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Silymarin is the most commonly used herbal medicine by patients with chronic liver disease. Silymarin flavonolignans undergo rapid first-pass metabolism primarily by glucuronidation. The aims of this investigation were: (1) to determine the association of UGT1A1*28 polymorphism with the area under the plasma concentration-time curves (AUCs) for silybin A (SA) and silybin B (SB); (2) to evaluate the effect of UGT1A1*28 polymorphism on the profile of flavonolignan glucuronide conjugates found in the plasma; and (3) to investigate the role of UGT1A1 enzyme kinetics on the pharmacokinetics of SA and SB. AUCs and metabolic ratios for thirty-three patients with chronic liver disease administered oral doses of silymarin were compared between different UGT1A1*28 genotypes. The AUCs, metabolic ratios, and the profiles of major SA and SB glucuronides did not differ significantly among the three UGT1A1 genotypes. In contrast, an increase in the proportion of sulfated flavonolignan conjugates in plasma was observed in subjects with UGT1A1*28/*28 genotype compared to subjects carrying wild type alleles. Differences in SA and SB in vitro intrinsic clearance estimates for UGTIA1 correlated inversely with SA and SB exposures observed in vivo indicating a major role for UGT1A1 in silymarin metabolism. In addition, a significant difference in the metabolic ratio observed between patients with NAFLD and HCV suggests that any effect of UGT1A1 polymorphism may be obscured by a greater effect of liver disease on the pharmacokinetics of silymarin. Taken together, these results suggest the presence of the UGT1A1*28 allele does not contribute significantly to a large inter-subject variability in the pharmacokinetics of silybin A and silybin B which may obscure the ability to detect beneficial effects of silymarin in patients with liver disease.

Curcumin is poorly absorbed, which is interest in new preparations. However, little is known about variations in its pharmacokinetics and tissue bioavailability between formulations. In this randomized, crossover study we evaluated the relationship between steady-state plasma and rectal tissue curcuminoid concentrations using standard and phosphatidylcholine curcumin extracts. There was no difference in the geometric mean plasma AUCs when adjusted for the 10-fold difference in curcumin dose between the 2 formulations. Phosphatidylcholine curcumin extract yielded only 20% to 30% plasma demethoxycurcumin and bisdemethoxycurcumin conjugates compared to standard extract, yet yielded 20-fold greater hexahydrocurcumin. When adjusting for curcumin dose, tissue curcumin concentrations were 5-fold greater for the phosphatidylcholine extract. Improvements in curcuminoid absorption due to phosphatidylcholine are not uniform across the curcuminoids. Furthermore, curcuminoid exposures in the intestinal mucosa are most likely due to luminal exposure rather than to plasma disposition. Finally, once-daily dosing is sufficient to maintain detectable curcuminoids at steady state in both plasma and rectal tissues.

The effects of sex, ethnicity, and genetic polymorphism on hepatic CYP2B6 (cytochrome P450 2B6) expression and activity were previously demonstrated in vitro. Race/ethnic differences in CYP2B6 genotype and phenotype were observed only in women. To identify important covariates associated with interindividual variation in CYP2B6 activity in vivo, we evaluated these effects in healthy volunteers using bupropion (Wellbutrin SR GlaxoSmithKline, Research Triangle Park, NC) as a CYP2B6 probe substrate. A fixed 150-mg oral sustained-release dose of bupropion was administered to 100 healthy volunteers comprising four sex/ethnicity cohorts (n = 25 each): Caucasian men and Caucasian, African American, and Hispanic women. Blood samples were obtained at 0 and 6 hours postdose for the measurement of serum bupropion (BU) and hydroxybupropion (HB) concentrations. Whole blood was obtained at baseline for CYP2B6 genotyping. To characterize the relationship between CYP2B6 activity and ethnicity, sex, and genotype when accounting for serum BU concentrations (dose-adjusted log(10)-transformed), analysis of covariance model was fitted in which the dependent variable was CYP2B6 activity represented as the log(10)-transformed, metabolic ratio of HB to BU concentrations. Several CYP2B6 polymorphisms were associated with CYP2B6 activity. Evidence of dependence of CYP2B6 activity on ethnicity or genotype-by-ethnicity interactions was not detected in women. These results suggest that CYP2B6 genotype is the most important patient variable for predicting the level of CYP2B6 activity in women, when measured by the metabolism of bupropion. The bupropion metabolic ratio appears to detect known differences in CYP2B6 activity associated with genetic polymorphism, across different ethnic groups. Prospective studies will be needed to validate the use of bupropion as a probe substrate for clinical use.

