Monday, August 29, 2011
Canada-Victrelis;New Hep C drug priced out of reach of most patients
New Hep C drug priced out of reach of most patients
The earliest the medication could be available through BC Pharmacare is April 2012 with two more reviews to go through
Despite approval by Health Canada, Boceprevir, a new drug that dramatically improves the effectiveness of standard hepatitis C treatments remains out of reach of most patients. Boceprevir (brand name Victrelis) is available at pharmacies at a price of $1,050 per week.
Given that the minimum recommended treatment period is 24 weeks, this means "it will remain out of reach of the majority of those who need it unless BC Pharmacare covers it," said Daryl Luster, chair of hepatitis C Global Initiatives, an advocacy group based in Vancouver.
"The drug is now available for those who are very wealthy or have private insurance, but most will require assistance from Pharmacare [to get the drug] and the process for that is long," said Dr. Eric Yoshida, head of the BC Hepatitis Program.
Approval by Health Canada is just the first step, he said. The federal agency only assesses the safety and therapeutic effect of a drug and grants permission to market the drug in Canada. Provincial governments must now decide whether to include the drug in their Pharmacare programs.
To be included in BC Pharmacare, the drug needs to go through two more reviews. First, it needs a positive recommendation from the Common Drug Review - a national review process managed by the Canadian Agency for Drugs and Technologies in Health (CADTH). As a second step, once a positive recommendation has been given, the B.C. Ministry of Health makes a Pharmacare coverage decision by considering Pharmacare policies, programs and resources and the evidence informed recommendations from the B.C. Drug Benefit Council (DBC).
The DBC's advice to the ministry is based upon a review of available clinical and pharmaco-economic evidence, clinical practice and ethical considerations, patient input, and the recommendations of the Common Drug Review, explained Brian Cotton, public affairs officer, B.C. Ministry of Health, in an email. The entire process, including the BC Pharmacare review, is expected to take at least 12 months. So the earliest Boceprevir could be available through Pharmacare in B.C. is April 2012. This may be too late.
"I hope you can get a sense of urgency for Boceprevir. It's needed now - not in April next year," said Douglas Laird, board member of the Hepatitis C Education and Prevention Society, who himself suffers from hepatitis C. "Many people infected with HCV [hepatitis C virus] are in critical condition and need the drug now."
medha@vancouversun.com
© Copyright (c) The Vancouver Sun
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Friday, August 26, 2011
Fatigue In HCV Infection: A Review (1989-2011)
Fatigue In HCV Infection: A Review (1989-2011)
From; AHCS = Australia Hepatitis C Support Group
Saturday, 11 June 2011 11:13
Written by Doug Mellors and Linda McInnes
To read the full review, please click the following link;
Fatigue in HCV Infection: A Review (1989-2011)
It is unusual to preface a review with an explanation of its genesis as this should be evident in its stated aims, nevertheless, a number of people who helped in creating this review have asked me to do so, and I thought, I should gratefully respond to their request.
The review began with a question “Why are the symptoms of hepatitis C such a mystery?” put to me by Kerry Paterson, (Executive Officer) of the South Australian Hepatitis C Council. We had been discussing symptoms and I had stated, with considerable consternation, that almost twenty years after the discovery of the hepatitis C virus there were still many health professionals who either denied the existence of subjective symptoms in HCV patients, or showed little interest in treating them.
My answer to Kerry’s question was that no one had done a comprehensive review of studies which, had examined the symptoms of hepatitis C; there wasn’t even a clear consensus on what these symptoms were until the first careful survey was published in 2006 – in a word, very few people would have known what research had been done. This answer was followed by a second question from Kerry “ Will you do it?” To which I answered, “Yes, if you can help me to get the journal articles I will need”. I hadn’t done any real research (my professional background was in psychology) for more than twelve years, my statistics, never brilliant, were very rusty, and my computer of archaic vintage – I realized I couldn’t possibly do this on my own, a brief visit to Adelaide University to do some preliminary searches to see what literature was out there, only confirmed my conclusion.
I first met Linda when she was visiting the Council towards the end of 2006, I was very impressed, that with only her son to help her, she had created the AHCS – Australian Hepatitis C Support website and forums. When I described the task ahead of me to Linda she showed a great deal of interest, – after a few further meetings with her, I asked her if she would help me with the review and was delighted when she accepted. A few months later Cecelia Lim, (Co-ordinator, Information and Resources) also from the Council, told us that her negotiations with the Department of Health, to allow us access to the journals we needed, had been successful.
When we had completed the first comprehensive searches (on five symptoms) we realized that there was much more material than we had expected, and too much for us to take on. We decided we would take one symptom at a time, we chose fatigue for three reasons: firstly, it is the symptom most commonly reported by people infected with the hepatitis C virus; secondly, fatigue has been studied more than any other symptom; and finally most studies that investigated fatigue also looked at other symptoms and this review also includes those results. It has taken three and a half years to produce the first half of the review.
By the end of the first year we had completed the first draft i.e. from 1989 – 2007, but during editing, it seemed too lacking in detail and depth of analysis. It had also begun to dawn on us that what we really wanted to create was an archive – if something is archived and is easily accessible it is no longer likely to be a ‘mystery’. We also wanted something that was not static so the commentaries could be changed or added to – providing a safeguard against any mistakes or misinterpretations that we may have made.
At the end of the second year the document was much improved but now it was too bulky and needed to be reduced – at the same time we were trying to catch up with more recent publications.
After about 9 months of revision we decided it was taking too long, we needed to get something out there, so we stopped and concentrated on getting the first half of the review finished – we hope we can finish off the remainder by the end of this year. Although mentioned in the “Introduction” it is probably worth stating here that the review is a very long document, more than 30,000 words (half the length of an average novel!). It takes 50 pages to describe and comment on 43 studies. It may be less taxing to first read the section “Results, Discussion, Summary and Conclusion” at the end of the document which only takes up a little more than 9 pages and is a brief summary of every study in the review. For those people who knew about this work, we apologise for its delay. We hope the reader will receive at least some small benefit from reading it.
Doug Mellors.
To read the full review, please click the following link;
Fatigue in HCV Infection: A Review (1989-2011)
Please note: If you are unable to view, please download adobe reader from here.
,
From; AHCS = Australia Hepatitis C Support Group
Saturday, 11 June 2011 11:13
Written by Doug Mellors and Linda McInnes
To read the full review, please click the following link;
Fatigue in HCV Infection: A Review (1989-2011)
It is unusual to preface a review with an explanation of its genesis as this should be evident in its stated aims, nevertheless, a number of people who helped in creating this review have asked me to do so, and I thought, I should gratefully respond to their request.
The review began with a question “Why are the symptoms of hepatitis C such a mystery?” put to me by Kerry Paterson, (Executive Officer) of the South Australian Hepatitis C Council. We had been discussing symptoms and I had stated, with considerable consternation, that almost twenty years after the discovery of the hepatitis C virus there were still many health professionals who either denied the existence of subjective symptoms in HCV patients, or showed little interest in treating them.
My answer to Kerry’s question was that no one had done a comprehensive review of studies which, had examined the symptoms of hepatitis C; there wasn’t even a clear consensus on what these symptoms were until the first careful survey was published in 2006 – in a word, very few people would have known what research had been done. This answer was followed by a second question from Kerry “ Will you do it?” To which I answered, “Yes, if you can help me to get the journal articles I will need”. I hadn’t done any real research (my professional background was in psychology) for more than twelve years, my statistics, never brilliant, were very rusty, and my computer of archaic vintage – I realized I couldn’t possibly do this on my own, a brief visit to Adelaide University to do some preliminary searches to see what literature was out there, only confirmed my conclusion.
I first met Linda when she was visiting the Council towards the end of 2006, I was very impressed, that with only her son to help her, she had created the AHCS – Australian Hepatitis C Support website and forums. When I described the task ahead of me to Linda she showed a great deal of interest, – after a few further meetings with her, I asked her if she would help me with the review and was delighted when she accepted. A few months later Cecelia Lim, (Co-ordinator, Information and Resources) also from the Council, told us that her negotiations with the Department of Health, to allow us access to the journals we needed, had been successful.
When we had completed the first comprehensive searches (on five symptoms) we realized that there was much more material than we had expected, and too much for us to take on. We decided we would take one symptom at a time, we chose fatigue for three reasons: firstly, it is the symptom most commonly reported by people infected with the hepatitis C virus; secondly, fatigue has been studied more than any other symptom; and finally most studies that investigated fatigue also looked at other symptoms and this review also includes those results. It has taken three and a half years to produce the first half of the review.
By the end of the first year we had completed the first draft i.e. from 1989 – 2007, but during editing, it seemed too lacking in detail and depth of analysis. It had also begun to dawn on us that what we really wanted to create was an archive – if something is archived and is easily accessible it is no longer likely to be a ‘mystery’. We also wanted something that was not static so the commentaries could be changed or added to – providing a safeguard against any mistakes or misinterpretations that we may have made.
At the end of the second year the document was much improved but now it was too bulky and needed to be reduced – at the same time we were trying to catch up with more recent publications.
After about 9 months of revision we decided it was taking too long, we needed to get something out there, so we stopped and concentrated on getting the first half of the review finished – we hope we can finish off the remainder by the end of this year. Although mentioned in the “Introduction” it is probably worth stating here that the review is a very long document, more than 30,000 words (half the length of an average novel!). It takes 50 pages to describe and comment on 43 studies. It may be less taxing to first read the section “Results, Discussion, Summary and Conclusion” at the end of the document which only takes up a little more than 9 pages and is a brief summary of every study in the review. For those people who knew about this work, we apologise for its delay. We hope the reader will receive at least some small benefit from reading it.
Doug Mellors.
To read the full review, please click the following link;
Fatigue in HCV Infection: A Review (1989-2011)
Please note: If you are unable to view, please download adobe reader from here.
,
Differences in the Disposition of Silymarin Between Patients with Non-Alcoholic Fatty Liver Disease and Chronic Hepatitis C
DMD #40212 1 Title Page Title:
Differences in the Disposition of Silymarin Between Patients with Non-Alcoholic Fatty Liver Disease and Chronic Hepatitis C
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Authors: Sarah J. Schrieber1, Roy L. Hawke, Zhiming Wen, Philip C. Smith,K. Rajender Reddy, Abdus S. Wahed, Steven H. Belle, Nezam H. Afdhal, Victor J. Navarro, Catherine M. Meyers, Edward Doo, and Michael. W. Fried for The SyNCH Trial Group Affiliations: Division of Pharmacotherapy & Experimental Therapeutics (S.J.S., R.L.H.), and Division of Molecular Pharmaceutics (Z.W., P.C.S.), UNC Eshelman School of Pharmacy, and Division of Gastroenterology and Hepatology, School of Medicine (M.W.F.), University of North Carolina, Chapel Hill, North Carolina; Division of Gastroenterology, University of Pennsylvania (K.R.R.); Department of Biostatistics (A.S.W.), and Department of Epidemiology (S.H.B.), University of Pittsburgh; Liver Center, Beth Israel Deaconess Medical Center (N.H.A.); Division of Gastroenterology and Hepatology, Thomas Jefferson University (V.J.N.); National Center for Complementary and Alternative Medicine (C.M.M.), and Liver Diseases Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases (E.D.), National Institutes of Health, Bethesda, Maryland. DMD Fast Forward.
Published on August 24, 2011 as doi:10.1124/dmd.111.040212
Copyright 2011 by the American Society for Pharmacology and Experimental Therapeutics.
ABSTRACT
Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is comprised of six major flavonolignans including silybin A and silybin B which are the predominant flavonolignans quantified in human plasma. The single and multiple dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine if silymarin’s disposition, and therefore its potential efficacy, varies between liver disease populations.
Cohorts of eight subjects with non-cirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 hours for 7 days. 48-Hour blood sampling was conducted following the first and final doses.
In general, plasma concentrations of silybin A and silybin B were higher while concentrations of conjugates were lower in NAFLD compared to HCV. After adjusting AUC0-8h for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC0-8h was higher for silybin B (p<0.05) but lower for silybin B conjugates (p<0.05) compared to HCV.
At the 280 mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC0-8h (p<0.05) and 42% lower Cmax (p<0.05) compared to HCV subjects.
Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects.
In summary, silymarin’s efficacy may be more readily observed in NAFLD patients due to higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared to patients with HCV.
DMD #40212 4
INTRODUCTION
Silymarin is an herbal product that has been used for centuries for diseases of the liver (Flora et al., 1998), and approximately one-third of patients seen in US liver clinics report the use of some CAM to self-treat their liver disease (Strader et al, 2002). Derived from the milk thistle plant, Silybum marianum, silymarin is a complex mixture of six major flavonolignans (silybins A and B, isosilybins A and B, silychristin, and silydianin), as well as other minor polyphenolic compounds (Kim et al., 2003).
Silymarin has been shown to have antioxidant, anti-inflammatory/immunomodulatory, and anti-fibrotic properties in various in vitro and animal models (Abenavoli et al., 2010). However, it is the antioxidant activity of silymarin that is most likely to attenuate the pathologic effects initiated by oxidative stress in the liver which influence pathways of inflammation, necrosis, and fibrosis in chronic liver disease (Galli et al., 2005; Medina and Moreno-Otero, 2005).
Silymarin may be the most potent antioxidant in nature by virtue of its free radical scavenger reactivity and favorable membrane-lipid/water partitioning (György et al., 1992). Oxidative stress is thought to play a central role in the etiology of nonalcoholic steatohepatitis (NASH), a specific subset of nonalcoholic fatty liver disease (NAFLD), and is hypothesized to represent a ‘second hit’ triggering the necroinflammatory response characteristic of NASH (Day and James, 1998).
Therefore, the antioxidant properties of silymarin may be particularly beneficial as a treatment for NASH since patients have significantly increased levels of serum lipid peroxidation products (Chalasani et al., 2004) as well as other oxidative stress markers and decreased levels of antioxidant enzymes (Koruk et al., 2004).
In addition, oxidative stress is a key feature of disease activity in HCV infection. Elevated levels of oxidative stress markers have been associated with the grade and stage of liver disease in patients with HCV (Jain et al., 2002) which suggests that antioxidant therapy may be effective in slowing disease DMD #40212 5 progression in the absence of antiviral effects.
These observations provide the rationale for current Phase 2 trials on the effects of silymarin in HCV and NASH populations.
The type and stage of liver disease has been recently shown to influence the single dose pharmacokinetics of the major silymarin flavonolignans (Schrieber et al., 2008). An unexpected finding was that total silymarin flavonolignan exposures were 3- to 5- fold higher for patient cohorts compared to healthy controls (Schrieber et al., 2008).
While this study demonstrated that the pharmacokinetics of silymarin depend upon the type and grade/stage of liver disease, pharmacokinetic differences between patients with chronic HCV infection and NAFLD were not fully elucidated due to the low plasma concentrations. Silymarin flavonolignans are metabolized via phase 2 conjugation pathways (Jancova et al., 2011; Sridar et al., 2004) and the majority of glucuronide and sulfate conjugates undergo hepatobiliary excretion via multi-drug resistance protein-2 (Mrp2) (Miranda et al., 2008). In obesity and NAFLD animal models, Mrp2 has been shown to have altered hepatic expression and function (Cheng et al., 2008; Geier et al., 2005). In addition, functional genetic polymorphisms in MRP2 have been associated with susceptibility to NAFLD and disease severity (Sookoian et al., 2009).
Therefore, disease-specific modulation of silymarin metabolizing enzymes or hepatic transporters may account for alterations in silymarin pharmacokinetics that have been previously observed in different types of liver diseases and therefore may have a profound effect on the efficacy in different patient populations.
We have previously reported on the ascending multiple dose pharmacokinetics of silymarin in noncirrhotic patients with chronic HCV infection (Hawke et al., 2010) obtained from a double-blind, placebo-controlled Phase 1 trial that was conducted in patients with either HCV or NAFLD. Unexpectedly, dose proportionality in the pharmacokinetics of parent silymarin flavonolignans was not DMD #40212 6 observed in HCV patients with well-compensated liver disease at silymarin doses above 560 mg when administered orally every eight hours (Hawke et al., 2010). Since the steady-state pharmacokinetics of silymarin in patients with NALFD has not been previously described, and because silymarin’s pharmacokinetics may be different in different types of liver diseases (Schrieber et al., 2008), we now report on the pharmacokinetics of silymarin in NAFLD subjects enrolled in the Phase 1 trial. To determine if the disposition of silymarin differs between patients with NAFLD or HCV liver disease, we also compare the single and multiple dose pharmacokinetics of silybin A and silybin B and their conjugates between patients with NAFLD or HCV.
Finally, since silymarin’s pharmacokinetics appears to be nonlinear in patients with HCV, the pharmacokinetics of silymarin was evaluated at silymarin doses of 280 mg and 560 mg to assess the interaction between dose and disease type.
These trials were conducted to optimize oral silymarin dosing for Phase 2 efficacy trials in patients with either HCV or NASH (Lang, 2006). In these Phase 2 trials, which are now ongoing, oral doses higher than the customary dose of 140 mg every 8 hours are utilized in an attempt to overcome silymarin’s high firstpass metabolism and achieve therapeutic, steady-state plasma concentrations. DMD #40212 7
MATERIALS AND METHODS
Subjects Forty male and female subjects ≥ 18 years of age with chronic noncirrhotic NAFLD and HCV were enrolled into the study within 28 days of screening (N=8 per cohort). Subjects were required to have elevated alanine aminotransferase levels ≥ 65 IU/L within 1 year prior to screening, and a creatinine clearance (calculated according to Cockcroft-Gault equation) > 60 ml/min at screening as well as a negative urine pregnancy screen for females of child-bearing potential who were also required to use barrier methods of contraception during the study. .
Subjects were excluded if they had either a history of or, in the clinical opinion of the investigator’s, evidence of decompensated liver disease defined by: serum albumin < 3.2 g/dl, total bilirubin > 1.5 mg/dl, or PT/INR > 1.3 times normal, history or presence of ascites, encephalopathy, portal hypertension, or bleeding from esophageal varices. Subjects were also excluded if they had evidence of other chronic liver disease or serologic evidence of infection with human immunodeficiency virus.
Other exclusion criteria included: an allergy to milk thistle or its preparations; use of silymarin or other milk thistle preparations, or use of high doses of other antioxidants such as vitamin E, vitamin C, glutathione, alpha-tocopherol, within 30 days of randomization through study completion. However, use of standard doses of over-the-counter multivitamins or cough/cold preparations was allowed.
