each subject was studied before and at the end of treatment, and also one month after treatment. HDL and LDL-VLDL containing lipoproteins were separated. Vitamin E and hsCRP levels were measured (by HPLC and an immunoturbidimetric method, respectively). RESULTS: Vitamin E treatment induced in both genders an approximately threefold increase in vitamin E concentration in HDL-cholesterol (8.1 +/- 1.7 micromol/l vs. 22.5 +/- 7.5 micromol/l, p < 0.001), and a twofold increase in LDL-VLDL-cholesterol (22.0 +/- 3.7 micromol/l vs. 49.0 +/- 9.0 micromol/l, p < 0.001). Plasma and HDL vitamin E levels were higher in women than in men at the onset of treatment (6.8 +/- 0.96 micromol/l vs. 9.5 +/- 1.10 micromol/l), but during the treatment these gender-related differences disappeared. When plasma vitamin E concentration were considered 100% and the changes of the vitamin E concentrations of lipoproteins were calculated, it was found that supplementation with vitamin E in men increased the vitamin E concentration of LDL-VLDL cholesterol to a higher extent compared to women (LDL-VLDL % in men: 59.8 +/- 7.43%, in women: 49.3 +/- 7.41%, p < 0.05). All the observed changes regressed one month after cessation of supplementation. The level of hsCRP decreased during vitamin E treatment (1.07 +/- 0.9 mg/l vs. 0.2 +/- 0.14 mg/l, p < 0.001), and remained suppressed after the cessation of treatment (0.37 +/- 0.4, p < 0.01). CONCLUSIONS: These results support the hypothesis that women at young age are better protected against lipid-peroxidation as compared to men because of higher HDL vitamin E concentrations. Vitamin E supplementation in men eliminates this concentration difference between genders, and also increases LDL-VLDL vitamin E. In both genders high concentration of vitamin E in lipoproteins was associated with low hsCRP concentration.

[Methods of monitoring oxidation-reduction balance and its potential role in diagnostics]. / A szervezet redox-egyensúlyának vizsgálati módszerei, lehetséges szerepük a diagnosztikában.

Results of the latest investigations confirm that the injury of redox homeostasis of human organism can be the starting point of many diseases. The pathogenesis of these diseases, including atherosclerosis, diabetes mellitus, chronic liver diseases, renal failure, rheumatoid arthritis and neurodegenerative diseases could be cleared up more deeply by the investigation of parameters of oxidative stress and by the observation of their changes in connection with the different organ and tissue damages. It is well known, that individuals with lowered antioxidant defences may be at greater risk of developing diseases induced by free radicals. The goal of the authors is to direct attention to the possible role of some redox parameters in detecting of general health status of the human body and in the risk assessment of the different diseases. These measurements can perhaps help the clinician in determining optimal treatment and monitoring its effectiveness.

[Possibilities of monitoring oxidative damage and its clinical aspects]. / Az oxidatív károsodás monitorozásának lehetóségei, és a vizsgálatok klinikai vonatkozásai.

In their earlier work the authors reviewed some methods, which appeared to be suitable for monitoring the redox-status of the human organism and, therefore, may be applied under routine clinical laboratory circumstances. This possibility can lead to a new perspective to set up epidemiological studies in different populations in order to investigate connecting points between the manner of life, alimentary customs (especially consumption of antioxidants), and the risk of chronic or acute illnesses. In this review the authors surveyed different methods for the measurements of end products (lipids, proteins, nucleic acids) produced by cells and tissues through oxidative injury, caused by the free radicals. These methods have already served the work of scientists for many years, helping them to obtain experience about the pathomechanisms of different diseases. With the help of these measurements it could be possible to monitor the results of medical therapy or surgical treatments, or in the field of chronic illnesses e.g. diabetes, to predict the possible development of late complications.

Extrahepatic biliary obstruction: can silymarin protect liver function?

The hepatoprotective property of silymarin is well known. However, it is not known whether the antioxidant silymarin might have a beneficial effect in extrahepatic cholestasis in common bile duct ligated rats. Malonaldehyde property concentrations, the hydrogen-donating ability and reducing power were measured in liver homogenates by spectrophotometry, as well as free SH-group levels and glutathione-reductase activities in sera. The total scavenger capacity of the livers was quantified by a chemiluminometric method. The elevated lipid peroxidation and decreased antioxidant capacity of liver homogenates and sera could be observed in ligated rats. Silymarin pretreatment improved the antioxidant capacity of the liver, diminished the direct bilirubin concentration and caused an increase of liver enzyme activities compared with the groups without treatment. These effects of silymarin suggest that it may be a useful agent for improving the antioxidant defensive system in extrahepatic cholestasis, but its choleretic property should be considered.