The goal of this study was to identify prehospital factors associated with increased likelihood of interfacility transfer of pediatric trauma patients. Such factors might serve as a basis for improvements in future field pediatric trauma triage guidelines.This was a retrospective cohort study of children aged 12 years or younger with blunt, penetrating, or thermal injuries who were transported by ground emergency medical services from the scene to the emergency department of a Level I, II, or III trauma center within the Denver metropolitan area from January 1, 2000, to December 31, 2008. Characteristics predicting subsequent interfacility transfer to a pediatric trauma center (PTC) were assessed.A total of 1673 patients were included in the analysis. Variables hypothesized to be most commonly associated with interfacility transfer were age, sex, mechanism of injury, body region of injury, and Glasgow Coma Scale score. The cohort included 1079 males and 593 females. Logistic regression analysis yielded the following as significant predictors of transfer: younger age (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.15-1.25), lower Glasgow Coma Scale score (OR, 1.08; 95% CI, 1.01-1.16), the presence of burns (OR, 37.52; 95% CI, 7.3-191.7), non-accidental trauma (OR, 6.09; 95% CI, 2.44-15.25), falls (OR, 1.62; 95% CI, 1.06-2.48), other motor vehicle-related incidents (OR, 2.37; 95% CI, 1.08-5.19), abdominal injury (OR, 5.39; 95% CI, 2.31-12.55), head/neck injury (OR, 7.89; 95% CI, 4.21-14.77), limb injury (OR, 5.31; 95% CI, 2.78-10.16), and multiple injuries (OR, 13.01; 95% CI, 5.0-33.8).Factors highly associated with transfer of an injured child from a non-PTC to a PTC included younger age, burns, non-accidental trauma, head/neck injury, and multiple injuries in younger children. Further investigation is warranted to determine whether these factors may have applicability in future improvements in field pediatric trauma patient triage guidelines.

Background Chronic hepatitis C is associated with significant morbidity and mortality as a consequence of progression to cirrhosis, hepatocellular carcinoma, and liver failure. Current treatment for chronic hepatitis C with pegylated interferon (IFN) and ribavirin is associated with suboptimal responses and numerous adverse effects. A number of botanical products have been used to treat hepatic disorders. Silymarin, extracted from the milk thistle plant, Silybum marianum (L) Gaertn. (Asteraceae), has been most widely used for various liver disorders, including chronic hepatitis C, B, and alcoholic liver disease. However, the safety and efficacy of silymarin have not been studied systematically in chronic hepatitis C. Purpose We describe our strategy for a phased approach for studying the impact of silymarin in hepatitis C, in the context of the unique challenges of botanical product clinical trials and the development of specific and curative antiviral therapy. Methods This multicenter, randomized, double-masked, placebo-controlled trial was conducted with four clinical centers and a data-coordinating center in the United States, to assess the impact of silymarin therapy in patients with chronic hepatitis C who failed conventional antiviral therapy. Results Key aspects relevant to performing clinical trials of botanical products include early identification of an appropriate product with standard product chemistry, acquisition of pharmacokinetic and dosing information, selection of the appropriate study group, and choosing rigorous outcome variables. Potential limitations Trial participants were chronic hepatitis C patients who were nonsustained virologic responders to IFN-based therapy; therefore, the findings are not generalizable to all hepatitis C populations. Further, alanine aminotransferase, a biochemical liver test, rather than hepatitis viral RNA or liver histology was the primary end point. Conclusions The challenges identified and addressed during development of this United States multicenter Phase II trial to evaluate silymarin for treatment of patients with chronic hepatitis C infection who had failed to respond successfully to previous IFN-based therapy are common and must be addressed to conduct rigorous trials of botanical products.