Also excluded was the chronic use of acetaminophen > 2 grams/day; use of oral contraceptive, warfarin, metronidazole, or concurrent use of the following cytochrome CYP3A4 inducers: aminoglutethimide, aprepitant, carbamazepine, dexamethasone, efavirenz, ethosuximide, garlic supplements, glucocorticoids, glutethimide, griseofulvin, modafinil, nafcillin, nevirapine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's Wort; historical liver DMD #40212 8 biopsy demonstrating the presence of cirrhosis (Ishak stage 5 or 6), or ≥ 15% steatosis, or evidence of steatohepatitis; positive urine screen for drugs of abuse; alcohol consumption of > 12 grams/day for ≥ 6 months prior to screening; or other evidence of alcohol or drug abuse within 6 months of screening.
Women who were pregnant or breast-feeding were also excluded.
All subjects agreed not to consume alcohol 48 hours prior to study randomization through study completion.
Trial Design Specific details on the design of this Phase 1 study have been previously described (Hawke et al., 2010). Briefly, dose cohorts of eight subjects each were randomized 3:1, via a web-based randomization system used by each site’s pharmacist, to receive oral silymarin or placebo every 8 hours for 7 days. 48- hour pharmacokinetic samples were collected following an initial single dose administration before the 7 day treatment and a final dose following the 7 day treatment for a total of 23 doses.
Only pharmacists were unblinded to treatment assignments until trial completion. The sample size was selected to provide information on safety, tolerability, and pharmacokinetics of silymarin and based on historical experience for Phase 1 trials and not on statistical considerations.
Cohorts were enrolled sequentially at doses of 280 mg or 560 mg Legalon®. Legalon® (Madaus, Germany now RottapharmMadaus, Italy) brand of silymarin was selected as the clinical trial material for the Silymarin Product Development Program for use in NIH-sponsored clinical trials for liver diseases from competing bids in response to a Notice of Opportunity by the National Center for Complementary and Alternative Medicine and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.
The first and last doses for the pharmacokinetic studies were administered on days 1 and 10, respectively. To control for potential variability induced by fed versus fasted states, doses were DMD #40212 9 administered with 240 ml of water 30 minutes after breakfast to subjects who were fasted overnight. Subjects were allowed to choose from a fixed list of items on the clinical research breakfast menu. Grapefruit juice was not allowed.
Subjects remained in the research unit for 48 hours for collection of blood. Fourteen serial blood samples were collected at 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 15, 18, 24, 32, and 48 hours post-dose. Twenty-one doses were dispensed to subjects upon discharge after collection of the 48 hour post-dose sample on day 3. The first of these 21 doses was self-administered under direct supervision in the clinical research center. 8-Hour post-dose trough plasma samples were collected during safety visits on days 6 and 8.
Patient adherence was assessed by patient drug diary, pill counts, and by maintaining records of drugs dispensed and returned. Subjects were enrolled from December 2006 to July 2008 at 4 clinical centers, which included University of North Carolina at Chapel Hill, Beth Israel Deaconess Medical Center, University of Pennsylvania, and Thomas Jefferson University. Institutional review boards of participating centers approved the protocol; all subjects provided written informed consent.
The study was conducted in accordance with the Declaration of Helsinki and guidelines on Good Clinical Practice. Safety Assessment Safety was assessed before dosing on study days 1 (baseline), 6, 8, and 10, which consisted of clinical laboratory tests and reports of clinical adverse events using a symptom assessment questionnaire.
Additionally, on days 1 and 10, the questionnaire was also completed at approximately 24 and 48 hours postdose. Common Terminology Criteria for Adverse Events (CTCAE v3.0) was utilized to grade the severity of adverse events.
Physical examinations and electrocardiograms were completed at baseline and at end-of-study. Decisions to dose escalate were made after a safety DMD #40212 10 evaluation by a designated safety committee masked to treatment.
The safety committee consisted of the principal investigators from the four clinical centers and an external safety monitor. Study Drug Silymarin (Legalon®) and matching placebo were manufactured in hard capsules by Madaus Rottapharm Group (Cologne, Germany); all study doses were administered from Lot No. 0418901.
Each dose consisted of five silymarin and/or placebo capsules packaged in single use medicine dose cups. The flavonolignan content of each capsule was determined according to previously published LCMS methods as follows: 23.2 mg, silybin A; 32.0 mg, silybin B; 11.8 mg, isosilybin A; 6.6 mg, isosilybin B; 24.9 mg, silychristin; and 29.0 mg, silydianin (Wen et al., 2008) .
These six flavonolignans account for 70.8% (127.5 mg silymarin equivalent to 140 mg of silymarin as determined by the manufacturer’s DNPH method) of the 180 mg milk thistle extract contained in each capsule. Based on interim stability testing results performed by the manufacturer, Legalon® capsules are stable under normal conditions (25° C, 60% relative humidity) for at least 9 months. For the purpose of the pharmacokinetic analyses described in this report, one Legalon® capsule was considered equal to 140 mg of silymarin in accordance with the manufacturer’s specifications.
Analysis of Silymarin Flavononlignans Whole blood samples were collected in two 3 ml EDTA-lined tubes (K2-EDTA tubes; BD, Franklin Lakes, NJ, USA) and centrifuged at 1200 x g for 10 minutes at 4oC. Plasma was aspirated and transferred to polypropylene tubes. Plasma samples were temporarily stored at -70°C by each clinical DMD #40212 11 site for < 30 days prior to shipment to the University of North Carolina where they were acidified by addition of glacial acetic acid (final concentration 1% acetic acid) and stored at -70°C until analysis. For the determination of parent (i.e. nonconjugated) flavonolignan concentrations in plasma, a 125 μl aliquot of each patient sample was buffered using sodium acetate (pH 5.0, 0.125 M) and incubated for 6 hours at 37ºC without hydrolytic enzymes. A second 125 μl aliquot was also buffered using sodium acetate (pH 5.0, 0.125 M) and incubated with a mixture of sulfatase (80 U/ml, S9626 Type H-1) and β-glucuronidase (8000 U/ml, G0501 Type B-10) (Sigma-Aldrich, St. Louis, MO) for the determination of total (i.e. parent + conjugates) flavonolignan concentrations which were expressed as “Parent Flavonolignan Equivalents”.
After incubation, 50 ng of naringenin (internal standard) in 25 μl of 50% MeOH was added to the samples which were then deproteinized and processed using a highthroughput protein filtration procedure as previously described (Hawke et al., 2010). Following filtration, 75 μl of the plasma sample supernatants were transferred to glass HPLC vials and concentrations of silymarin flavonolignans were quantified by LC-ESI-MS as previously described using a Luna C18 analytical column (50 × 2.0 mm i.d., 3 μm; Phenomenex, Torrance, CA); an isocratic mobile phase consisting of 43% methanol, 56% water, and 1% glacial acetic acid (pH 2.8); a flow rate, 0.3 ml/min; a 25 μl injection volume; and a 13 minute run time (Wen et al., 2008).
For each silymarin flavonolignan, the limit of detection was 20 ng/ml and the quantitative ranges for parent and for total flavonolignan were 50 – 2,500 ng/ml and 100 – 20,000 ng/ml, respectively. The accuracy for each flavonolignan was within 95.4 – 107.4% and intra- and inter-day precisions were 1.7 – 11% and 4.5 – 14%, respectively. Data Analysis DMD #40212 12 Pharmacokinetic parameters including: area under plasma concentration-time curve (AUC); maximum plasma concentration (Cmax); time to Cmax (Tmax); and terminal half-life (T½) were calculated using noncompartmental methods, WinNonlin-Pro (v5.2; Pharsight Corp, Mountain View, CA).
A constant dosing interval (tau) of 8 hours was assumed for the calculation of steady-state AUC0-8h using the linear up/log down trapezoidal method. To obtain pharmacokinetic parameters for the conjugate flavonolignan concentrations, the parent flavonolignan concentrations were subtracted from the total flavonolignan concentrations at each time point over the entire sampling period prior to performing a pharmacokinetic analysis. Pharmacokinetic parameters are reported as geometric means with 95% confidence intervals, except for Tmax which is reported as median with minimum and maximum values. For our primary analysis, differences in steady-state exposures (i.e., AUC0-8h) between disease cohorts were compared, following log transformation, using a parametric two-sample t-test, p < 0.05 was used for statistical significance. In addition, to eliminate weight as a potential confounder in the assessment of differences in flavonolignan exposures between cohorts, a linear regression model with log AUC0-8h as outcome was used.
The model included dose, disease, and weight as independent variables in order to adjust for variable weights across dose groups (280 mg vs. 560 mg) or disease type (HCV vs. NAFLD) while comparing AUC0-8h. Least-square means (adjusted means) were reported with 95% confidence intervals and tested using t-tests.
All statistical analyses were performed by using SAS 9.2 or SAS JMP 9 (SAS Institute Inc., Cary, NC). DMD #40212 13
RESULTS
Subjects Baseline demographics are presented in Table I.
Study subjects in the HCV cohorts were predominantly males with ages ranging from 43 – 59 years, while males and females were more equally represented in the NAFLD cohorts with ages ranging from 28 – 58 years. Subjects were characterized by well-compensated, noncirrhotic liver disease as evidenced by total bilirubin (range: 0. 3 – 2.6 mg/dl) and platelet counts (range: 150 – 327 cells/mm3).
Efficacy and Safety Endpoints
When compared to their screening baseline values, no reductions in serum transaminases for either HCV or NAFLD subjects, or reductions in HCV RNA titer for HCV subjects were observed at the end of the 7 day treatment period (data not shown).
There were no abnormal deviations from baseline laboratory values reported with silymarin administration for any cohort. For the HCV cohorts, 3 subjects who received a single 280 mg dose of silymarin reported a total of 4 adverse events.
Three of the adverse events were classified as neurological (e.g., headache) while the other was classified as gastrointestinal. Only one adverse event (dizziness) was considered possibly related Legalon® administration and resolved in less than 1 day. For NAFLD cohorts, two out of 12 subjects (16.7%) receiving silymarin reported at least one adverse event compared to 1 out of 4 subjects (25%) receiving placebo.
Adverse events reported with silymarin included upper respiratory infection and abdominal pain, both of which occurred in the 560 mg dose cohort. All adverse events reported with silymarin were determined to be mild to moderate, self-limiting, and were considered unrelated to treatment.
DMD #40212 14
Single dose Pharmacokinetics of Silybin A and Silybin B A comparison of the pharmacokinetics of silybin A and silybin B between HCV and NAFLD cohorts following single oral doses of either 280 or 560 mg silymarin are presented in Table II. Silybin A was the predominant flavonolignan in plasma for both HCV and NAFLD cohorts and was characterized by a 2.7- to 3.3-fold greater Cmax and a 2- to 4.5-fold greater AUC0-48h compared to silybin B. At the 280 mg dose, no differences were observed in the pharmacokinetics of silybin A or silybin B between HCV and NAFLD subjects. Short elimination half-lives were observed for both silybin A and silybin B (range 0.9 – 1.8 hours).
However, at the 560 mg dose, pharmacokinetic differences were observed between HCV and NAFLD subjects. Compared to HCV subjects, AUC0-48h for silybin A and silybin B were 1.5-fold (p > 0.05) and 2.1-fold (p < 0.05) greater, respectively, for NAFLD subjects. A similar trend was observed in the Cmax for silybin A and silybin B, although the 1.4- to 1.6-fold differences between HCV and NAFLD subjects did not achieve statistical significance.
Elimination half-lives were similar between the disease groups (range 1.1 – 1.5 hours), while Tmax was delayed by 1 hour in NAFLD subjects. Steady-State Pharmacokinetics of Silybin A and Silybin B The steady-state pharmacokinetics of silybin A and silybin B for the HCV and NAFLD cohorts following chronic oral administration of either 280 or 560 mg silymarin every 8 hours for 7 days are presented in Table III.
Similar to the data obtained following single doses, silybin A was the predominant flavonolignan in plasma for both HCV and NAFLD cohorts and was characterized by a 2.1- to 3.6-fold greater Cmax and a 2.6- to 4.9-fold greater AUC0-8h compared to silybin B. In addition, DMD #40212 15 there was no evidence of accumulation for either flavonolignan following repeated dosing with elimination half-lives ranging between 0.7 to 1.3 hours.
Also similar to the single dose data, pharmacokinetic differences between HCV and NAFLD cohorts were only observed at the 560 mg dose. The AUC0-8h for silybin A and silybin B were 1.6-fold and 2.5-fold greater, respectively, in NAFLD subjects compared to HCV subjects at the 560 mg while differences in the Cmax between cohorts ranged between 1.5- to 2.2-fold. After adjusting for weight and disease type, silybin A and silybin B AUC0-8h differed significantly between the 280 and 560 mg dose groups (p ≤ 0.004), such that for either HCV or NAFLD or at any weight level, the 560 mg dose was associated with higher AUC0-8h. When adjusted for weight and dose, only silybin B differed significantly across disease types such that adjusted mean AUC0-8h for silybin B was higher for NAFLD compared to HCV (p = 0.004).
The higher silybin B exposures in NAFLD subjects suggest the metabolism or hepatic uptake of silybin B may be reduced in NAFLD compared to HCV.
Single dose and Steady-State Pharmacokinetics of Silybin A and Silybin B Conjugates To further explore the effect of NAFLD on silymarin’s metabolism, differences in the plasma concentrations of silybin A and silybin B conjugates between HCV and NAFLD subjects were examined. As defined in Methods, plasma concentrations of conjugates were estimated from the subtraction of parent flavonolignan concentrations from total (parent + conjugate) flavonolignan concentrations.
The single dose and steady-state pharmacokinetic data for total conjugates of silybin A and silybin B for both disease cohorts are presented in Tables IV and V, respectively. Whereas plasma concentrations were observed to be greater for silybin A than for silybin B, the converse was true for DMD #40212 16 their conjugates.
The Cmax and AUC0-8h for silybin B conjugates were 3- to 4-fold greater than for silybin A conjugates across both dose levels and disease cohorts. Differences between HCV and NAFLD subjects were observed in the pharmacokinetics for plasma conjugates of silybin A and silybin B at either dose level following single or chronic dosing. However, these differences only achieved significance between HCV and NAFLD cohorts dosed at 280 mg every 8 hours whereas conjugates of silybin B in plasma of NAFLD subjects were characterized by 46% lower AUC0-8h (p < 0.05) and 42% lower Cmax (p < 0.05) compared to HCV subjects.
Figure 1 depicts the mean steady-state plasma concentration versus time profiles for silybin B (inset) and silybin B conjugates for HCV and NAFLD subjects at the 280 mg dose. Plasma concentrations of silybin B conjugates were lower in NAFLD subjects compared to HCV subjects over the entire 8 hour dosing interval (Figure 1). In contrast, plasma concentrations of silybin B were higher in NAFLD subjects until peak concentrations were achieved and then declined similarly (Figure 1 inset).
These data suggest that reduced silymarin metabolism may result in differences in silymarin exposures between NAFLD and HCV subjects, rather than differences in absorption. After adjusting for weight and disease type, the AUC0-8h for silybin A conjugates and for silybin B conjugates differed significantly between the 280 and 560 mg dose groups (p ≤ 0.004), such that for either HCV or NAFLD or at any weight level, the 560 mg dose was associated with higher AUC0-8h. When adjusted for weight and dose, only silybin B conjugates differed significantly across disease types such that adjusted mean AUC0-8h for silybin B conjugates was significantly lower for NAFLD subjects compared to HCV (p = 0.03).
To further quantify differences in the extent of flavonolignan conjugation between HCV and NAFLD subjects, steady-state metabolic ratios were calculated as the ratio of AUC0-8h for silybin B DMD #40212 17 divided by AUC0-8h for silybin B conjugates at the 560 mg dose. Metabolic ratios differed 4-fold (p < 0.05) between HCV and NAFLD with means (± SD) of 0.016 ± 0.011 and 0.060 ± 0.041, respectively. These data suggest that there is less conjugation of silybin B in NAFLD subjects compared to HCV at a silymarin dose of 560 mg. In summary, plasma concentrations of silybin A and silybin B were generally greater and the concentrations of their conjugates lower in NAFLD subjects compared to HCV subjects irrespective of the dose and frequency of oral silymarin administration.
Flavonolignan Accumulation
The ratio of parent silybin A steady-state AUC0-8h divided by single-dose AUC0-8h was calculated as an indication of the extent of accumulation following chronic three times daily dosing. Silybin A ratios of 1.3 and 1.4 were calculated for HCV and NAFLD, respectively, at the 560 mg dose, which indicates no significant accumulation in either cohort with repeated dosing. Similar ratios were calculated for silybin B. This finding is consistent with the short half-life of the silymarin flavonolignans. While no evidence for parent silybin A and silybin B accumulation was observed, the overall amount of parent flavonolignans in plasma was significantly higher in NAFLD subjects compared to HCV subjects at the 560 mg dose due to the appearance of additional parent flavonolignans.
Figure 2 compares mean steady-state peak plasma concentrations of the six parent silymarin flavonolignans for HCV and NAFLD subjects at the 560 mg dose, as well as their sum concentration. As seen in Figure 2, plasma concentrations of isosilybin A, isosilybin B, silychristin, and silydianin were significantly greater in NAFLD subjects compared to HCV subjects. Interestingly, silychristin and silydianin were not detected in the plasma of HCV subjects.
To gain insight into the mechanism(s) behind these observed DMD #40212 18 differences, we evaluated the plasma concentration versus time profile for each flavonolignan over the 48 hour sampling period following administration of the last 560 mg dose (Figure 3). Significant enterohepatic cycling of the six flavonolignans were observed in NAFLD subjects as indicated by a prominent second peak at 4 hours following the absorption peak at 1 hour.