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.

Silymarin, used by 30 to 40% of liver disease patients, is composed of six major flavonolignans, each of which may contribute to silymarin's hepatoprotective properties. Previous studies have only described the pharmacokinetics for two flavonolignans, silybin A and silybin B, in healthy volunteers. The aim of this study was to determine the pharmacokinetics of the major silymarin flavonolignans in liver disease patients. Healthy volunteers and three patient cohorts were administered a single, 600-mg p.o. dose of milk thistle extract, and 14 blood samples were obtained over 24 h. Silybin A and B accounted for 43% of the exposure to the sum of total silymarin flavonolignans in healthy volunteers and only 31 to 38% in liver disease cohorts as a result of accumulation of silychristin (20-36%). Area under the curve (AUC(0-24h)) for the sum of total silymarin flavonolignans was 2.4-, 3.3-, and 4.7-fold higher for hepatitis C virus (HCV) noncirrhosis, nonalcoholic fatty liver disease (p

Assessing fitness to drive is part of the role of general practitioners. Cognitive impairment may affect an individual's ability to drive safely. The aims of our study were to question GPs about their experience of assessing patients with cognitive impairment for driving fitness and to explore their attitudes to this role. We carried out a quantitative cross-sectional anonymous postal survey of 200 GPs in counties Galway, Mayo and Roscommon. Ethical approval was obtained from the Irish College of General Practitioners. Data was analysed using Epi Info. The response rate was 62.5% (n=125). 86 (68.8%) GPs used guidelines when assessing fitness to drive in cognitive impairment. 83 (66.4%) respondents formally assess cognitive function. 52 (41.6%) GPs would certify someone as fit to drive with verbal restrictions. 102 (81.6%) respondents feel confident in assessing fitness to drive. 98 (78.4%) GPs have referred patients for further assessment.

Gemcitabine administered at a fixed dose rate of 10 mg/m(2) per min has been reported to achieve plasma steady-state concentrations ranging from 10 to 20 microM in patients with acute leukemia. These concentrations have been shown to saturate the intracellular accumulation of the active triphosphate metabolite. We designed this pharmacokinetic study to assess the ability of a fixed dose rate of gemcitabine to achieve the desired steady-state concentration in the absence and presence of paclitaxel in patients with solid tumors.A group of 14 patients with advanced non-small-cell lung cancer received paclitaxel 110 mg/m(2) over 3 h on days 1 and 8 and gemcitabine 800 mg/m(2) over 80 min on days 1 and 8 every 21 days. Patients received gemcitabine alone on cycle (C) 1, day (D) 1. Pharmacokinetic samples were collected at 0, 15, 30, 45, 60 and 80 min during infusion and 0.25, 0.5, 1, 2, 4, 6, and 8 h after infusion on C1D1, C1D8, C2D1, C4D1 and C6D1.Of 13 patients included in the pharmacokinetic analysis, 61% achieved the desired steady-state concentration (C(ss)) with gemcitabine alone (C1D1), whereas only 0 to 45% of patients achieved the desired C(ss) with paclitaxel and gemcitabine, depending on the treatment cycle. Paclitaxel significantly decreased systemic clearance (Cl(T); P=0.012) and volume of distribution (V(d); P=0.050) and significantly increased C(ss) ( P=0.009). Gemcitabine plasma pharmacokinetic parameters demonstrated great interpatient variability in the absence of paclitaxel (C(ss) 30%, Cl(T) 30%, V(d) 55%). Interpatient and intrapatient variability in gemcitabine pharmacokinetics were not observed when gemcitabine was administered in combination with paclitaxel (P0.05).Gemcitabine plasma pharmacokinetic parameters are significantly altered in the presence of paclitaxel.

This study examined the effects of 2 manipulations--a brief, regular period of human contact and diet--on the behavior of dogs confined in a public animal shelter. A behavioral battery designed to assess reactions to novel situations, and a test of responsiveness to an unfamiliar human were administered both prior to (pretest) and immediately following (posttest) the 8-week intervention period. Overall, the regular periods of increased human contact together with a diet that contained augmented levels of digestible protein, fat, calories, and animal-derived ingredients reduced signs of behavioral reactivity from pretest to posttest. In some cases, the comparison diet appeared more effective, but only for dogs receiving minimal human interaction. The results indicate that a combination of human interaction and high quality diet may positively affect the behavior of dogs in animal shelters.

Objective—To determine whether a program of human interaction or alterations in diet composition would alter activity of the hypothalamic-pituitaryadrenal (HPA) axis in dogs housed in an animal shelter. Design—Prospective study. Animals—40 dogs. Procedure—Dogs were (n = 20) or were not (20) enrolled in a program of regular supplemental human interaction (20 min/d, 5 d/wk, for 8 weeks) involving stroking, massaging, and behavioral training. In addition, half the dogs in each group were fed a typical maintenance-type diet, and the other half were fed a premium diet. Plasma cortisol and ACTH concentrations were measured during weeks 0, 2, 4, and 8 and before and after exposure to a battery of novel situations during weeks 0 and 8. Results—Plasma cortisol concentration was significantly decreased by week 2, but plasma ACTH concentration was not significantly decreased until week 8 and then only in dogs fed the premium diet. Following exposure to novel situations, plasma cortisol and ACTH concentrations were significantly increased. However, during week 8, dogs enrolled in the program of human interaction had significantly lower increases in cortisol concentration than did dogs not enrolled in the program. Conclusions and Clinical Relevance—Results suggest that both a program of human interaction and alterations in diet composition have moderating effects on activity of the HPA axis in dogs housed in an animal shelter and that activity of the HPA axis may be increased for a longer period during shelter housing than measurement of plasma cortisol concentration alone would suggest. (J Am Vet Med Assoc 2002;221:65–71)

With the advent of the direct-acting antiviral agents, significant drug-drug interaction (DDI) potential now exists for patients treated for chronic hepatitis C virus (HCV) infection. However, little is known about how often patients with HCV infection use medications that may interact with newer HCV treatments, especially those with cytochrome P450 3A (CYP3A) DDI potential.Using a large US commercial insurance database, medication use and comorbidity burden were examined among adult patients with a chronic HCV diagnosis from 2006 to 2010. Medications were examined in terms of total number of prescription claims, proportion of patients exposed, and DDI potential with the prototypical CYP3A direct-acting antiviral agents boceprevir and telaprevir, for which data were available.Patient comorbidity burden was high and increased over the study period. Medication use was investigated in 53 461 patients with chronic HCV. Twenty-one (53%) of the top 40 most utilized medications were classified as having interaction potential, with 62% of patients receiving at least one of the top 22 interacting medications by exposure. Of these, 59 and 41% were listed in a common DDI resource but not in medication-prescribing information, 77 and 77% had not been investigated in DDI studies, 41 and 36% did not have clear recommendations for DDI management, and only 14 and 23% carried a recommendation to avoid coadministration for boceprevir and telaprevir, respectively.Practitioners may expect a medication with CYP3A DDI potential in two-thirds of patients with HCV and may expect almost one-half of the most frequently used medications to have CYP3A DDI potential. However, DDI potential may not be reflected in prescribing information.