Most flavonolignans also showed evidence of a third peak at 8 hours post dose. In contrast, there was less evidence of enterohepatic cycling in HCV subjects where no secondary peaks were observed for either silybin A or silybin B following the early absorption peak. Silychristin represented a major flavonolignan in the plasma of NAFLD subjects at the dose 560 mg dose. Silychristin’s steady-state pharmacokinetics (geometric mean and 95% confident intervals) were characterized by a Cmax of 67 ng/ml (-2.5, 174), an AUC0-8h of 325 ng
●hr/ml (-145, 1100), and a T½ of 3.1 hr (1.2, 6.3). The steady-state pharmacokinetics of the conjugates of silychristin in NAFLD subjects were characterized by a Cmax of 663 ng/ml (367, 1394), an AUC0-8h of 3800 ng
●hr/ml (1628, 8462), and a T½ of 4.5 hr (2.2, 8.6). DMD #40212 19
DISCUSSION
The expression of drug disposition genes and their protein products have been shown to be altered in liver disease (Congiu et al., 2009; Fisher et al., 2009; Congiu et al., 2002), and effects of liver disease on the disposition of drugs have been demonstrated and tend to be more severe in patients with more advanced cirrhotic disease (Chalon et al., 2003). In contrast, significant differences in the disposition of drugs between different types of liver disease have not been demonstrated. We have shown that the disposition of silymarin, an herbal medicine widely used by patients with liver disease, is significantly altered in patients with liver disease (Schrieber et al., 2008).
Concentrations of total silymarin species found in plasma, which consist primarily of flavonolignan conjugates, were found to be approximately 5-fold higher in patients with chronic HCV infection or NAFLD when compared to healthy controls. Pharmacokinetic differences were also observed between healthy subjects and patients with NAFLD or patients with HCV cirrhosis. In contrast, differences were not observed between healthy subjects and patients with noncirrhotic
HCV disease possibly due to wide disease heterogeneity in patient cohorts or reduced sensitivity as a result of low plasma concentrations of flavonolignans associated with the low oral dose of a generic brand of silymarin that was used in this study (Schrieber et al., 2008). These results raised the possibility that the disposition of silymarin, and its potential beneficial effects, may be different in various liver disease populations with early stage disease. To determine if the disposition of silymarin is different between patients with different types of the liver disease, this study examined the pharmacokinetics of higher than customary oral doses of silymarin in noncirrhotic patients with either chronic HCV infection or NAFLD.
The results of our study show that NAFLD patients are characterized by higher plasma concentrations of certain silymarin flavonolignans and lower concentrations of flavonolignan conjugates compared to HCV patients administered the same DMD #40212 20 dose. While silymarin flavonolignans appear to share common pathways of metabolism and transport, differences in their affinity for these processes have been noted (Miranda et al., 2008; Sridar et al., 2004) which likely account for the different relationships between AUC exposure and dose for silybin A and silybin B observed in our study. In vitro and in vivo studies suggest silymarin flavonolignans are primarily metabolized through glucuronidation and sulfation pathways with various UDP-glucuronosyltransferases (UGTs) sharing overlapping specificity (Sridar et al., 2004; Jancova et al., 2011). In addition, the extent in which various flavonolignans undergo glucuronidation or sulfation appears to vary (Wen et al., 2008).
There are several possibilities that could explain why the ratio of parent flavonolignan (e.g., silybin B) to flavonolignan conjugates was higher in patients with NAFLD compared to HCV in our study. The simplest explanation is that the expression or activity of UGTs is decreased in NAFLD subjects. Nonalcoholic steatohepatitis, a specific subset of NAFLD, is characterized by hepatic steatosis, and varying degrees of inflammation which can lead to decreased UGT expression which has been observed in rodents (Richardson et al., 2006) and in human liver tissue (Congiu et al., 2002).
Therefore it is plausible that the major UGT isoforms involved in metabolism of silymarin may be lower in NAFLD subjects resulting in higher plasma levels of parent flavonolignans and lower concentrations of conjugates. Since silybin B conjugates represents 99% of the total (parent + conjugates) silybin B species in HCV patient plasma, metabolism stoichiometry predicts that the 40% reduction in silymarin conjugates observed in our NAFLD cohort should result in an ~30-fold increase in silybin B plasma concentrations. However, plasma concentrations of silybin B were comparable between HCV and NAFLD patients.
Therefore, reduced UGT activity does not appear to be a viable explanation for the differences in silymarin pharmacokinetics between HCV and NAFLD in our study. In addition, the DMD #40212 21 lower plasma concentration of flavonolignan conjugates in NAFLD compared to HCV does not appear to be related to reduced intestinal absorption since parent flavonolignans would also be expected to be lower in plasma.
Alterations in the expression and function of hepatobilary transporters may be a more plausible explanation for the decrease in flavonolignan conjugates and the higher plasma concentrations of parent flavonolignans observed in the NAFLD cohorts. Evidence for extensive enterohepatic cycling of silymarin and their conjugates has been observed at high doses of silymarin (Hawke et al., 2010; Schrieber et al., 2008). Enterohepatic cycling is regulated by hepatobiliary transporters involved in the active uptake of anionic and cationic compounds from the blood such as the organic anion transporting polypeptides, OATP1B1 and OATP2B1, located on the basolateral membrane of the hepatocyte (Chandra et al., 2004). In many instances, these compounds undergo metabolism to more polar conjugates followed by transport and biliary excretion by ATP-binding cassette transporters such as Pglycoprotein , multidrug resistance associated protein 2 (MRP2), and breast cancer resistance protein, located at the canalicular membrane of the hepatocyte (Leslie et al., 2005; Schinkel and Jonker, 2003).
Once delivered to the small intestine, parent compounds can be reformed by bacterial deconjugation and returned to portal blood for delivery to the liver for reuptake. In competition with biliary efflux, is the efflux of substrates from the hepatocyte to blood by other members of the MRP family, such as MRP3 and MRP4 (MRPs 3/4), which are located on the basolateral (sinusoidal) membrane. It is generally thought that MRP2 and MRP3 work in concert in liver disease to promote hepatic efflux and protect the hepatocyte from the effects of cholestasis (Van de Steeg et al., 2010; Wagner et al., 2005).
The most intriguing observation in the current study was the suggestion of significant enterohepatic recycling of silymarin flavonolignans in NAFLD subjects in contrast to HCV subjects DMD #40212 22 where there was no evidence of enterohepatic cycling (see Figure 3). Silymarin flavonolignans demonstrate high affinity for MRP4 (Wu et al., 2005) while silymarin conjugates, but not parent flavonolignans, appear to be better substrates for MRP2 (Miranda et al., 2008).
Glucuronides that are substrates for MRP2, such as conjugated bilirubin, can also be substrates for MRPs 3/4 (Borst et al., 2006; Zelcer et al., 2006). Therefore, differences in the disposition and enterohepatic cycling of silymarin flavonolignans may reflect alterations in the function of hepatobilary transporters as a result of liver disease.
In obesity and NAFLD animal models, Mrp2 has been shown to have altered hepatic expression and function (Cheng et al., 2008; Geier et al., 2005). In addition, Mrp2, Mrp3, and Mrp4 protein expression were significantly increased in a rodent model of NAFLD (Lickteig et al., 2007). The biliary excretion of glucuronide and sulfate conjugates of silymarin flavonolignans was shown to be dependent on Mrp2 using isolated perfused livers, and some flavonolignans such as silychristin and silydianin were almost quantitatively secreted into bile (Miranda et al., 2008).
Therefore, enterohepatic cycling of silymarin flavonolignans may be increased in NAFLD due to increased MRP2-dependent biliary efflux and diversion of silymarin conjugates away from sinusoidal efflux to blood. An increase in MRP4 would also contribute to greater sinusoidal efflux of parent flavonolignans. These changes would result in lower plasma concentrations of silymarin conjugates with higher concentrations of recycling silymarin flavonolignans in NAFLD patients compared to HCV. Alternatively, the differences observed in the disposition of silymarin between NAFLD and HCV patients may reflect HCV-specific alterations in hepatobiliary function.
HCV infection was shown to be associated with increased hepatic expression of MRP4, decreased expression of MRP2, and decreased expression of OATP1B1 in cirrhotic and noncirrhotic liver while the expression of MRP3 and DMD #40212 23 OATP2B1 were similar to that in normal human liver (Ogasawara et al., 2010).
Therefore, the differences in the disposition of silymarin between HCV and NAFLD subjects observed in our study may reflect a diversion of silymarin conjugates to sinusoidal efflux in HCV patients due to reduced biliary efflux by MRP2 or reduced uptake by OATP1B1, which would also result in higher plasma concentrations of silymarin conjugates and decreased enterohepatic cycling of silymarin flavonolignans compared to patients with NAFLD.
While the results of our study cannot delineate between these various potential mechanisms, it is possible that silymarin’s disposition is altered by different, diseasespecific mechanisms in NAFLD and HCV populations.
This conclusion is supported by our previous observation that plasma concentrations of silymarin conjugates are significantly higher in both NAFLD and HCV patients compared to concentrations found in healthy volunteers (Schrieber et al., 2008).
In summary, differences in the disposition of silymarin between NAFLD and HCV patients may reflect different disease-specific alterations in the function of hepatobiliary transport proteins.
These observations are significant because differences in the disposition of drugs between different types of liver disease have not been demonstrated, perhaps because of their more restrictive use indications.
Importantly, the antioxidant activity and potential antiinflammatory and antifibrotic effects of silymarin on disease progression will be dependent on its hepatic disposition. Oxidative stress has been associated with all stages of chronic HCV liver disease (Jain et al., 2002) and recent data from the HALT-C trial suggest that silymarin use among patients with advanced HCV liver disease may be associated with reduced progression to cirrhosis (Freedman et al., 2011). Compared to HCV infection, silymarin may demonstrate greater benefits in patients with NAFLD since oxidative stress is thought to play a central role in the etiology of NASH (Day et al., 1998) and there are no approved therapies.
In addition, the results of this study suggest silymarin’s effects on liver disease progression may also be greater in DMD #40212 24 NAFLD patients due to higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared to patients with HCV.
These observations were critical in the design of a Phase 2 silymarin trial in NASH which is currently ongoing (Lang, 2006). DMD #40212 25
Acknowledgements The authors are indebted to Dr. Josh Berman and Dr. Qi-Ying Liu for their important early efforts in study design and to Dr. Ulrich Mengs for championing this work. In addition, the authors wish to thank the patients who volunteered for this trial, and Dr. Tedi Soule, Joseph Colagreco, Mary Hammond, and Deborah Moretti, who served as the study coordinators, and Sharon Lawlor, who was the DCC coordinator, for their invaluable assistance in the conduct of this trial. The authors would also like to thank Dr. Craig W. Hendrix, M.D. who graciously agreed to serve as the independent safety monitor. DMD #40212 26 Authorship Contributions Participated in research design: Hawke, Reddy, Belle, Afdhal, Navarro, Meyers, Doo, Fried Conducted experiments: Wen, Schrieber Contributed new reagents or analytic tools: Hawke, Smith Performed data analysis: Schrieber, Wahed Wrote or contributed to the writing of the manuscript: Schrieber, Hawke DMD #40212 27
REFERENCES
Differences in the Disposition of Silymarin Between Patients with Non-Alcoholic Fatty Liver Disease and Chronic Hepatitis C
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Authors: Sarah J. Schrieber1, Roy L. Hawke, Zhiming Wen, Philip C. Smith,K. Rajender Reddy, Abdus S. Wahed, Steven H. Belle, Nezam H. Afdhal, Victor J. Navarro, Catherine M. Meyers, Edward Doo, and Michael. W. Fried for The SyNCH Trial Group Affiliations: Division of Pharmacotherapy & Experimental Therapeutics (S.J.S., R.L.H.), and Division of Molecular Pharmaceutics (Z.W., P.C.S.), UNC Eshelman School of Pharmacy, and Division of Gastroenterology and Hepatology, School of Medicine (M.W.F.), University of North Carolina, Chapel Hill, North Carolina; Division of Gastroenterology, University of Pennsylvania (K.R.R.); Department of Biostatistics (A.S.W.), and Department of Epidemiology (S.H.B.), University of Pittsburgh; Liver Center, Beth Israel Deaconess Medical Center (N.H.A.); Division of Gastroenterology and Hepatology, Thomas Jefferson University (V.J.N.); National Center for Complementary and Alternative Medicine (C.M.M.), and Liver Diseases Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases (E.D.), National Institutes of Health, Bethesda, Maryland. DMD Fast Forward.
Published on August 24, 2011 as doi:10.1124/dmd.111.040212
Copyright 2011 by the American Society for Pharmacology and Experimental Therapeutics.
ABSTRACT
Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is comprised of six major flavonolignans including silybin A and silybin B which are the predominant flavonolignans quantified in human plasma. The single and multiple dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine if silymarin’s disposition, and therefore its potential efficacy, varies between liver disease populations.
Cohorts of eight subjects with non-cirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 hours for 7 days. 48-Hour blood sampling was conducted following the first and final doses.
In general, plasma concentrations of silybin A and silybin B were higher while concentrations of conjugates were lower in NAFLD compared to HCV. After adjusting AUC0-8h for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC0-8h was higher for silybin B (p<0.05) but lower for silybin B conjugates (p<0.05) compared to HCV.
At the 280 mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC0-8h (p<0.05) and 42% lower Cmax (p<0.05) compared to HCV subjects.
Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects.
In summary, silymarin’s efficacy may be more readily observed in NAFLD patients due to higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared to patients with HCV.
DMD #40212 4
INTRODUCTION
Silymarin is an herbal product that has been used for centuries for diseases of the liver (Flora et al., 1998), and approximately one-third of patients seen in US liver clinics report the use of some CAM to self-treat their liver disease (Strader et al, 2002). Derived from the milk thistle plant, Silybum marianum, silymarin is a complex mixture of six major flavonolignans (silybins A and B, isosilybins A and B, silychristin, and silydianin), as well as other minor polyphenolic compounds (Kim et al., 2003).
Silymarin has been shown to have antioxidant, anti-inflammatory/immunomodulatory, and anti-fibrotic properties in various in vitro and animal models (Abenavoli et al., 2010). However, it is the antioxidant activity of silymarin that is most likely to attenuate the pathologic effects initiated by oxidative stress in the liver which influence pathways of inflammation, necrosis, and fibrosis in chronic liver disease (Galli et al., 2005; Medina and Moreno-Otero, 2005).
Silymarin may be the most potent antioxidant in nature by virtue of its free radical scavenger reactivity and favorable membrane-lipid/water partitioning (György et al., 1992). Oxidative stress is thought to play a central role in the etiology of nonalcoholic steatohepatitis (NASH), a specific subset of nonalcoholic fatty liver disease (NAFLD), and is hypothesized to represent a ‘second hit’ triggering the necroinflammatory response characteristic of NASH (Day and James, 1998).
Therefore, the antioxidant properties of silymarin may be particularly beneficial as a treatment for NASH since patients have significantly increased levels of serum lipid peroxidation products (Chalasani et al., 2004) as well as other oxidative stress markers and decreased levels of antioxidant enzymes (Koruk et al., 2004).
In addition, oxidative stress is a key feature of disease activity in HCV infection. Elevated levels of oxidative stress markers have been associated with the grade and stage of liver disease in patients with HCV (Jain et al., 2002) which suggests that antioxidant therapy may be effective in slowing disease DMD #40212 5 progression in the absence of antiviral effects.
These observations provide the rationale for current Phase 2 trials on the effects of silymarin in HCV and NASH populations.
The type and stage of liver disease has been recently shown to influence the single dose pharmacokinetics of the major silymarin flavonolignans (Schrieber et al., 2008). An unexpected finding was that total silymarin flavonolignan exposures were 3- to 5- fold higher for patient cohorts compared to healthy controls (Schrieber et al., 2008).
While this study demonstrated that the pharmacokinetics of silymarin depend upon the type and grade/stage of liver disease, pharmacokinetic differences between patients with chronic HCV infection and NAFLD were not fully elucidated due to the low plasma concentrations. Silymarin flavonolignans are metabolized via phase 2 conjugation pathways (Jancova et al., 2011; Sridar et al., 2004) and the majority of glucuronide and sulfate conjugates undergo hepatobiliary excretion via multi-drug resistance protein-2 (Mrp2) (Miranda et al., 2008). In obesity and NAFLD animal models, Mrp2 has been shown to have altered hepatic expression and function (Cheng et al., 2008; Geier et al., 2005). In addition, functional genetic polymorphisms in MRP2 have been associated with susceptibility to NAFLD and disease severity (Sookoian et al., 2009).
Therefore, disease-specific modulation of silymarin metabolizing enzymes or hepatic transporters may account for alterations in silymarin pharmacokinetics that have been previously observed in different types of liver diseases and therefore may have a profound effect on the efficacy in different patient populations.
We have previously reported on the ascending multiple dose pharmacokinetics of silymarin in noncirrhotic patients with chronic HCV infection (Hawke et al., 2010) obtained from a double-blind, placebo-controlled Phase 1 trial that was conducted in patients with either HCV or NAFLD. Unexpectedly, dose proportionality in the pharmacokinetics of parent silymarin flavonolignans was not DMD #40212 6 observed in HCV patients with well-compensated liver disease at silymarin doses above 560 mg when administered orally every eight hours (Hawke et al., 2010). Since the steady-state pharmacokinetics of silymarin in patients with NALFD has not been previously described, and because silymarin’s pharmacokinetics may be different in different types of liver diseases (Schrieber et al., 2008), we now report on the pharmacokinetics of silymarin in NAFLD subjects enrolled in the Phase 1 trial. To determine if the disposition of silymarin differs between patients with NAFLD or HCV liver disease, we also compare the single and multiple dose pharmacokinetics of silybin A and silybin B and their conjugates between patients with NAFLD or HCV.
Finally, since silymarin’s pharmacokinetics appears to be nonlinear in patients with HCV, the pharmacokinetics of silymarin was evaluated at silymarin doses of 280 mg and 560 mg to assess the interaction between dose and disease type.
These trials were conducted to optimize oral silymarin dosing for Phase 2 efficacy trials in patients with either HCV or NASH (Lang, 2006). In these Phase 2 trials, which are now ongoing, oral doses higher than the customary dose of 140 mg every 8 hours are utilized in an attempt to overcome silymarin’s high firstpass metabolism and achieve therapeutic, steady-state plasma concentrations. DMD #40212 7
MATERIALS AND METHODS
Subjects Forty male and female subjects ≥ 18 years of age with chronic noncirrhotic NAFLD and HCV were enrolled into the study within 28 days of screening (N=8 per cohort). Subjects were required to have elevated alanine aminotransferase levels ≥ 65 IU/L within 1 year prior to screening, and a creatinine clearance (calculated according to Cockcroft-Gault equation) > 60 ml/min at screening as well as a negative urine pregnancy screen for females of child-bearing potential who were also required to use barrier methods of contraception during the study. .