Background Epigallocatechin-3-gallate (EGCG) has antiangiogenic, antioxidant, and antifibrotic properties that may have therapeutic potential for the treatment of cirrhosis induced by hepatitis C virus (HCV). However, cirrhosis might affect EGCG disposition and augment its reported dose-dependent hepatotoxic potential. Objective The safety, tolerability, and disposition of a single oral dose of EGCG in cirrhotic patients with HCV were examined in an exploratory fashion. Methods Eleven patients with hepatitis C and detectable viremia were enrolled. Four had Child-Pugh (CP) class A cirrhosis, 4 had Child-Pugh class B cirrhosis, and 3 were noncirrhotic. After a single oral dose of green tea extract 400 mg containing 94% pure EGCG, blood for EGCG levels and safety parameters was ascertained at 2, 4, and 10 hours. Results Cmax and AUC to EGCG overlapped among the 3 groups, which suggests that the disposition of EGCG was not significantly altered in these patients with cirrhosis. Conclusions A single 400-mg oral dose of EGCG was safe and well tolerated by all of the patients in the study. These results provide guidance for the continued investigation of the long-term safety and antitumor potential of EGCG in cirrhotic patients with HCV.

The prevalence of reading difficulties is typically higher in males than females in both referred and research-identified samples, and the ratio of males to females is greater in more affected samples. To explore possible gender differences in reading performance, we analyzed data from 1,133 twin pairs in which at least one member of each pair had a school-history of reading problems and from 684 twin pairs from a comparison sample with no reading difficulties. Although the difference between the average scores of males and females in these two samples was very small, the variance of reading performance was significantly greater for males in both groups. We suggest that a greater variance of reading performance measures in males may account at least in part for their higher prevalence of reading difficulties as well as for the higher gender ratios that are observed in more severely impaired samples.

Despite several studies suggesting that CYP3A5 expression can influence the extent of hepatic CYP3A-mediated inhibition, a systematic in vitro-in vivo evaluation of this potential clinically important issue has not been reported. Using representative probes from two distinct CYP3A substrate subgroups (midazolam, erythromycin), the inhibitory potency of fluconazole was evaluated in pooled human liver microsomes (HLM) with a low or high specific CYP3A5 content, in recombinant CYP3A enzymes (rCYP3A), and in healthy volunteers lacking or carrying the CYP3A5(*)1 allele. Fluconazole was a slightly more potent inhibitor of CYP3A activity in CYP3A5-HLM than in CYP3A5+ HLM with midazolam (K(i) of 15 and 25 microM, respectively) but not with erythromycin (IC(50) of 70 and 54 microM, respectively). In comparison, fluconazole was a much more potent inhibitor of rCYP3A4 than rCYP3A5 with both midazolam (K(i) of 7.7 and 54 microM, respectively) and erythromycin (IC(50) of 100 and 350 microM, respectively). As predicted from HLM, with i.v. midazolam, the average (+/- S.D.) in vivo K(i) (K(i,iv)) was significantly higher in CYP3A5(*)1 carriers (24 +/- 17 and 17 +/- 8 microM for homozygous and heterozygous groups, respectively) than in noncarriers (13 +/- 6 microM) (p = 0.02). With the erythromycin breath test, the average K(i,iv) was not different between homozygous CYP3A5(*)1 carriers (30 +/- 12 microM) and noncarriers (58 +/- 53 microM). In conclusion, the effect of CYP3A5 on hepatic CYP3A-mediated inhibitory drug-drug interactions is substrate-dependent, and HLM, rather than rCYP3A, are the preferred in vitro system for predicting these interactions in vivo.

In various species, the presence of an attachment figure can reduce hypothalamic-pituitary-adrenal (HPA) responses. In the guinea pig, the mother reduces HPA elevations of her young both prior to and following weaning. Recently, an unfamiliar female was also found to reduce the HPA responses of postweaning guinea pigs. The present study evaluated the specificity and ontogenetic course of the effect of the unfamiliar female. Experiment 1 found that an unfamiliar adult male did not reduce the cortisol response of periadolescent subjects during novelty exposure. Experiment 2 showed that the effect of the unfamiliar female was present as early as the second week of life. Experiment 3 found that neither an unfamiliar adult female nor male affected the cortisol response in adult guinea pigs. In all experiments, the mother reduced the cortisol elevations of her offspring. The ability to buffer the cortisol response could not be explained by the amount of agonistic behavior subjects received from the stimulus animals. Results indicate that the mother guinea pig has a persisting ability to buffer HPA responses in her developing offspring; that during at least a large portion of the time that the mother can moderate the cortisol response of her young, so too can an unfamiliar adult female, but not an unfamiliar adult male; and that the ability of social partners to moderate HPA activity is not readily predictable from behavioral interactions.