Subjects were excluded if they had either a history of or, in the clinical opinion of the investigator’s, evidence of decompensated liver disease defined by: serum albumin < 3.2 g/dl, total bilirubin > 1.5 mg/dl, or PT/INR > 1.3 times normal, history or presence of ascites, encephalopathy, portal hypertension, or bleeding from esophageal varices. Subjects were also excluded if they had evidence of other chronic liver disease or serologic evidence of infection with human immunodeficiency virus.
Other exclusion criteria included: an allergy to milk thistle or its preparations; use of silymarin or other milk thistle preparations, or use of high doses of other antioxidants such as vitamin E, vitamin C, glutathione, alpha-tocopherol, within 30 days of randomization through study completion. However, use of standard doses of over-the-counter multivitamins or cough/cold preparations was allowed.
Also excluded was the chronic use of acetaminophen > 2 grams/day; use of oral contraceptive, warfarin, metronidazole, or concurrent use of the following cytochrome CYP3A4 inducers: aminoglutethimide, aprepitant, carbamazepine, dexamethasone, efavirenz, ethosuximide, garlic supplements, glucocorticoids, glutethimide, griseofulvin, modafinil, nafcillin, nevirapine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's Wort; historical liver DMD #40212 8 biopsy demonstrating the presence of cirrhosis (Ishak stage 5 or 6), or ≥ 15% steatosis, or evidence of steatohepatitis; positive urine screen for drugs of abuse; alcohol consumption of > 12 grams/day for ≥ 6 months prior to screening; or other evidence of alcohol or drug abuse within 6 months of screening.
Women who were pregnant or breast-feeding were also excluded.
All subjects agreed not to consume alcohol 48 hours prior to study randomization through study completion.
Trial Design Specific details on the design of this Phase 1 study have been previously described (Hawke et al., 2010). Briefly, dose cohorts of eight subjects each were randomized 3:1, via a web-based randomization system used by each site’s pharmacist, to receive oral silymarin or placebo every 8 hours for 7 days. 48- hour pharmacokinetic samples were collected following an initial single dose administration before the 7 day treatment and a final dose following the 7 day treatment for a total of 23 doses.
Only pharmacists were unblinded to treatment assignments until trial completion. The sample size was selected to provide information on safety, tolerability, and pharmacokinetics of silymarin and based on historical experience for Phase 1 trials and not on statistical considerations.
Cohorts were enrolled sequentially at doses of 280 mg or 560 mg Legalon®. Legalon® (Madaus, Germany now RottapharmMadaus, Italy) brand of silymarin was selected as the clinical trial material for the Silymarin Product Development Program for use in NIH-sponsored clinical trials for liver diseases from competing bids in response to a Notice of Opportunity by the National Center for Complementary and Alternative Medicine and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.
The first and last doses for the pharmacokinetic studies were administered on days 1 and 10, respectively. To control for potential variability induced by fed versus fasted states, doses were DMD #40212 9 administered with 240 ml of water 30 minutes after breakfast to subjects who were fasted overnight. Subjects were allowed to choose from a fixed list of items on the clinical research breakfast menu. Grapefruit juice was not allowed.
Subjects remained in the research unit for 48 hours for collection of blood. Fourteen serial blood samples were collected at 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 15, 18, 24, 32, and 48 hours post-dose. Twenty-one doses were dispensed to subjects upon discharge after collection of the 48 hour post-dose sample on day 3. The first of these 21 doses was self-administered under direct supervision in the clinical research center. 8-Hour post-dose trough plasma samples were collected during safety visits on days 6 and 8.
Patient adherence was assessed by patient drug diary, pill counts, and by maintaining records of drugs dispensed and returned. Subjects were enrolled from December 2006 to July 2008 at 4 clinical centers, which included University of North Carolina at Chapel Hill, Beth Israel Deaconess Medical Center, University of Pennsylvania, and Thomas Jefferson University. Institutional review boards of participating centers approved the protocol; all subjects provided written informed consent.
The study was conducted in accordance with the Declaration of Helsinki and guidelines on Good Clinical Practice. Safety Assessment Safety was assessed before dosing on study days 1 (baseline), 6, 8, and 10, which consisted of clinical laboratory tests and reports of clinical adverse events using a symptom assessment questionnaire.
Additionally, on days 1 and 10, the questionnaire was also completed at approximately 24 and 48 hours postdose. Common Terminology Criteria for Adverse Events (CTCAE v3.0) was utilized to grade the severity of adverse events.
Physical examinations and electrocardiograms were completed at baseline and at end-of-study. Decisions to dose escalate were made after a safety DMD #40212 10 evaluation by a designated safety committee masked to treatment.
The safety committee consisted of the principal investigators from the four clinical centers and an external safety monitor. Study Drug Silymarin (Legalon®) and matching placebo were manufactured in hard capsules by Madaus Rottapharm Group (Cologne, Germany); all study doses were administered from Lot No. 0418901.
Each dose consisted of five silymarin and/or placebo capsules packaged in single use medicine dose cups. The flavonolignan content of each capsule was determined according to previously published LCMS methods as follows: 23.2 mg, silybin A; 32.0 mg, silybin B; 11.8 mg, isosilybin A; 6.6 mg, isosilybin B; 24.9 mg, silychristin; and 29.0 mg, silydianin (Wen et al., 2008) .
These six flavonolignans account for 70.8% (127.5 mg silymarin equivalent to 140 mg of silymarin as determined by the manufacturer’s DNPH method) of the 180 mg milk thistle extract contained in each capsule. Based on interim stability testing results performed by the manufacturer, Legalon® capsules are stable under normal conditions (25° C, 60% relative humidity) for at least 9 months. For the purpose of the pharmacokinetic analyses described in this report, one Legalon® capsule was considered equal to 140 mg of silymarin in accordance with the manufacturer’s specifications.
Analysis of Silymarin Flavononlignans Whole blood samples were collected in two 3 ml EDTA-lined tubes (K2-EDTA tubes; BD, Franklin Lakes, NJ, USA) and centrifuged at 1200 x g for 10 minutes at 4oC. Plasma was aspirated and transferred to polypropylene tubes. Plasma samples were temporarily stored at -70°C by each clinical DMD #40212 11 site for < 30 days prior to shipment to the University of North Carolina where they were acidified by addition of glacial acetic acid (final concentration 1% acetic acid) and stored at -70°C until analysis. For the determination of parent (i.e. nonconjugated) flavonolignan concentrations in plasma, a 125 μl aliquot of each patient sample was buffered using sodium acetate (pH 5.0, 0.125 M) and incubated for 6 hours at 37ºC without hydrolytic enzymes. A second 125 μl aliquot was also buffered using sodium acetate (pH 5.0, 0.125 M) and incubated with a mixture of sulfatase (80 U/ml, S9626 Type H-1) and β-glucuronidase (8000 U/ml, G0501 Type B-10) (Sigma-Aldrich, St. Louis, MO) for the determination of total (i.e. parent + conjugates) flavonolignan concentrations which were expressed as “Parent Flavonolignan Equivalents”.
After incubation, 50 ng of naringenin (internal standard) in 25 μl of 50% MeOH was added to the samples which were then deproteinized and processed using a highthroughput protein filtration procedure as previously described (Hawke et al., 2010). Following filtration, 75 μl of the plasma sample supernatants were transferred to glass HPLC vials and concentrations of silymarin flavonolignans were quantified by LC-ESI-MS as previously described using a Luna C18 analytical column (50 × 2.0 mm i.d., 3 μm; Phenomenex, Torrance, CA); an isocratic mobile phase consisting of 43% methanol, 56% water, and 1% glacial acetic acid (pH 2.8); a flow rate, 0.3 ml/min; a 25 μl injection volume; and a 13 minute run time (Wen et al., 2008).
For each silymarin flavonolignan, the limit of detection was 20 ng/ml and the quantitative ranges for parent and for total flavonolignan were 50 – 2,500 ng/ml and 100 – 20,000 ng/ml, respectively. The accuracy for each flavonolignan was within 95.4 – 107.4% and intra- and inter-day precisions were 1.7 – 11% and 4.5 – 14%, respectively. Data Analysis DMD #40212 12 Pharmacokinetic parameters including: area under plasma concentration-time curve (AUC); maximum plasma concentration (Cmax); time to Cmax (Tmax); and terminal half-life (T½) were calculated using noncompartmental methods, WinNonlin-Pro (v5.2; Pharsight Corp, Mountain View, CA).
A constant dosing interval (tau) of 8 hours was assumed for the calculation of steady-state AUC0-8h using the linear up/log down trapezoidal method. To obtain pharmacokinetic parameters for the conjugate flavonolignan concentrations, the parent flavonolignan concentrations were subtracted from the total flavonolignan concentrations at each time point over the entire sampling period prior to performing a pharmacokinetic analysis. Pharmacokinetic parameters are reported as geometric means with 95% confidence intervals, except for Tmax which is reported as median with minimum and maximum values. For our primary analysis, differences in steady-state exposures (i.e., AUC0-8h) between disease cohorts were compared, following log transformation, using a parametric two-sample t-test, p < 0.05 was used for statistical significance. In addition, to eliminate weight as a potential confounder in the assessment of differences in flavonolignan exposures between cohorts, a linear regression model with log AUC0-8h as outcome was used.
The model included dose, disease, and weight as independent variables in order to adjust for variable weights across dose groups (280 mg vs. 560 mg) or disease type (HCV vs. NAFLD) while comparing AUC0-8h. Least-square means (adjusted means) were reported with 95% confidence intervals and tested using t-tests.
All statistical analyses were performed by using SAS 9.2 or SAS JMP 9 (SAS Institute Inc., Cary, NC). DMD #40212 13
RESULTS
Subjects Baseline demographics are presented in Table I.
Study subjects in the HCV cohorts were predominantly males with ages ranging from 43 – 59 years, while males and females were more equally represented in the NAFLD cohorts with ages ranging from 28 – 58 years. Subjects were characterized by well-compensated, noncirrhotic liver disease as evidenced by total bilirubin (range: 0. 3 – 2.6 mg/dl) and platelet counts (range: 150 – 327 cells/mm3).
Efficacy and Safety Endpoints
When compared to their screening baseline values, no reductions in serum transaminases for either HCV or NAFLD subjects, or reductions in HCV RNA titer for HCV subjects were observed at the end of the 7 day treatment period (data not shown).
There were no abnormal deviations from baseline laboratory values reported with silymarin administration for any cohort. For the HCV cohorts, 3 subjects who received a single 280 mg dose of silymarin reported a total of 4 adverse events.
Three of the adverse events were classified as neurological (e.g., headache) while the other was classified as gastrointestinal. Only one adverse event (dizziness) was considered possibly related Legalon® administration and resolved in less than 1 day. For NAFLD cohorts, two out of 12 subjects (16.7%) receiving silymarin reported at least one adverse event compared to 1 out of 4 subjects (25%) receiving placebo.
Adverse events reported with silymarin included upper respiratory infection and abdominal pain, both of which occurred in the 560 mg dose cohort. All adverse events reported with silymarin were determined to be mild to moderate, self-limiting, and were considered unrelated to treatment.
DMD #40212 14
Single dose Pharmacokinetics of Silybin A and Silybin B A comparison of the pharmacokinetics of silybin A and silybin B between HCV and NAFLD cohorts following single oral doses of either 280 or 560 mg silymarin are presented in Table II. Silybin A was the predominant flavonolignan in plasma for both HCV and NAFLD cohorts and was characterized by a 2.7- to 3.3-fold greater Cmax and a 2- to 4.5-fold greater AUC0-48h compared to silybin B. At the 280 mg dose, no differences were observed in the pharmacokinetics of silybin A or silybin B between HCV and NAFLD subjects. Short elimination half-lives were observed for both silybin A and silybin B (range 0.9 – 1.8 hours).
However, at the 560 mg dose, pharmacokinetic differences were observed between HCV and NAFLD subjects. Compared to HCV subjects, AUC0-48h for silybin A and silybin B were 1.5-fold (p > 0.05) and 2.1-fold (p < 0.05) greater, respectively, for NAFLD subjects. A similar trend was observed in the Cmax for silybin A and silybin B, although the 1.4- to 1.6-fold differences between HCV and NAFLD subjects did not achieve statistical significance.
Elimination half-lives were similar between the disease groups (range 1.1 – 1.5 hours), while Tmax was delayed by 1 hour in NAFLD subjects. Steady-State Pharmacokinetics of Silybin A and Silybin B The steady-state pharmacokinetics of silybin A and silybin B for the HCV and NAFLD cohorts following chronic oral administration of either 280 or 560 mg silymarin every 8 hours for 7 days are presented in Table III.
Similar to the data obtained following single doses, silybin A was the predominant flavonolignan in plasma for both HCV and NAFLD cohorts and was characterized by a 2.1- to 3.6-fold greater Cmax and a 2.6- to 4.9-fold greater AUC0-8h compared to silybin B. In addition, DMD #40212 15 there was no evidence of accumulation for either flavonolignan following repeated dosing with elimination half-lives ranging between 0.7 to 1.3 hours.
Also similar to the single dose data, pharmacokinetic differences between HCV and NAFLD cohorts were only observed at the 560 mg dose. The AUC0-8h for silybin A and silybin B were 1.6-fold and 2.5-fold greater, respectively, in NAFLD subjects compared to HCV subjects at the 560 mg while differences in the Cmax between cohorts ranged between 1.5- to 2.2-fold. After adjusting for weight and disease type, silybin A and silybin B AUC0-8h differed significantly between the 280 and 560 mg dose groups (p ≤ 0.004), such that for either HCV or NAFLD or at any weight level, the 560 mg dose was associated with higher AUC0-8h. When adjusted for weight and dose, only silybin B differed significantly across disease types such that adjusted mean AUC0-8h for silybin B was higher for NAFLD compared to HCV (p = 0.004).
The higher silybin B exposures in NAFLD subjects suggest the metabolism or hepatic uptake of silybin B may be reduced in NAFLD compared to HCV.
Single dose and Steady-State Pharmacokinetics of Silybin A and Silybin B Conjugates To further explore the effect of NAFLD on silymarin’s metabolism, differences in the plasma concentrations of silybin A and silybin B conjugates between HCV and NAFLD subjects were examined. As defined in Methods, plasma concentrations of conjugates were estimated from the subtraction of parent flavonolignan concentrations from total (parent + conjugate) flavonolignan concentrations.
The single dose and steady-state pharmacokinetic data for total conjugates of silybin A and silybin B for both disease cohorts are presented in Tables IV and V, respectively. Whereas plasma concentrations were observed to be greater for silybin A than for silybin B, the converse was true for DMD #40212 16 their conjugates.
The Cmax and AUC0-8h for silybin B conjugates were 3- to 4-fold greater than for silybin A conjugates across both dose levels and disease cohorts. Differences between HCV and NAFLD subjects were observed in the pharmacokinetics for plasma conjugates of silybin A and silybin B at either dose level following single or chronic dosing. However, these differences only achieved significance between HCV and NAFLD cohorts dosed at 280 mg every 8 hours whereas conjugates of silybin B in plasma of NAFLD subjects were characterized by 46% lower AUC0-8h (p < 0.05) and 42% lower Cmax (p < 0.05) compared to HCV subjects.
Figure 1 depicts the mean steady-state plasma concentration versus time profiles for silybin B (inset) and silybin B conjugates for HCV and NAFLD subjects at the 280 mg dose. Plasma concentrations of silybin B conjugates were lower in NAFLD subjects compared to HCV subjects over the entire 8 hour dosing interval (Figure 1). In contrast, plasma concentrations of silybin B were higher in NAFLD subjects until peak concentrations were achieved and then declined similarly (Figure 1 inset).
These data suggest that reduced silymarin metabolism may result in differences in silymarin exposures between NAFLD and HCV subjects, rather than differences in absorption. After adjusting for weight and disease type, the AUC0-8h for silybin A conjugates and for silybin B conjugates differed significantly between the 280 and 560 mg dose groups (p ≤ 0.004), such that for either HCV or NAFLD or at any weight level, the 560 mg dose was associated with higher AUC0-8h. When adjusted for weight and dose, only silybin B conjugates differed significantly across disease types such that adjusted mean AUC0-8h for silybin B conjugates was significantly lower for NAFLD subjects compared to HCV (p = 0.03).
To further quantify differences in the extent of flavonolignan conjugation between HCV and NAFLD subjects, steady-state metabolic ratios were calculated as the ratio of AUC0-8h for silybin B DMD #40212 17 divided by AUC0-8h for silybin B conjugates at the 560 mg dose. Metabolic ratios differed 4-fold (p < 0.05) between HCV and NAFLD with means (± SD) of 0.016 ± 0.011 and 0.060 ± 0.041, respectively. These data suggest that there is less conjugation of silybin B in NAFLD subjects compared to HCV at a silymarin dose of 560 mg. In summary, plasma concentrations of silybin A and silybin B were generally greater and the concentrations of their conjugates lower in NAFLD subjects compared to HCV subjects irrespective of the dose and frequency of oral silymarin administration.
Flavonolignan Accumulation
The ratio of parent silybin A steady-state AUC0-8h divided by single-dose AUC0-8h was calculated as an indication of the extent of accumulation following chronic three times daily dosing. Silybin A ratios of 1.3 and 1.4 were calculated for HCV and NAFLD, respectively, at the 560 mg dose, which indicates no significant accumulation in either cohort with repeated dosing. Similar ratios were calculated for silybin B. This finding is consistent with the short half-life of the silymarin flavonolignans. While no evidence for parent silybin A and silybin B accumulation was observed, the overall amount of parent flavonolignans in plasma was significantly higher in NAFLD subjects compared to HCV subjects at the 560 mg dose due to the appearance of additional parent flavonolignans.
Figure 2 compares mean steady-state peak plasma concentrations of the six parent silymarin flavonolignans for HCV and NAFLD subjects at the 560 mg dose, as well as their sum concentration. As seen in Figure 2, plasma concentrations of isosilybin A, isosilybin B, silychristin, and silydianin were significantly greater in NAFLD subjects compared to HCV subjects. Interestingly, silychristin and silydianin were not detected in the plasma of HCV subjects.
To gain insight into the mechanism(s) behind these observed DMD #40212 18 differences, we evaluated the plasma concentration versus time profile for each flavonolignan over the 48 hour sampling period following administration of the last 560 mg dose (Figure 3). Significant enterohepatic cycling of the six flavonolignans were observed in NAFLD subjects as indicated by a prominent second peak at 4 hours following the absorption peak at 1 hour.
Most flavonolignans also showed evidence of a third peak at 8 hours post dose. In contrast, there was less evidence of enterohepatic cycling in HCV subjects where no secondary peaks were observed for either silybin A or silybin B following the early absorption peak. Silychristin represented a major flavonolignan in the plasma of NAFLD subjects at the dose 560 mg dose. Silychristin’s steady-state pharmacokinetics (geometric mean and 95% confident intervals) were characterized by a Cmax of 67 ng/ml (-2.5, 174), an AUC0-8h of 325 ng
●hr/ml (-145, 1100), and a T½ of 3.1 hr (1.2, 6.3). The steady-state pharmacokinetics of the conjugates of silychristin in NAFLD subjects were characterized by a Cmax of 663 ng/ml (367, 1394), an AUC0-8h of 3800 ng
●hr/ml (1628, 8462), and a T½ of 4.5 hr (2.2, 8.6). DMD #40212 19
DISCUSSION
The expression of drug disposition genes and their protein products have been shown to be altered in liver disease (Congiu et al., 2009; Fisher et al., 2009; Congiu et al., 2002), and effects of liver disease on the disposition of drugs have been demonstrated and tend to be more severe in patients with more advanced cirrhotic disease (Chalon et al., 2003). In contrast, significant differences in the disposition of drugs between different types of liver disease have not been demonstrated. We have shown that the disposition of silymarin, an herbal medicine widely used by patients with liver disease, is significantly altered in patients with liver disease (Schrieber et al., 2008).
Concentrations of total silymarin species found in plasma, which consist primarily of flavonolignan conjugates, were found to be approximately 5-fold higher in patients with chronic HCV infection or NAFLD when compared to healthy controls. Pharmacokinetic differences were also observed between healthy subjects and patients with NAFLD or patients with HCV cirrhosis. In contrast, differences were not observed between healthy subjects and patients with noncirrhotic
HCV disease possibly due to wide disease heterogeneity in patient cohorts or reduced sensitivity as a result of low plasma concentrations of flavonolignans associated with the low oral dose of a generic brand of silymarin that was used in this study (Schrieber et al., 2008). These results raised the possibility that the disposition of silymarin, and its potential beneficial effects, may be different in various liver disease populations with early stage disease. To determine if the disposition of silymarin is different between patients with different types of the liver disease, this study examined the pharmacokinetics of higher than customary oral doses of silymarin in noncirrhotic patients with either chronic HCV infection or NAFLD.
The results of our study show that NAFLD patients are characterized by higher plasma concentrations of certain silymarin flavonolignans and lower concentrations of flavonolignan conjugates compared to HCV patients administered the same DMD #40212 20 dose. While silymarin flavonolignans appear to share common pathways of metabolism and transport, differences in their affinity for these processes have been noted (Miranda et al., 2008; Sridar et al., 2004) which likely account for the different relationships between AUC exposure and dose for silybin A and silybin B observed in our study. In vitro and in vivo studies suggest silymarin flavonolignans are primarily metabolized through glucuronidation and sulfation pathways with various UDP-glucuronosyltransferases (UGTs) sharing overlapping specificity (Sridar et al., 2004; Jancova et al., 2011). In addition, the extent in which various flavonolignans undergo glucuronidation or sulfation appears to vary (Wen et al., 2008).
There are several possibilities that could explain why the ratio of parent flavonolignan (e.g., silybin B) to flavonolignan conjugates was higher in patients with NAFLD compared to HCV in our study. The simplest explanation is that the expression or activity of UGTs is decreased in NAFLD subjects. Nonalcoholic steatohepatitis, a specific subset of NAFLD, is characterized by hepatic steatosis, and varying degrees of inflammation which can lead to decreased UGT expression which has been observed in rodents (Richardson et al., 2006) and in human liver tissue (Congiu et al., 2002).
Therefore it is plausible that the major UGT isoforms involved in metabolism of silymarin may be lower in NAFLD subjects resulting in higher plasma levels of parent flavonolignans and lower concentrations of conjugates. Since silybin B conjugates represents 99% of the total (parent + conjugates) silybin B species in HCV patient plasma, metabolism stoichiometry predicts that the 40% reduction in silymarin conjugates observed in our NAFLD cohort should result in an ~30-fold increase in silybin B plasma concentrations. However, plasma concentrations of silybin B were comparable between HCV and NAFLD patients.
Therefore, reduced UGT activity does not appear to be a viable explanation for the differences in silymarin pharmacokinetics between HCV and NAFLD in our study. In addition, the DMD #40212 21 lower plasma concentration of flavonolignan conjugates in NAFLD compared to HCV does not appear to be related to reduced intestinal absorption since parent flavonolignans would also be expected to be lower in plasma.
Alterations in the expression and function of hepatobilary transporters may be a more plausible explanation for the decrease in flavonolignan conjugates and the higher plasma concentrations of parent flavonolignans observed in the NAFLD cohorts. Evidence for extensive enterohepatic cycling of silymarin and their conjugates has been observed at high doses of silymarin (Hawke et al., 2010; Schrieber et al., 2008). Enterohepatic cycling is regulated by hepatobiliary transporters involved in the active uptake of anionic and cationic compounds from the blood such as the organic anion transporting polypeptides, OATP1B1 and OATP2B1, located on the basolateral membrane of the hepatocyte (Chandra et al., 2004). In many instances, these compounds undergo metabolism to more polar conjugates followed by transport and biliary excretion by ATP-binding cassette transporters such as Pglycoprotein , multidrug resistance associated protein 2 (MRP2), and breast cancer resistance protein, located at the canalicular membrane of the hepatocyte (Leslie et al., 2005; Schinkel and Jonker, 2003).
Once delivered to the small intestine, parent compounds can be reformed by bacterial deconjugation and returned to portal blood for delivery to the liver for reuptake. In competition with biliary efflux, is the efflux of substrates from the hepatocyte to blood by other members of the MRP family, such as MRP3 and MRP4 (MRPs 3/4), which are located on the basolateral (sinusoidal) membrane. It is generally thought that MRP2 and MRP3 work in concert in liver disease to promote hepatic efflux and protect the hepatocyte from the effects of cholestasis (Van de Steeg et al., 2010; Wagner et al., 2005).
The most intriguing observation in the current study was the suggestion of significant enterohepatic recycling of silymarin flavonolignans in NAFLD subjects in contrast to HCV subjects DMD #40212 22 where there was no evidence of enterohepatic cycling (see Figure 3). Silymarin flavonolignans demonstrate high affinity for MRP4 (Wu et al., 2005) while silymarin conjugates, but not parent flavonolignans, appear to be better substrates for MRP2 (Miranda et al., 2008).
Glucuronides that are substrates for MRP2, such as conjugated bilirubin, can also be substrates for MRPs 3/4 (Borst et al., 2006; Zelcer et al., 2006). Therefore, differences in the disposition and enterohepatic cycling of silymarin flavonolignans may reflect alterations in the function of hepatobilary transporters as a result of liver disease.
In obesity and NAFLD animal models, Mrp2 has been shown to have altered hepatic expression and function (Cheng et al., 2008; Geier et al., 2005). In addition, Mrp2, Mrp3, and Mrp4 protein expression were significantly increased in a rodent model of NAFLD (Lickteig et al., 2007). The biliary excretion of glucuronide and sulfate conjugates of silymarin flavonolignans was shown to be dependent on Mrp2 using isolated perfused livers, and some flavonolignans such as silychristin and silydianin were almost quantitatively secreted into bile (Miranda et al., 2008).
Therefore, enterohepatic cycling of silymarin flavonolignans may be increased in NAFLD due to increased MRP2-dependent biliary efflux and diversion of silymarin conjugates away from sinusoidal efflux to blood. An increase in MRP4 would also contribute to greater sinusoidal efflux of parent flavonolignans. These changes would result in lower plasma concentrations of silymarin conjugates with higher concentrations of recycling silymarin flavonolignans in NAFLD patients compared to HCV. Alternatively, the differences observed in the disposition of silymarin between NAFLD and HCV patients may reflect HCV-specific alterations in hepatobiliary function.
HCV infection was shown to be associated with increased hepatic expression of MRP4, decreased expression of MRP2, and decreased expression of OATP1B1 in cirrhotic and noncirrhotic liver while the expression of MRP3 and DMD #40212 23 OATP2B1 were similar to that in normal human liver (Ogasawara et al., 2010).
Therefore, the differences in the disposition of silymarin between HCV and NAFLD subjects observed in our study may reflect a diversion of silymarin conjugates to sinusoidal efflux in HCV patients due to reduced biliary efflux by MRP2 or reduced uptake by OATP1B1, which would also result in higher plasma concentrations of silymarin conjugates and decreased enterohepatic cycling of silymarin flavonolignans compared to patients with NAFLD.
While the results of our study cannot delineate between these various potential mechanisms, it is possible that silymarin’s disposition is altered by different, diseasespecific mechanisms in NAFLD and HCV populations.
This conclusion is supported by our previous observation that plasma concentrations of silymarin conjugates are significantly higher in both NAFLD and HCV patients compared to concentrations found in healthy volunteers (Schrieber et al., 2008).
In summary, differences in the disposition of silymarin between NAFLD and HCV patients may reflect different disease-specific alterations in the function of hepatobiliary transport proteins.
These observations are significant because differences in the disposition of drugs between different types of liver disease have not been demonstrated, perhaps because of their more restrictive use indications.
Importantly, the antioxidant activity and potential antiinflammatory and antifibrotic effects of silymarin on disease progression will be dependent on its hepatic disposition. Oxidative stress has been associated with all stages of chronic HCV liver disease (Jain et al., 2002) and recent data from the HALT-C trial suggest that silymarin use among patients with advanced HCV liver disease may be associated with reduced progression to cirrhosis (Freedman et al., 2011). Compared to HCV infection, silymarin may demonstrate greater benefits in patients with NAFLD since oxidative stress is thought to play a central role in the etiology of NASH (Day et al., 1998) and there are no approved therapies.
In addition, the results of this study suggest silymarin’s effects on liver disease progression may also be greater in DMD #40212 24 NAFLD patients due to higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared to patients with HCV.
These observations were critical in the design of a Phase 2 silymarin trial in NASH which is currently ongoing (Lang, 2006). DMD #40212 25
Acknowledgements The authors are indebted to Dr. Josh Berman and Dr. Qi-Ying Liu for their important early efforts in study design and to Dr. Ulrich Mengs for championing this work. In addition, the authors wish to thank the patients who volunteered for this trial, and Dr. Tedi Soule, Joseph Colagreco, Mary Hammond, and Deborah Moretti, who served as the study coordinators, and Sharon Lawlor, who was the DCC coordinator, for their invaluable assistance in the conduct of this trial. The authors would also like to thank Dr. Craig W. Hendrix, M.D. who graciously agreed to serve as the independent safety monitor. DMD #40212 26 Authorship Contributions Participated in research design: Hawke, Reddy, Belle, Afdhal, Navarro, Meyers, Doo, Fried Conducted experiments: Wen, Schrieber Contributed new reagents or analytic tools: Hawke, Smith Performed data analysis: Schrieber, Wahed Wrote or contributed to the writing of the manuscript: Schrieber, Hawke DMD #40212 27
REFERENCES
HCV News; Higher serum testosterone is assoc w-increased risk of advanced hepatitis C-related liver disease in males
Higher serum testosterone is associated with increased risk of advanced hepatitis C-related liver disease in males
White DL, Tavakoli-Tabasi S, Kuzniarek J, Pascua R, Ramsey DJ, El-Serag HB; Hepatology (Aug 2011)
BACKGROUND: Males have strikingly increased risk of advanced liver disease. However, the association between testosterone and risk of hepatitis C virus (HCV)-related advanced liver disease is unknown.
METHODS: We performed a cross-sectional study in male veterans with chronic HCV. Blood samples were obtained to measure total serum testosterone and perform the FibroSURE-ActiTest. Other risk factor data were obtained through systematic questionnaires (e.g., alcohol), physical measurements (e.g., BMI) and serological tests (e.g., viral load). The association between total testosterone and risk of advanced hepatic fibrosis (F3 and F3/F4) and inflammatory activity (A3 and A2/3) measured by FibroSURE-ActiTest was evaluated with logistic regression.
RESULTS: A total of 308 eligible study participants were prospectively recruited (mean age 57, 52% African-American). There were 105 cases with advanced fibrosis and 203 mild fibrosis controls; and 88 cases with advanced inflammatory activity and 220 mild activity controls. Mean total serum testosterone was significantly higher in advanced fibrosis cases as well as advanced inflammatory activity cases compared to mild disease controls (6.0 ng/ml vs. 5.3 ng/ml and 5.9 ng/ml vs. 5.4 ng/ml, respectively). We observed a significant 27% increase in advanced fibrosis risk and 16% increase in advanced inflammatory activity risk for each 1 ng/ml increase in total serum testosterone. Total testosterone in the upper tertile was associated with an even greater excess risk of advanced fibrosis than advanced inflammatory activity (OR(adjusted advanced fibrosis) =3.78, 95% CI 1.88-7.61 vs. OR(adjusted advanced inflammatory activity) =2.64, 95% CI 1.29-5.45, respectively).
CONCLUSIONS: Total serum testosterone is associated with an increased risk of both advanced hepatic fibrosis and advanced hepatic inflammatory activity in HCV-infected men. Testosterone may be important in the pathogenesis of HCV-related advanced liver disease in males. (HEPATOLOGY 2011.)
New HCV Symposium to Debut at The Liver Meeting® in 2011
By Ann Haran, AASLD Staff
AASLD is excited to debut our new HCV Symposium at The Liver Meeting® 2011. This inaugural symposium Integrating HCV Practice Guidelines and Treatment Advances into Clinical Practice was developed by the Hepatitis C Special Interest Group (SIG) and will be led by moderators Gary L. Davis, MD, Raymond Chung, MD, and John Ward, MD.
The program was designed to educate providers on newly approved and anticipated therapies for HCV and how these therapies should be integrated into clinical practice. As these agents represent a new class of drugs in this field, they will present new challenges for treatment monitoring, side effect management, drug resistance emergence, and personalization of therapy. This program will lay a basic mechanistic foundation upon which to build clinical management guidelines, but the emphasis will be on the latter.
Important emerging issues on public policy and methods of implementation will also be discussed. The symposium will review the updated AASLD Treatment Guidelines for HCV, which will be published prior to The Liver Meeting® 2011. HCV is certain to be a hot topic at The Liver Meeting® with the recent approval of the direct acting antiviral agents (DAA) telaprevir and boceprevir.
Therefore, Dr. Chung and his colleagues encourage those persons involved in the evaluation and management of HCV to attend this symposium, as speakers will discuss not only these two new drug therapies, but will also “provide attendees with a horizon view of the many other exciting developments that are just around the corner for HCV.” This meeting will focus “not just on theory, but also on the practice of implementing the new therapies and understanding both their promise and limitations.”
Dr. Chung expects there to be a great deal of interest in both the therapies themselves and in gaining an understanding of who should be treated and who may justifiably defer therapy. He predicts that, with expansion of DAA classes, “an interferon-free universe will be possible.”Dr. Chung also points out the potential public health benefit of identifying future candidates for these new therapies. ”How do we identify those people so they won’t miss out? With improved treatment efficacy, duration, and tolerability, we don’t want to leave undiagnosed patients at the dock.” No final set of recommendations for who should be screened has been established as yet; this issue will be discussed in Dr. Ron Valdiserri’s presentation on the DHHS Action Plan on Viral Hepatitis.
Dr. Sanjeev Arora will also give an implementation-focused presentation, describing the ECHO Project and its efforts to expand health care to areas with less access to experienced treaters. The symposium will also discuss many of the challenges associated with using the new HCV treatments. As Dr. Chung reminds us, “no therapy comes without its own set of issues.” The challenges involved with using boceprevir and telaprevir include the frequency of dosing, effect of food, potential drug interactions, and new and more stringent stopping rules for virologic failure. Dr. Chung states that the symposium will also consider the role of host genetic tests such as IL28B genotyping, in treatment decision-making.
In addition to Dr. Chung, Dr. Valdiserri, and Dr. Arora, the symposium will include presentations from Hepatitis SIG members Dr. Michael Fried, Dr. Andrew Muir, and Dr. David Nelson, as AASLD’s recently formed Hepatitis C SIG played a key role in developing the new HCV Symposium. Dr. Valdiserri is the Deputy Assistant Secretary for Health, Infectious Diseases, for DHHS, while Dr. Arora was the originator of the ECHO Project. Overall, Dr. Chung hopes the symposium will “convey an understanding of the optimal and rational use of direct antiviral therapies.” Participants will be provided with an opportunity not only to learn how the new therapies are used now, but also to envision how they will be used in the future.
Click here to view the complete program for this exciting new symposium.
The symposium is included as part of the Annual Meeting registration fee. This electronic newsletter is a bi-weekly publication of AASLD and replaces the former bi-monthly print newsletter and weekly e-news. Members are welcome to submit articles and may send suggestions to aharan@aasld.org.
Pharmaceutical
From Fierce Biotech
Medivir deals generics biz amid HepC drug trials
August 26, 2011 — 10:45am ET By Ryan McBride
Eyeing the prospects of its experimental hepatitis C drug, Swedish biotech Medivir ($MVIR) has sold off the generics unit of its subsidiary BioPhausia to Bluefish Pharmaceuticals. Medivir scooped up BioPhausia in June to tap the Nordic market in case its hepatitis C drug, TMC435, is approved. Medivir offloaded BioPhausia's generics unit, called BMM Pharma, for SEK 26 million ($4.12 million) along with inventories valued at SEK 12 million (or $1.9 million), Genetic Engineering News reports. The transaction comes as Medivir and its partner, Johnson & Johnson's ($JNJ) Tibotec, move full steam in late-stage development of TMC435, which is the top candidate in Medivir's R&D pipeline, according to a release.
The company's first product, a cold sore treatment called Xerese, was launched in the U.S. in February. "This deal is a natural last step in the concentration and focus of BioPhausia's business, which began about a year ago. We will now be focusing on the ongoing commercial development of our proprietary products and parallel imported Products," said Maris Hartmanis, CEO of BioPhausia.
Clearly, Medivir is keeping focused on ushering TMC435, a protease inhibitor, through trials and to potential regulatory approvals for hepatitis C. With the white-hot market for drugs against the liver disease nowadays, that's not a bad bet.
here's the Medivir release- see the coverage in Genetic Engineering News Related Articles: J&J's success with Hep C partners might hit a snag
What Are Biosimilars?
Biosimilars are copycat versions of expensive biotechnology drugs. Although technically these "biosimilars" are not called generic.