Purpose The aims of these experiments were to determine the effect of a therapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers; and the concentration-effect relationship between dexamethasone and CYP3A4 activity in primary human hepatocyte cultures. Methods The effect of dexamethasone (8 mg administered by mouth two times a day for 5 days) on CYP3A4 activity in 12 healthy volunteers was assessed with the erythromycin breath test and urinary ratio of dextromethorphan to 3-methoxymorphinan. Concentration-effect of dexamethasone on CYP3A4-dependent testosterone 6-β-hydroxylation was determined in human hepatocytes treated with 2 to 250 μmol/L dexamethasone. Results The percent of erythromycin metabolized per hour increased from 2.20% ± 0.60% (mean ± SD) at baseline to 2.67% ± 0.55% on day 5 of dexamethasone (mean increase in hepatic CYP3A4 activity 25.7% ± 24.6% P = .004). The mean urinary ratio of dextromethorphan to 3-methoxymorphinan was 28 (4.8 to 109) and 7 (1 to 23) at baseline and on day 5 of dexamethasone (mean decrease = 49% P = .06). Substantial intersubject variability was observed in the extent of CYP3A4 induction. The extent of CYP3A4 induction was inversely correlated with baseline erythromycin breath test (r 2 = 0.58). In hepatocytes, dexamethasone 2 to 250 μmol/L resulted in an average 1.7-fold to 6.9-fold increase in CYP3A4 activity, respectively. The extent of CYP3A4 induction with dexamethasone in hepatocyte preparations was inversely correlated with baseline activity (r 2 = 0.59). Conclusions These data demonstrate that dexamethasone at doses used clinically increased CYP3A4 activity with extensive intersubject variability and that the extent of CYP3A4 induction was, in part, predicted by the baseline activity of CYP3A4 in both healthy volunteers and human hepatocyte cultures. (Clin Pharmacol Ther 2000;68:356-66.) Clinical Pharmacology & Therapeutics (2000) 68, 356–366; doi: 10.1067/mcp.2000.110215

The hypocholesterolemic activity for novel ureido fibrate analogues was found to be over 100-fold greater than for any "second-generation" fibrate in cholesterol-fed rats. A comparison of 12 related analogues revealed that the optimal configuration for a urea-bridging region located between two aromatic rings consisted of a trisubstituted nitrogen, optimally substituted with a C7 alkyl chain and linked by dimethylene to a phenoxyisobutyrate moiety found in most fibrate analogues. The hypocholesterolemic potency of these compounds was found to correlate with their increased intrinsic fibrate activity as determined by the ability to induce omega-hydroxylase activity either in rat hepatocyte cultures or in vivo, and not with their 10-fold increased ACAT inhibitory potency when compared to other fibrates. The most active compound, 2-(4-(2-(N'-(2,4- difluorophenyl)-N-heptylureido)ethyl)phenoxy)-2-methylpropionic acid, referred to as (2), was found to induce omega-hydroxylase activity in hepatocytes at concentrations between 5 and 100 nM compared to 1-20 microM concentrations for bezafibrate, and lower serum VLDL+LDL cholesterol in rats at doses between 0.1 and 0.5 mg/kg per day compared to doses of 25-100 mg/kg per day for bezafibrate. Single-dose pharmacokinetic studies with 2 indicated that total drug exposure will be much lower at hypocholesterolemic doses due to the enhanced intrinsic activity, and may result in an improved safety profile for these novel trisubstituted ureido fibrate analogues in rats and humans compared to other fibrates.