Quoted from an article @ Reuters in Jan 2011;"Because of the complexity of biotech drugs, which are produced through biological processes that generally involve recombinant DNA technologies, they are often called "biosimilars" rather than generic copies. Biotech drugs are usually made from living cell lines controlled by different manufacturers, it is impossible for generic companies to make identical copies as they do with simple chemical-based drugs, which do not require fresh clinical trials. Biosimilars of drugs like Amgen's white blood cell-booster Neupogen are already on the market in Europe."
Biosimilars In Todays News;
Biosimilars: physicians cite concerns over supporting data
World News August 26, 2011 Lynne Taylor The majority of US and European physicians are wary of using a biosimilar medicine for an indication for which supporting clinical data are lacking, according to new research. Physicians' attitudes towards "indication extrapolation" - where a biosimilar (generic biologic product) needs only to show similarity in a Phase III study for one indication for the product to be granted approval for other indications for which the original branded product is used - vary from country to country, according to the study, which is published by business information firm Decision Resources. Moreover, the authors found that, out of the specialists which they surveyed, rheumatologists, nephrologists and gastroenterologists in particular told them that indication extrapolation should not be permitted, or should be done carefully, because of minute differences between the biosimilar and the branded original product which might be clinically significant........
From Pharmalot
Hospitals Keep Buying Those Gray Market Meds
The ongoing shortage of many medications is generating not only considerable angst among physicians and politicians, but mushrooming gray market activity, as we have reported previously. And yet another survey reveals that shadowy offers and purchases are on the rise, along with an accompanying rise in price. To be specific, purchasing agents and pharmacists at 549 hospitals were queried by the Institute for Safe Medicine Practices, a non-profit watchdog group, and 56 percent reported receiving daily solicitations from up to 10 different gray market vendors by phone, e-mail and fax. And 52 percent acknowledged by one or more meds from gray market vendors in the last two years. Not surprisingly 80 percent reported such purchases had increased in the last two years as shortages rose..........
FDA: High-Dose Citalopram Tied to Heart Risks
By: DIANA MAHONEY, Internal Medicine News Digital Network
The antidepressant citalopram should not be used at doses greater than 40 mg per day because such doses can lead to prolongation of the QT interval, the Food and Drug Administration announced Aug. 24 in a drug safety communication. Further, the drug should not be prescribed to patients with congenital long QT syndrome, and extra precautions should be taken for patients with other underlying heart conditions, the agency said. Studies do not show a benefit in the treatment of depression at doses of the selective serotonin reuptake inhibitor higher than 40 mg/day. Previously, the citalopram (Celexa) label stated that some patients might require a dose of 60 mg/day.
The agency’s dosage recommendation is based on postmarketing reports of QT prolongation associated with citalopram and results of a randomized, double-blind, placebo-controlled crossover study evaluating the effects of 20-mg and 60-mg doses of citalopram on the QT interval in adults. The latter study showed that, compared with placebo, the maximum mean prolongations in the individually corrected QT intervals for patients randomized to 20-mg and 60-mg doses of citalopram, respectively, were 8.5 msec and 18.0 msec. The prolongation of the corrected QT interval was estimated to be 12.6 msec, based on the relationship between serum citalopram concentration and QT interval, the FDA statement said. Because such dose-dependent changes in the electrical activity of the heart can lead to abnormal heart rhythms, including the potentially fatal torsades de pointes, and in the absence of evidence demonstrating that citalopram at doses higher than 40 mg/day is beneficial in the treatment of depression, the FDA determined that citalopram should no longer be used at doses above 40 mg/day and that it should never be used in patients with congenital long QT syndrome.
Also, because individuals with underlying heart conditions, such as heart failure or bradyarrhythmias and those predisposed to insufficient serum potassium and magnesium because of comorbid illness or other drugs are at particular risk, the FDA has made the following safety recommendations:
• Correct hypokalemia and hypomagnesemia before administering citalopram and monitor electrolytes as clinically indicated.
• Consider more frequent electrocardiogram monitoring for patients with congestive heart failure, bradyarrhythmias, or patients on concomitant medications that prolong the QT interval. • The maximum recommended dose for patients with hepatic impairment, who are older than 60 years, who are CYP 2C19 poor metabolizers, or who are taking cimetidine is 20 mg/day because each of these factors can increase blood levels of citalopram, thus increasing the risk of QT interval prolongation and torsades de points.
• Advise patients to contact a health care professional if they experience signs or symptoms of an abnormal heart rate or rhythm while taking citalopram.
The citalopram drug label has been revised to include the new drug dosage and usage recommendations, and the revised package insert will include information about the potential for QT interval prolongation and torsades de pointes.
Healthy You
Activity Eases RA Pain
This report is part of a 12-month Clinical Context series.
By Nancy Walsh, Staff Writer, MedPage Today Published: August 26, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
The extent to which rheumatoid arthritis patients achieve their individual goals for physical activity can predict the beneficial effects of activity on pain and quality of life, a statistical modeling analysis showed.The belief that one can achieve one's goals -- a concept known as self-efficacy -- explained 31.4% of the indirect effects of physical activity on arthritis pain after six months, according to Keegan P. Knittle, MSc, from Leiden University in the Netherlands, and colleagues.Self-efficacy also explained 43.8% of change in physical quality of life and 60% of variance in mental quality of life at six months, both of which were significant differences, the Dutch researchers reported online in Arthritis Care & Research. Action Points Explain that the extent to which rheumatoid arthritis patients achieve their individual goals for physical activity can predict the beneficial effects of activity on pain and quality of life.Note that self-efficacy also explained some of the change in physical quality of life and most of the variance in mental quality of life at six months.
It has become clear that patients with rheumatoid arthritis can derive significant benefits from physical activity, but most patients do not meet the goal of exercising one half hour five days each week.
Self-efficacy and autonomous motivation have both been shown to be positively correlated with increased exercise in patients with rheumatoid arthritis, but a possible relationship with goal achievement and quality of life has not been determined.Accordingly, the researchers used multiple-mediation models "which assume that physical activity and goal achievement mediate the relationships between self-efficacy and autonomous motivation on the one hand, and either pain, physical quality of life, or mental quality of life on the other hand," they explained.
They enrolled 106 patients who completed questionnaires at baseline, providing detailed, numerical information about their attitudes and symptoms.Participants then completed a second questionnaire six months later in which they determined the extent to which they achieved their goals, and what the effects were on their arthritis symptoms and sense of well-being.
Three-quarters of the participants reported meeting their goals for physical activity by at least 50%, according to Knittle and associates.
For their analysis, the researchers then constructed a two-step model with autonomous motivation and self-efficacy as independent variables, goal achievement and physical activity as mediators, and age and sex as covariates.The model was designed to examine the indirect effects of each independent variable, adjusting not only for the contribution of the other independent variable but also for the covariates.
The mediation analyses first considered the associations between the independent variable and the mediators (a) and physical activity with pain (b).
The analysis found no direct association between physical activity and pain, but did show indirect effects (an × bn) of self-efficacy and goal achievement on pain and quality of life -- when mediated through goal achievement: Arthritis pain, a3 × b1 = −0.059 (95% CI −0.151 to −0.008) Physical quality of life, a3 × b1 = 0.670 (95% CI 0.128 to 1.593) Mental quality of life, a3 × b1 = 0.388 (95% CI 0.032 to 1.072) "The indirect effects through goal achievement may therefore reflect a tendency of highly self-efficacious individuals to set more difficult physical activity goals, perhaps involving more dynamic conditioning or strengthening exercises, which in turn have greater effects on arthritis pain," the researchers observed.
These results confirmed that patients with rheumatoid arthritis who are active consider themselves able to continue being active, with the implication that clinicians should attempt to foster self-efficacy in their patients, according to the researchers.Interventions that can increase self-efficacy for physical activity, they noted, include setting specific goals, developing action plans, and providing feedback."The idea behind these goal-setting interventions is that the more realistic and achievable a goal is, and the more concrete its plan of execution, the more likely it is to be achieved," wrote Knittle and colleagues.
Setting goals that are realistic is particularly important, they noted, because unmet goals can further diminish self-efficacy and autonomous motivation.Limitations included participant attrition and the unavailability of data on their specific activities.
Source reference:Knittle K, et al "Self-efficacy and physical activity goal achievement predict arthritis pain and quality of life among patients with rheumatoid arthritis" Arthritis Care Res 2011; DOI: 10.1002/acr.20587.
Primary source: Arthritis Care & Research
International Progress On Non-Communicable Disease Epidemic Jeopardized By UN Member States
26 August 2011
The fight against non-communicable diseases (NCDs) such as cancer, diabetes, cardiovascular disease, chronic respiratory disease and liver disease, is at grave risk, because of recent efforts by some countries to stall and...
[read article]
Complementary and Alternative Medicine
Complementary Medicine Used More by Health Care Workers
U.S. health care providers use complementary, alternative medicine more than support workers
FRIDAY, Aug. 26 (HealthDay News) -- U.S. health care workers, especially health care providers, are more likely to use complementary and alternative medicine (CAM) than the general, employed U.S. population, according to a study published online Aug. 22 in Health Services Research.
Pamela Jo Johnson, M.P.H., Ph.D., from the Allina Hospitals and Clinics in Minneapolis, and colleagues examined the personal use of 36 types of CAM therapies among U.S. health care workers. Data were collected from the 2007 Alternative Health Supplement of the National Health Interview Survey. A nationally representative sample of 14,329 employed adults, including a subsample of 1,280 adults employed in hospitals or ambulatory care settings, were examined. Health care workers were divided into four categories: providers, technicians, support workers, and other occupations. The odds of CAM use in each category in the past year were assessed by multivariate logistic regression.
The investigators found that, compared to the general population, health care workers were more likely to use CAM (76 versus 63 percent). Health care workers were significantly more likely to use and self-treat with CAM compared with employees in other industries. Health care workers in ambulatory care were significantly more likely to have used CAM in the past year compared to those working in hospitals. Health care providers were more likely to have past-year practitioner-based CAM use and self-treatment with CAM compared to support workers (adjusted odds ratio, 2.2 and 2.7, respectively).
"This study provides the first population-based description of CAM use by U.S. health care workers. Our analyses reveal that, overall, health care workers are significantly more likely to use CAM therapies, particularly mind-body therapies, than the employed U.S. population," the authors write.
AbstractFull Text (subscription or payment may be required)
Last Updated: August 26, 2011
Copyright © 2011 HealthDay. All rights reserved.
For Your Reading Pleasure
Grand Rounds is a weekly summary of the best health blog posts on the Internet. Each week a different blogger takes turns hosting Grand Rounds, and summarizing the best submissions for the week.
This Week Hosted By; Suture for a Living
Thank you for coming to Grand Rounds 7:48, the weekly collection of the some of the best in online medical writing from all (doctors, nurses, patients, healthcare professionals). Next week’s will be hosted by Health 3.0 Blog.Along with the excellent posts, I’ve included pictures of the changes cameras have gone through over the years – from the pin-hole camera to digital phone cameras. Enjoy!
A Few Submissions below, read all entries here
Dr. Schattner, MedicalLessons, talks about what she has learned from the offbeat and in some ways disturbing story of a young woman who's made a business of having had a rare form of cancer, epithelioid hemangioendothelioma: Notes on Crazy Sexy Cancer
Carolyn is a heart attack survivor who blogs at HEART SISTERS. In her post, "How to be a good patient" , she shares her experiences and expertise she has gained in having a chronic illness.
Ryan, ACP Internist blog, looks at the recent trends in healthy lifestyle choices by adapting two recent studies (and adding a touch of humor): Smoking in front of the television must be really bad
Continue reading here
White DL, Tavakoli-Tabasi S, Kuzniarek J, Pascua R, Ramsey DJ, El-Serag HB; Hepatology (Aug 2011)
BACKGROUND: Males have strikingly increased risk of advanced liver disease. However, the association between testosterone and risk of hepatitis C virus (HCV)-related advanced liver disease is unknown.
METHODS: We performed a cross-sectional study in male veterans with chronic HCV. Blood samples were obtained to measure total serum testosterone and perform the FibroSURE-ActiTest. Other risk factor data were obtained through systematic questionnaires (e.g., alcohol), physical measurements (e.g., BMI) and serological tests (e.g., viral load). The association between total testosterone and risk of advanced hepatic fibrosis (F3 and F3/F4) and inflammatory activity (A3 and A2/3) measured by FibroSURE-ActiTest was evaluated with logistic regression.
RESULTS: A total of 308 eligible study participants were prospectively recruited (mean age 57, 52% African-American). There were 105 cases with advanced fibrosis and 203 mild fibrosis controls; and 88 cases with advanced inflammatory activity and 220 mild activity controls. Mean total serum testosterone was significantly higher in advanced fibrosis cases as well as advanced inflammatory activity cases compared to mild disease controls (6.0 ng/ml vs. 5.3 ng/ml and 5.9 ng/ml vs. 5.4 ng/ml, respectively). We observed a significant 27% increase in advanced fibrosis risk and 16% increase in advanced inflammatory activity risk for each 1 ng/ml increase in total serum testosterone. Total testosterone in the upper tertile was associated with an even greater excess risk of advanced fibrosis than advanced inflammatory activity (OR(adjusted advanced fibrosis) =3.78, 95% CI 1.88-7.61 vs. OR(adjusted advanced inflammatory activity) =2.64, 95% CI 1.29-5.45, respectively).
CONCLUSIONS: Total serum testosterone is associated with an increased risk of both advanced hepatic fibrosis and advanced hepatic inflammatory activity in HCV-infected men. Testosterone may be important in the pathogenesis of HCV-related advanced liver disease in males. (HEPATOLOGY 2011.)
New HCV Symposium to Debut at The Liver Meeting® in 2011
By Ann Haran, AASLD Staff
AASLD is excited to debut our new HCV Symposium at The Liver Meeting® 2011. This inaugural symposium Integrating HCV Practice Guidelines and Treatment Advances into Clinical Practice was developed by the Hepatitis C Special Interest Group (SIG) and will be led by moderators Gary L. Davis, MD, Raymond Chung, MD, and John Ward, MD.
The program was designed to educate providers on newly approved and anticipated therapies for HCV and how these therapies should be integrated into clinical practice. As these agents represent a new class of drugs in this field, they will present new challenges for treatment monitoring, side effect management, drug resistance emergence, and personalization of therapy. This program will lay a basic mechanistic foundation upon which to build clinical management guidelines, but the emphasis will be on the latter.
Important emerging issues on public policy and methods of implementation will also be discussed. The symposium will review the updated AASLD Treatment Guidelines for HCV, which will be published prior to The Liver Meeting® 2011. HCV is certain to be a hot topic at The Liver Meeting® with the recent approval of the direct acting antiviral agents (DAA) telaprevir and boceprevir.
Therefore, Dr. Chung and his colleagues encourage those persons involved in the evaluation and management of HCV to attend this symposium, as speakers will discuss not only these two new drug therapies, but will also “provide attendees with a horizon view of the many other exciting developments that are just around the corner for HCV.” This meeting will focus “not just on theory, but also on the practice of implementing the new therapies and understanding both their promise and limitations.”
Dr. Chung expects there to be a great deal of interest in both the therapies themselves and in gaining an understanding of who should be treated and who may justifiably defer therapy. He predicts that, with expansion of DAA classes, “an interferon-free universe will be possible.”Dr. Chung also points out the potential public health benefit of identifying future candidates for these new therapies. ”How do we identify those people so they won’t miss out? With improved treatment efficacy, duration, and tolerability, we don’t want to leave undiagnosed patients at the dock.” No final set of recommendations for who should be screened has been established as yet; this issue will be discussed in Dr. Ron Valdiserri’s presentation on the DHHS Action Plan on Viral Hepatitis.
Dr. Sanjeev Arora will also give an implementation-focused presentation, describing the ECHO Project and its efforts to expand health care to areas with less access to experienced treaters. The symposium will also discuss many of the challenges associated with using the new HCV treatments. As Dr. Chung reminds us, “no therapy comes without its own set of issues.” The challenges involved with using boceprevir and telaprevir include the frequency of dosing, effect of food, potential drug interactions, and new and more stringent stopping rules for virologic failure. Dr. Chung states that the symposium will also consider the role of host genetic tests such as IL28B genotyping, in treatment decision-making.
In addition to Dr. Chung, Dr. Valdiserri, and Dr. Arora, the symposium will include presentations from Hepatitis SIG members Dr. Michael Fried, Dr. Andrew Muir, and Dr. David Nelson, as AASLD’s recently formed Hepatitis C SIG played a key role in developing the new HCV Symposium. Dr. Valdiserri is the Deputy Assistant Secretary for Health, Infectious Diseases, for DHHS, while Dr. Arora was the originator of the ECHO Project. Overall, Dr. Chung hopes the symposium will “convey an understanding of the optimal and rational use of direct antiviral therapies.” Participants will be provided with an opportunity not only to learn how the new therapies are used now, but also to envision how they will be used in the future.
Click here to view the complete program for this exciting new symposium.
The symposium is included as part of the Annual Meeting registration fee. This electronic newsletter is a bi-weekly publication of AASLD and replaces the former bi-monthly print newsletter and weekly e-news. Members are welcome to submit articles and may send suggestions to aharan@aasld.org.
Pharmaceutical
From Fierce Biotech
Medivir deals generics biz amid HepC drug trials
August 26, 2011 — 10:45am ET By Ryan McBride
Eyeing the prospects of its experimental hepatitis C drug, Swedish biotech Medivir ($MVIR) has sold off the generics unit of its subsidiary BioPhausia to Bluefish Pharmaceuticals. Medivir scooped up BioPhausia in June to tap the Nordic market in case its hepatitis C drug, TMC435, is approved. Medivir offloaded BioPhausia's generics unit, called BMM Pharma, for SEK 26 million ($4.12 million) along with inventories valued at SEK 12 million (or $1.9 million), Genetic Engineering News reports. The transaction comes as Medivir and its partner, Johnson & Johnson's ($JNJ) Tibotec, move full steam in late-stage development of TMC435, which is the top candidate in Medivir's R&D pipeline, according to a release.
The company's first product, a cold sore treatment called Xerese, was launched in the U.S. in February. "This deal is a natural last step in the concentration and focus of BioPhausia's business, which began about a year ago. We will now be focusing on the ongoing commercial development of our proprietary products and parallel imported Products," said Maris Hartmanis, CEO of BioPhausia.
Clearly, Medivir is keeping focused on ushering TMC435, a protease inhibitor, through trials and to potential regulatory approvals for hepatitis C. With the white-hot market for drugs against the liver disease nowadays, that's not a bad bet.
here's the Medivir release- see the coverage in Genetic Engineering News Related Articles: J&J's success with Hep C partners might hit a snag
What Are Biosimilars?
Biosimilars are copycat versions of expensive biotechnology drugs. Although technically these "biosimilars" are not called generic.
Quoted from an article @ Reuters in Jan 2011;"Because of the complexity of biotech drugs, which are produced through biological processes that generally involve recombinant DNA technologies, they are often called "biosimilars" rather than generic copies. Biotech drugs are usually made from living cell lines controlled by different manufacturers, it is impossible for generic companies to make identical copies as they do with simple chemical-based drugs, which do not require fresh clinical trials. Biosimilars of drugs like Amgen's white blood cell-booster Neupogen are already on the market in Europe."
Biosimilars In Todays News;
Biosimilars: physicians cite concerns over supporting data
World News August 26, 2011 Lynne Taylor The majority of US and European physicians are wary of using a biosimilar medicine for an indication for which supporting clinical data are lacking, according to new research. Physicians' attitudes towards "indication extrapolation" - where a biosimilar (generic biologic product) needs only to show similarity in a Phase III study for one indication for the product to be granted approval for other indications for which the original branded product is used - vary from country to country, according to the study, which is published by business information firm Decision Resources. Moreover, the authors found that, out of the specialists which they surveyed, rheumatologists, nephrologists and gastroenterologists in particular told them that indication extrapolation should not be permitted, or should be done carefully, because of minute differences between the biosimilar and the branded original product which might be clinically significant........
From Pharmalot
Hospitals Keep Buying Those Gray Market Meds
The ongoing shortage of many medications is generating not only considerable angst among physicians and politicians, but mushrooming gray market activity, as we have reported previously. And yet another survey reveals that shadowy offers and purchases are on the rise, along with an accompanying rise in price. To be specific, purchasing agents and pharmacists at 549 hospitals were queried by the Institute for Safe Medicine Practices, a non-profit watchdog group, and 56 percent reported receiving daily solicitations from up to 10 different gray market vendors by phone, e-mail and fax. And 52 percent acknowledged by one or more meds from gray market vendors in the last two years. Not surprisingly 80 percent reported such purchases had increased in the last two years as shortages rose..........
FDA: High-Dose Citalopram Tied to Heart Risks
By: DIANA MAHONEY, Internal Medicine News Digital Network
The antidepressant citalopram should not be used at doses greater than 40 mg per day because such doses can lead to prolongation of the QT interval, the Food and Drug Administration announced Aug. 24 in a drug safety communication. Further, the drug should not be prescribed to patients with congenital long QT syndrome, and extra precautions should be taken for patients with other underlying heart conditions, the agency said. Studies do not show a benefit in the treatment of depression at doses of the selective serotonin reuptake inhibitor higher than 40 mg/day. Previously, the citalopram (Celexa) label stated that some patients might require a dose of 60 mg/day.
The agency’s dosage recommendation is based on postmarketing reports of QT prolongation associated with citalopram and results of a randomized, double-blind, placebo-controlled crossover study evaluating the effects of 20-mg and 60-mg doses of citalopram on the QT interval in adults. The latter study showed that, compared with placebo, the maximum mean prolongations in the individually corrected QT intervals for patients randomized to 20-mg and 60-mg doses of citalopram, respectively, were 8.5 msec and 18.0 msec. The prolongation of the corrected QT interval was estimated to be 12.6 msec, based on the relationship between serum citalopram concentration and QT interval, the FDA statement said. Because such dose-dependent changes in the electrical activity of the heart can lead to abnormal heart rhythms, including the potentially fatal torsades de pointes, and in the absence of evidence demonstrating that citalopram at doses higher than 40 mg/day is beneficial in the treatment of depression, the FDA determined that citalopram should no longer be used at doses above 40 mg/day and that it should never be used in patients with congenital long QT syndrome.
Also, because individuals with underlying heart conditions, such as heart failure or bradyarrhythmias and those predisposed to insufficient serum potassium and magnesium because of comorbid illness or other drugs are at particular risk, the FDA has made the following safety recommendations:
• Correct hypokalemia and hypomagnesemia before administering citalopram and monitor electrolytes as clinically indicated.
• Consider more frequent electrocardiogram monitoring for patients with congestive heart failure, bradyarrhythmias, or patients on concomitant medications that prolong the QT interval. • The maximum recommended dose for patients with hepatic impairment, who are older than 60 years, who are CYP 2C19 poor metabolizers, or who are taking cimetidine is 20 mg/day because each of these factors can increase blood levels of citalopram, thus increasing the risk of QT interval prolongation and torsades de points.
• Advise patients to contact a health care professional if they experience signs or symptoms of an abnormal heart rate or rhythm while taking citalopram.
The citalopram drug label has been revised to include the new drug dosage and usage recommendations, and the revised package insert will include information about the potential for QT interval prolongation and torsades de pointes.
Healthy You
Activity Eases RA Pain
This report is part of a 12-month Clinical Context series.
By Nancy Walsh, Staff Writer, MedPage Today Published: August 26, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
The extent to which rheumatoid arthritis patients achieve their individual goals for physical activity can predict the beneficial effects of activity on pain and quality of life, a statistical modeling analysis showed.The belief that one can achieve one's goals -- a concept known as self-efficacy -- explained 31.4% of the indirect effects of physical activity on arthritis pain after six months, according to Keegan P. Knittle, MSc, from Leiden University in the Netherlands, and colleagues.Self-efficacy also explained 43.8% of change in physical quality of life and 60% of variance in mental quality of life at six months, both of which were significant differences, the Dutch researchers reported online in Arthritis Care & Research. Action Points Explain that the extent to which rheumatoid arthritis patients achieve their individual goals for physical activity can predict the beneficial effects of activity on pain and quality of life.Note that self-efficacy also explained some of the change in physical quality of life and most of the variance in mental quality of life at six months.
It has become clear that patients with rheumatoid arthritis can derive significant benefits from physical activity, but most patients do not meet the goal of exercising one half hour five days each week.
Self-efficacy and autonomous motivation have both been shown to be positively correlated with increased exercise in patients with rheumatoid arthritis, but a possible relationship with goal achievement and quality of life has not been determined.Accordingly, the researchers used multiple-mediation models "which assume that physical activity and goal achievement mediate the relationships between self-efficacy and autonomous motivation on the one hand, and either pain, physical quality of life, or mental quality of life on the other hand," they explained.
They enrolled 106 patients who completed questionnaires at baseline, providing detailed, numerical information about their attitudes and symptoms.Participants then completed a second questionnaire six months later in which they determined the extent to which they achieved their goals, and what the effects were on their arthritis symptoms and sense of well-being.
Three-quarters of the participants reported meeting their goals for physical activity by at least 50%, according to Knittle and associates.
For their analysis, the researchers then constructed a two-step model with autonomous motivation and self-efficacy as independent variables, goal achievement and physical activity as mediators, and age and sex as covariates.The model was designed to examine the indirect effects of each independent variable, adjusting not only for the contribution of the other independent variable but also for the covariates.
The mediation analyses first considered the associations between the independent variable and the mediators (a) and physical activity with pain (b).
The analysis found no direct association between physical activity and pain, but did show indirect effects (an × bn) of self-efficacy and goal achievement on pain and quality of life -- when mediated through goal achievement: Arthritis pain, a3 × b1 = −0.059 (95% CI −0.151 to −0.008) Physical quality of life, a3 × b1 = 0.670 (95% CI 0.128 to 1.593) Mental quality of life, a3 × b1 = 0.388 (95% CI 0.032 to 1.072) "The indirect effects through goal achievement may therefore reflect a tendency of highly self-efficacious individuals to set more difficult physical activity goals, perhaps involving more dynamic conditioning or strengthening exercises, which in turn have greater effects on arthritis pain," the researchers observed.
These results confirmed that patients with rheumatoid arthritis who are active consider themselves able to continue being active, with the implication that clinicians should attempt to foster self-efficacy in their patients, according to the researchers.Interventions that can increase self-efficacy for physical activity, they noted, include setting specific goals, developing action plans, and providing feedback."The idea behind these goal-setting interventions is that the more realistic and achievable a goal is, and the more concrete its plan of execution, the more likely it is to be achieved," wrote Knittle and colleagues.
Setting goals that are realistic is particularly important, they noted, because unmet goals can further diminish self-efficacy and autonomous motivation.Limitations included participant attrition and the unavailability of data on their specific activities.
Source reference:Knittle K, et al "Self-efficacy and physical activity goal achievement predict arthritis pain and quality of life among patients with rheumatoid arthritis" Arthritis Care Res 2011; DOI: 10.1002/acr.20587.
Primary source: Arthritis Care & Research
International Progress On Non-Communicable Disease Epidemic Jeopardized By UN Member States
26 August 2011
The fight against non-communicable diseases (NCDs) such as cancer, diabetes, cardiovascular disease, chronic respiratory disease and liver disease, is at grave risk, because of recent efforts by some countries to stall and...
[read article]
Complementary and Alternative Medicine
Complementary Medicine Used More by Health Care Workers
U.S. health care providers use complementary, alternative medicine more than support workers
FRIDAY, Aug. 26 (HealthDay News) -- U.S. health care workers, especially health care providers, are more likely to use complementary and alternative medicine (CAM) than the general, employed U.S. population, according to a study published online Aug. 22 in Health Services Research.
Pamela Jo Johnson, M.P.H., Ph.D., from the Allina Hospitals and Clinics in Minneapolis, and colleagues examined the personal use of 36 types of CAM therapies among U.S. health care workers. Data were collected from the 2007 Alternative Health Supplement of the National Health Interview Survey. A nationally representative sample of 14,329 employed adults, including a subsample of 1,280 adults employed in hospitals or ambulatory care settings, were examined. Health care workers were divided into four categories: providers, technicians, support workers, and other occupations. The odds of CAM use in each category in the past year were assessed by multivariate logistic regression.
The investigators found that, compared to the general population, health care workers were more likely to use CAM (76 versus 63 percent). Health care workers were significantly more likely to use and self-treat with CAM compared with employees in other industries. Health care workers in ambulatory care were significantly more likely to have used CAM in the past year compared to those working in hospitals. Health care providers were more likely to have past-year practitioner-based CAM use and self-treatment with CAM compared to support workers (adjusted odds ratio, 2.2 and 2.7, respectively).
"This study provides the first population-based description of CAM use by U.S. health care workers. Our analyses reveal that, overall, health care workers are significantly more likely to use CAM therapies, particularly mind-body therapies, than the employed U.S. population," the authors write.
AbstractFull Text (subscription or payment may be required)
Last Updated: August 26, 2011
Copyright © 2011 HealthDay. All rights reserved.
For Your Reading Pleasure
Grand Rounds is a weekly summary of the best health blog posts on the Internet. Each week a different blogger takes turns hosting Grand Rounds, and summarizing the best submissions for the week.
This Week Hosted By; Suture for a Living
Thank you for coming to Grand Rounds 7:48, the weekly collection of the some of the best in online medical writing from all (doctors, nurses, patients, healthcare professionals). Next week’s will be hosted by Health 3.0 Blog.Along with the excellent posts, I’ve included pictures of the changes cameras have gone through over the years – from the pin-hole camera to digital phone cameras. Enjoy!
A Few Submissions below, read all entries here
Dr. Schattner, MedicalLessons, talks about what she has learned from the offbeat and in some ways disturbing story of a young woman who's made a business of having had a rare form of cancer, epithelioid hemangioendothelioma: Notes on Crazy Sexy Cancer
Carolyn is a heart attack survivor who blogs at HEART SISTERS. In her post, "How to be a good patient" , she shares her experiences and expertise she has gained in having a chronic illness.
Ryan, ACP Internist blog, looks at the recent trends in healthy lifestyle choices by adapting two recent studies (and adding a touch of humor): Smoking in front of the television must be really bad
Continue reading here
Maternal hepatitis B and hepatitis C carrier status influences perinatal outcomes
View all Updates Here
Maternal hepatitis B and hepatitis C carrier status influences perinatal outcomes
A study in the latest issue of Liver International investigates the influence of maternal hepatitis B and hepatitis C carrier status on perinatal outcomes.
Dr Laura Connell and colleagues from Florida, USA examined the association between maternal hepatitis B and C mono- and co-infections with singleton pregnancy outcomes in the state of Florida.
The research team analyzed all Florida births from 1998 to 2007 using birth certificate records linked to hospital discharge data.
The team's main outcomes of interest were selected pregnancy outcomes including preterm birth, low birth weight, small for gestational age, fetal distress, neonatal jaundice and congenital anomaly.
Women with Hep B were less likely to have infants born small gestational age
Liver International
The study sample consisted of 1,670,369 records. Human immunodeficiency virus co-infection and all forms of substance abuse were more frequent in mothers with hepatitis B and C infection.
The research team found that important socio-demographical variables and obstetric complications, women with hepatitis C infection were more likely to have infants born preterm, with low birth weight and congenital anomaly.
In addition, women with hepatitis B infection were less likely to have infants born small gestational age.
Dr Connell's team concluded, "Our findings provide further understanding of the association between maternal hepatitis B or C carrier status and perinatal outcomes."
"Infants born to women with hepatitis C infection appear to be at risk for poor birth outcomes, including preterm birth, low birth weight and congenital anomaly."
Liver Int 2011: 31(8): 1163–1170
29 August 2011
Maternal hepatitis B and hepatitis C carrier status influences perinatal outcomes
A study in the latest issue of Liver International investigates the influence of maternal hepatitis B and hepatitis C carrier status on perinatal outcomes.
Dr Laura Connell and colleagues from Florida, USA examined the association between maternal hepatitis B and C mono- and co-infections with singleton pregnancy outcomes in the state of Florida.
The research team analyzed all Florida births from 1998 to 2007 using birth certificate records linked to hospital discharge data.
The team's main outcomes of interest were selected pregnancy outcomes including preterm birth, low birth weight, small for gestational age, fetal distress, neonatal jaundice and congenital anomaly.
Women with Hep B were less likely to have infants born small gestational age
Liver International
The study sample consisted of 1,670,369 records. Human immunodeficiency virus co-infection and all forms of substance abuse were more frequent in mothers with hepatitis B and C infection.
The research team found that important socio-demographical variables and obstetric complications, women with hepatitis C infection were more likely to have infants born preterm, with low birth weight and congenital anomaly.
In addition, women with hepatitis B infection were less likely to have infants born small gestational age.
Dr Connell's team concluded, "Our findings provide further understanding of the association between maternal hepatitis B or C carrier status and perinatal outcomes."
"Infants born to women with hepatitis C infection appear to be at risk for poor birth outcomes, including preterm birth, low birth weight and congenital anomaly."
Liver Int 2011: 31(8): 1163–1170
29 August 2011
Thursday, August 25, 2011
Telaprevir (Incivek) / Boceprevir (Victrelis)- Adult Dosing & Uses
Complete Information @ Medscape
Hepatitis C Medication
Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC; Chief Editor: Julian Katz, MD
Overview
Presentation
DDx
Workup
Treatment
Medication
Follow-up
Telaprevir (Incivek)
Inhibits HCV NS3/4A protease needed for proteolytic cleavage of the HCV encoded polyprotein into mature forms. Indicated for treatment of chronic hepatitis C (CHC) genotype 1 infection in combination with peginterferon alfa and ribavirin. Indication is specifically for adults with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.
Adult Dosing & Uses
Dosing Forms & Strengths
tablet 375mg
Chronic Hepatitis C
Indicated for treatment of chronic hepatitis C (CHC) genotype 1 infection in combination with peginterferon alfa and ribavirin
Indication is specifically for adults with compensated liver disease, including cirrhosis, who are treatment-naïve or who have been previously treated with interferon-based treatment, including prior null responders, partial responders, and relapsers
750 mg PO TID (ie, q7-9hr) with food (not low fat)
Administer for 12 weeks in combination with peginterferon alfa and ribavirin (telaprevir must not be used as monotherapy)
Treatment Duration
Duration of treatment depends on HCV-RNA levels
Triple therapy: telaprevir, peginterferon alfa, and ribavirin
Dual therapy: peginterferon alfa and ribavirin
Treatment-naïve and prior relapse patients
HCV-RNA levels undetectable at weeks 4 and 12: Administer triple therapy first 12 weeks, then dual therapy an additional 12 weeks
HCV-RNA levels detectable at weeks 4 and 12 (ie, <1000 IU/mL): Administer triple therapy first 12 weeks, then dual therapy an additional 36 weeks
Prior partial and null responder patients
All patients: Administer triple therapy first 12 weeks, then dual therapy an additional 36 weeks
Treatment futility
Patients with inadequate viral response are unlikely to achieve sustained virologic response, and may develop treatment-emergent resistance substitutions
Discontinuation of therapy is recommended in all patients with either of the following circumstances:
HCV-RNA levels >1000 IU/mL at treatment weeks 4 or 12, OR
HCV-RNA levels detectable at treatment week 24
Renal or Hepatic Impairment
See peginterferon alfa and ribavirin monographs for recommended dose adjustments
Renal impairment
Mild, moderate, or severe: No dosage adjustment required
Has not been studied in patients with end-stage renal disease (ESRD) or on hemodialysis
Hepatic impairment
Moderate-to-severe (Child-Pugh B or C, score 7 or greater): Not recommended
Decompensated liver disease: Not recommended
Administration
Must be administered in combination with peginterferon alfa and ribavirin
If peginterferon alfa or ribavirin is discontinued for any reason, telaprevir must also be discontinued
To prevent treatment failure, dose must not be reduced or interrupted
Administer with a meal or snack (not low fat)
Also View;
Drug Interactions
Adverse Effects
Contraindications & Cautions
Pregnancy & Lactation
Pharmacology
Boceprevir (Victrelis)
Inhibits HCV NS3/4A protease needed for proteolytic cleavage of the HCV encoded polyprotein into mature forms. Indicated for treatment of chronic hepatitis C (CHC) genotype 1 infection in combination with peginterferon alfa and ribavirin. Indication is specifically for adults with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.