Context The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy. Objective To determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV) infection unsuccessfully treated with interferon-based therapy. Design, Setting, and Participants Multicenter, double-blind, placebo-controlled trial conducted at 4 medical centers in the United States. Participants included 154 persons with chronic HCV infection and serum alanine aminotransferase (ALT) levels of 65 U/L or greater who were previously unsuccessfully treated with interferon-based therapy. Enrollment began in May 2008 and was completed in May 2010, with the last follow-up visit completed in March 2011. Intervention Participants were randomly assigned to receive 420-mg silymarin, 700-mg silymarin, or matching placebo administered 3 times per day for 24 weeks. Main Outcome Measures The primary outcome measure was serum ALT level of 45 U/L or less (considered within the normal range) or less than 65 U/L, provided this was at least a 50% decline from baseline values. Secondary outcomes included changes in ALT levels, HCV RNA levels, and quality-of-life measures. Results After 24 weeks of treatment, only 2 participants in each treatment group (P ≥ .99) met the primary outcome measure (3.8% [95% CI, 0.5% to 13.2%] for placebo, 4.0% [95% CI, 0.5% to 13.7%] for 420-mg silymarin, and 3.8% [95% CI, 0.5% to 13.2%] for 700-mg silymarin). The mean decline in serum ALT activity at the end of treatment did not differ significantly (P = .75) across the 3 treatment groups (mean decline, −4.3 [95% CI, −17.3 to 8.7] U/L for placebo, −14.4 [95% CI, −41.6 to 12.7] U/L for 420-mg silymarin, −11.3 [95% CI, −27.9 to 5.4] U/L for 700-mg silymarin); there likewise were no significant differences in HCV RNA levels (mean change, 0.07 [95% CI, −0.05 to 0.18] log 10 IU/mL for placebo, −0.03 [95% CI, −0.18 to 0.12] log 10 IU/mL for 420-mg silymarin, 0.04 [95% CI, −0.08 to 0.16] log 10 IU/mL for 700-mg silymarin; P = .54) or quality-of-life measures. The adverse event profile of silymarin was comparable with that of placebo. Conclusion Higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy. Trial Registration clinicaltrials.gov Identifier: NCT00680342

In the present study we have investigated the influence of sex on the specificity of mouse renal microsomes toward endogenous and xenobiotic substrates. Renal microsomes from C3H/HeJ mice were characterized by the following: a 4- to 5-fold male predominance in cytochrome P-450 concentration; a difference between male and female renal microsomes in the absorption maximum for the reduced P-450 . CO complex, 450 and 452 nm, respectively; a lack of a sex difference in lauric acid 12-hydroxylase activity; an 18-fold sex difference (M greater than F) in progesterone 16 alpha-hydroxylase activity; and 8- to 10-fold sex differences (M greater than F) in progesterone 15 alpha-hydroxylase, dimethylnitrosamine demethylase, and lauric acid 11-hydroxylase activities. Treatment of female mice with testosterone propionate selectively induced lauric acid 11-hydroxylase and dimethylnitrosamine demethylase activities 8- and 14-fold, respectively, but had no effect on progesterone 15 alpha- and 16 alpha-hydroxylase activities or on the high female rate of lauric acid 12-hydroxylation. Inhibition studies conducted with male mouse renal microsomes revealed that of the substrates examined, only testosterone inhibited the 15 alpha- and 16 alpha-hydroxylations of progesterone in vitro. In addition, progesterone 15 alpha-hydroxylase was distinguished from 16 alpha-hydroxylase by the greater degree of testosterone inhibition (68 and 44%, respectively) and by sensitivity to metyrapone inhibition. Mouse renal cytochrome P-450 heterogeneity is indicated by the selective effects of androgen induction and metyrapone inhibition. Moreover, distinct modes of regulation are observed between the isozymes involved in steroid hydroxylation and those which catalyze the 11- and 12-hydroxylations of lauric acid in mouse renal microsomes.