Adult Dosing & Uses
Dosing Forms & Strengths
capsule 200mg
Chronic Hepatitis C
Indicated for treatment of chronic hepatitis C (CHC) genotype 1 infection in combination with peginterferon alfa and ribavirin
Indication is specifically for adults with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy
Initiate therapy with peginterferon alfa and ribavirin for 4 weeks, THEN
Add boceprevir 800 mg PO TID (ie, q7-9hr) with food
Treatment duration
Duration of treatment depends on HCV-RNA levels at treatment weeks 8, 12, and 24
HCV-RNA levels at 8 weeks
Previously untreated and HCV-RNA levels undetectable: Complete 3-medication regimen at week 28
Previously untreated and HCV-RNA levels detectable: Continue 3 medication regimen through week 36, then continue peginterferon alfa and ribavirin through week 48
Partial responders or relapsed and HCV-RNA levels undetectable: Complete 3-medication regimen at week 36
Partial responders or relapsed and HCV-RNA levels detectable: Continue 3 medication regimen through week 36, then continue peginterferon alfa and ribavirin through week 48
HCV-RNA levels at 12 weeks
Response-guided therapy was not studied in individuals who had less than a 2-log10 HCV-RNA decline by treatment week 12 during prior therapy with peginterferon alfa and ribavirin
If considered for treatment, these patients should receive peginterferon alfa and ribavirin x4 weeks followed by boceprevir x44 weeks in combination with peginterferon alfa and ribavirin
In addition, consideration should be given to treating previously untreated patients who are poorly interferon responsive (as determined at TW 4) with 4 weeks peginterferon alfa and ribavirin followed by boceprevir x44 weeks in combination with peginterferon alfa and ribavirin in order to maximize rates of a sustained virologic response
HCV-RNA levels at 24 weeks
If HCV-RNA levels are undetectable at treatment week 24, continue with treatment regiment identified at week 8
Treatment futility
Discontinuation of therapy is recommended in all patients with either of the following circumstances:
If HCV-RNA levels 100 IU/mL or greater at week 12, discontinue 3-medication regimen, OR
If confirmed, detectable HCV-RNA levels at week 24, discontinue 3-medication regimen
Compensated cirrhosis
Peginterferon alfa and ribavirin x 4 weeks followed by boceprevir x44 weeks in combination with peginterferon alfa and ribavirin
Renal or Hepatic Impairment
No dose adjustment for boceprevir is required
See peginterferon alfa and ribavirin monographs for recommended dose adjustments
Administration
Must be administered in combination with peginterferon alfa and ribavirin
Administer with a meal or light snack
AlsoView;
Drug Interactions
Adverse Effects
Contraindications & Cautions
Pregnancy & Lactation
Pharmacology
View full drug information Interferon alfa-2b (Intron-A)
Protein product manufactured by recombinant DNA technology. Modulation of host immune response may play important roles in the treatment of viral diseases.
View full drug information Interferon alfacon 1 (Infergen)
Protein product manufactured by recombinant DNA technology. Modulation of host immune response may play important roles in the treatment of viral diseases.
Synthesized by combining most common amino acid sequences from all 12 naturally occurring IFNs.
View full drug information Peginterferon alfa 2b (PEG-Intron)
Consists of IFN alfa-2b attached to a single 12-kd PEG chain. Excreted by kidneys. Has sustained absorption, slower rate of clearance, and longer half-life than unmodified IFN. Permits more convenient once-weekly dosing. Significantly improves quality of life for patients.
View full drug information Pegylated interferon alfa-2a (Pegasys)
Consists of IFN alfa-2a attached to a 40-kd branched PEG molecule. Predominantly metabolized by liver.
View full drug information Ribavirin (Rebetol)
Antiviral nucleoside analog. Chemical name is D -ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. Given alone, has little effect on course of hepatitis C. Given with IFN, significantly augments SVR rate.
Hepatitis C Medication
Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC; Chief Editor: Julian Katz, MD
Overview
Presentation
DDx
Workup
Treatment
Medication
Follow-up
Telaprevir (Incivek)
Inhibits HCV NS3/4A protease needed for proteolytic cleavage of the HCV encoded polyprotein into mature forms. Indicated for treatment of chronic hepatitis C (CHC) genotype 1 infection in combination with peginterferon alfa and ribavirin. Indication is specifically for adults with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.
Adult Dosing & Uses
Dosing Forms & Strengths
tablet 375mg
Chronic Hepatitis C
Indicated for treatment of chronic hepatitis C (CHC) genotype 1 infection in combination with peginterferon alfa and ribavirin
Indication is specifically for adults with compensated liver disease, including cirrhosis, who are treatment-naïve or who have been previously treated with interferon-based treatment, including prior null responders, partial responders, and relapsers
750 mg PO TID (ie, q7-9hr) with food (not low fat)
Administer for 12 weeks in combination with peginterferon alfa and ribavirin (telaprevir must not be used as monotherapy)
Treatment Duration
Duration of treatment depends on HCV-RNA levels
Triple therapy: telaprevir, peginterferon alfa, and ribavirin
Dual therapy: peginterferon alfa and ribavirin
Treatment-naïve and prior relapse patients
HCV-RNA levels undetectable at weeks 4 and 12: Administer triple therapy first 12 weeks, then dual therapy an additional 12 weeks
HCV-RNA levels detectable at weeks 4 and 12 (ie, <1000 IU/mL): Administer triple therapy first 12 weeks, then dual therapy an additional 36 weeks
Prior partial and null responder patients
All patients: Administer triple therapy first 12 weeks, then dual therapy an additional 36 weeks
Treatment futility
Patients with inadequate viral response are unlikely to achieve sustained virologic response, and may develop treatment-emergent resistance substitutions
Discontinuation of therapy is recommended in all patients with either of the following circumstances:
HCV-RNA levels >1000 IU/mL at treatment weeks 4 or 12, OR
HCV-RNA levels detectable at treatment week 24
Renal or Hepatic Impairment
See peginterferon alfa and ribavirin monographs for recommended dose adjustments
Renal impairment
Mild, moderate, or severe: No dosage adjustment required
Has not been studied in patients with end-stage renal disease (ESRD) or on hemodialysis
Hepatic impairment
Moderate-to-severe (Child-Pugh B or C, score 7 or greater): Not recommended
Decompensated liver disease: Not recommended
Administration
Must be administered in combination with peginterferon alfa and ribavirin
If peginterferon alfa or ribavirin is discontinued for any reason, telaprevir must also be discontinued
To prevent treatment failure, dose must not be reduced or interrupted
Administer with a meal or snack (not low fat)
Also View;
Drug Interactions
Adverse Effects
Contraindications & Cautions
Pregnancy & Lactation
Pharmacology
Boceprevir (Victrelis)
Inhibits HCV NS3/4A protease needed for proteolytic cleavage of the HCV encoded polyprotein into mature forms. Indicated for treatment of chronic hepatitis C (CHC) genotype 1 infection in combination with peginterferon alfa and ribavirin. Indication is specifically for adults with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.
Adult Dosing & Uses
Dosing Forms & Strengths
capsule 200mg
Chronic Hepatitis C
Indicated for treatment of chronic hepatitis C (CHC) genotype 1 infection in combination with peginterferon alfa and ribavirin
Indication is specifically for adults with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy
Initiate therapy with peginterferon alfa and ribavirin for 4 weeks, THEN
Add boceprevir 800 mg PO TID (ie, q7-9hr) with food
Treatment duration
Duration of treatment depends on HCV-RNA levels at treatment weeks 8, 12, and 24
HCV-RNA levels at 8 weeks
Previously untreated and HCV-RNA levels undetectable: Complete 3-medication regimen at week 28
Previously untreated and HCV-RNA levels detectable: Continue 3 medication regimen through week 36, then continue peginterferon alfa and ribavirin through week 48
Partial responders or relapsed and HCV-RNA levels undetectable: Complete 3-medication regimen at week 36
Partial responders or relapsed and HCV-RNA levels detectable: Continue 3 medication regimen through week 36, then continue peginterferon alfa and ribavirin through week 48
HCV-RNA levels at 12 weeks
Response-guided therapy was not studied in individuals who had less than a 2-log10 HCV-RNA decline by treatment week 12 during prior therapy with peginterferon alfa and ribavirin
If considered for treatment, these patients should receive peginterferon alfa and ribavirin x4 weeks followed by boceprevir x44 weeks in combination with peginterferon alfa and ribavirin
In addition, consideration should be given to treating previously untreated patients who are poorly interferon responsive (as determined at TW 4) with 4 weeks peginterferon alfa and ribavirin followed by boceprevir x44 weeks in combination with peginterferon alfa and ribavirin in order to maximize rates of a sustained virologic response
HCV-RNA levels at 24 weeks
If HCV-RNA levels are undetectable at treatment week 24, continue with treatment regiment identified at week 8
Treatment futility
Discontinuation of therapy is recommended in all patients with either of the following circumstances:
If HCV-RNA levels 100 IU/mL or greater at week 12, discontinue 3-medication regimen, OR
If confirmed, detectable HCV-RNA levels at week 24, discontinue 3-medication regimen
Compensated cirrhosis
Peginterferon alfa and ribavirin x 4 weeks followed by boceprevir x44 weeks in combination with peginterferon alfa and ribavirin
Renal or Hepatic Impairment
No dose adjustment for boceprevir is required
See peginterferon alfa and ribavirin monographs for recommended dose adjustments
Administration
Must be administered in combination with peginterferon alfa and ribavirin
Administer with a meal or light snack
AlsoView;
Drug Interactions
Adverse Effects
Contraindications & Cautions
Pregnancy & Lactation
Pharmacology
View full drug information Interferon alfa-2b (Intron-A)
Protein product manufactured by recombinant DNA technology. Modulation of host immune response may play important roles in the treatment of viral diseases.
View full drug information Interferon alfacon 1 (Infergen)
Protein product manufactured by recombinant DNA technology. Modulation of host immune response may play important roles in the treatment of viral diseases.
Synthesized by combining most common amino acid sequences from all 12 naturally occurring IFNs.
View full drug information Peginterferon alfa 2b (PEG-Intron)
Consists of IFN alfa-2b attached to a single 12-kd PEG chain. Excreted by kidneys. Has sustained absorption, slower rate of clearance, and longer half-life than unmodified IFN. Permits more convenient once-weekly dosing. Significantly improves quality of life for patients.
View full drug information Pegylated interferon alfa-2a (Pegasys)
Consists of IFN alfa-2a attached to a 40-kd branched PEG molecule. Predominantly metabolized by liver.
View full drug information Ribavirin (Rebetol)
Antiviral nucleoside analog. Chemical name is D -ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. Given alone, has little effect on course of hepatitis C. Given with IFN, significantly augments SVR rate.
HCV Resistance Testing - Launch of HCV GenoSure
Related;Hepatitis C-New Protease Inhibitor (NS3/4A) Drug Resistance Test
08/25/2011 09:05 am
LABORATORY AMER :
LabCorp Introduces HCV Resistance Testing through Monogram Biosciences with the Launch of HCV GenoSure® NS3/4A
Laboratory Corporation of America® Holdings (LabCorp®) (NYSE: LH) announced today the nationwide availability of a nucleic acid sequencing assay that reports NS3 and NS4A mutations and NS3 associated resistance to the recently approved hepatitis C virus (HCV) protease inhibitors, adding to LabCorp's suite of HCV testing. Identification of certain mutations may be useful to clinicians considering patient treatment decisions.
"HCV GenoSure NS3/4A represents the first in a series of HCV drug resistance assays that have been developed at Monogram Biosciences to support the clinical evaluation of HCV direct-acting antiviral (DAA) agents and their use in the management of HCV infection," commented Chris Petropoulos, PhD, LabCorp's Vice President of Monogram Research & Development. "We look forward to expanding our broad HCV assay portfolio to support the development and clinical application of additional DAA agents that target other distinct steps in the HCV replication cycle."
HCV GenoSure NS3/4A is currently available exclusively through LabCorp and its Monogram Biosciences Center of Excellence. The test is available for commercial use as well as clinical trial use. Monogram is an established leader in anti-viral drug resistance with 15 years experience in virology and infectious disease testing.
An estimated 3.2 million people in the United States and up to 170 million people worldwide are infected by HCV. Since 2002, the standard of care for HCV infection in the US has been treatment with pegylated ?-interferon and ribavirin. In May 2011, the FDA approved the first two DAA agents, boceprevir (Victrelis?, Merck & Co) and telaprevir (Incivek?, Vertex Pharmaceuticals). Either agent is used in combination with pegylated ?-interferon and ribavirin for the treatment of HCV genotype 1 infection. During clinical trials conducted to support regulatory approval, HCV variants containing mutations that confer reduced susceptibility to boceprevir and telaprevir emerged in patients who experienced sub-optimal treatment response.
HCV GenoSure NS3/4A analyzes the genetic sequence for the non-structural proteins NS3 and NS4A of HCV genotypes 1a and 1b that encode for an enzyme essential to viral replication. The assay detects mutations in NS3 and NS4A and specifically identifies those associated with boceprevir and telaprevir resistance.
Recommendations recently developed by the HCV Drug Resistance Advisory Group emphasize the value of resistance testing at treatment baseline and failure in support of the development and clinical evaluation of new drug candidates. In HIV, the routine use of resistance testing to guide antiviral drug treatment is established in clinical practice. In response to the recent and future availability of DAA agents, some experts anticipate that drug resistance testing will provide similar value to the clinical management of HCV infection.
About LabCorp®
Laboratory Corporation of America® Holdings, an S&P 500 company, is a pioneer in commercializing new diagnostic technologies and the first in its industry to embrace genomic testing. With annual revenues of $5.0 billion in 2010, over 31,000 employees worldwide, and more than 220,000 clients, LabCorp offers a broad test menu ranging from routine blood analyses to reproductive genetics to DNA sequencing. LabCorp furthers its scientific expertise and innovative clinical testing technology with its Centers of Excellence: The Center for Molecular Biology and Pathology, National Genetics Institute, ViroMed Laboratories, Inc., The Center for Esoteric Testing, Litholink Corporation, Genzyme GeneticsSM*, DIANON Systems, Inc., US LABS, Monogram Biosciences, Inc., and Esoterix and its Colorado Coagulation, Endocrine Sciences, and Cytometry Associates laboratories. LabCorp conducts clinical trials testing through its Esoterix Clinical Trials Services division. LabCorp clients include physicians, government agencies, managed care organizations, hospitals, clinical labs, and pharmaceutical companies. To learn more about our organization, visit our Web site at: www.labcorp.com.
*Genzyme Genetics and its logo are trademarks of Genzyme Corporation and used by Esoterix Genetic Laboratories, LLC, a wholly-owned subsidiary of LabCorp, under license. Esoterix Genetic Laboratories and LabCorp are operated independently from Genzyme Corporation.
This press release contains forward-looking statements. Each of the forward-looking statements is subject to change based on various important factors, including without limitation, competitive actions in the marketplace and adverse actions of governmental and other third-party payors. Actual results could differ materially from those suggested by these forward-looking statements. Further information on potential factors that could affect LabCorp's financial results is included in the Company's Form 10-K for the year ended December 31, 2010, and subsequent SEC filings.
Laboratory Corporation of America® Holdings (LabCorp®)
Investor/Media Contact:
Stephen Anderson, 336-436-5274
Company Information: www.labcorp.com
08/25/2011 09:05 am
LABORATORY AMER :
LabCorp Introduces HCV Resistance Testing through Monogram Biosciences with the Launch of HCV GenoSure® NS3/4A
Laboratory Corporation of America® Holdings (LabCorp®) (NYSE: LH) announced today the nationwide availability of a nucleic acid sequencing assay that reports NS3 and NS4A mutations and NS3 associated resistance to the recently approved hepatitis C virus (HCV) protease inhibitors, adding to LabCorp's suite of HCV testing. Identification of certain mutations may be useful to clinicians considering patient treatment decisions.
"HCV GenoSure NS3/4A represents the first in a series of HCV drug resistance assays that have been developed at Monogram Biosciences to support the clinical evaluation of HCV direct-acting antiviral (DAA) agents and their use in the management of HCV infection," commented Chris Petropoulos, PhD, LabCorp's Vice President of Monogram Research & Development. "We look forward to expanding our broad HCV assay portfolio to support the development and clinical application of additional DAA agents that target other distinct steps in the HCV replication cycle."
HCV GenoSure NS3/4A is currently available exclusively through LabCorp and its Monogram Biosciences Center of Excellence. The test is available for commercial use as well as clinical trial use. Monogram is an established leader in anti-viral drug resistance with 15 years experience in virology and infectious disease testing.
An estimated 3.2 million people in the United States and up to 170 million people worldwide are infected by HCV. Since 2002, the standard of care for HCV infection in the US has been treatment with pegylated ?-interferon and ribavirin. In May 2011, the FDA approved the first two DAA agents, boceprevir (Victrelis?, Merck & Co) and telaprevir (Incivek?, Vertex Pharmaceuticals). Either agent is used in combination with pegylated ?-interferon and ribavirin for the treatment of HCV genotype 1 infection. During clinical trials conducted to support regulatory approval, HCV variants containing mutations that confer reduced susceptibility to boceprevir and telaprevir emerged in patients who experienced sub-optimal treatment response.
HCV GenoSure NS3/4A analyzes the genetic sequence for the non-structural proteins NS3 and NS4A of HCV genotypes 1a and 1b that encode for an enzyme essential to viral replication. The assay detects mutations in NS3 and NS4A and specifically identifies those associated with boceprevir and telaprevir resistance.
Recommendations recently developed by the HCV Drug Resistance Advisory Group emphasize the value of resistance testing at treatment baseline and failure in support of the development and clinical evaluation of new drug candidates. In HIV, the routine use of resistance testing to guide antiviral drug treatment is established in clinical practice. In response to the recent and future availability of DAA agents, some experts anticipate that drug resistance testing will provide similar value to the clinical management of HCV infection.
About LabCorp®
Laboratory Corporation of America® Holdings, an S&P 500 company, is a pioneer in commercializing new diagnostic technologies and the first in its industry to embrace genomic testing. With annual revenues of $5.0 billion in 2010, over 31,000 employees worldwide, and more than 220,000 clients, LabCorp offers a broad test menu ranging from routine blood analyses to reproductive genetics to DNA sequencing. LabCorp furthers its scientific expertise and innovative clinical testing technology with its Centers of Excellence: The Center for Molecular Biology and Pathology, National Genetics Institute, ViroMed Laboratories, Inc., The Center for Esoteric Testing, Litholink Corporation, Genzyme GeneticsSM*, DIANON Systems, Inc., US LABS, Monogram Biosciences, Inc., and Esoterix and its Colorado Coagulation, Endocrine Sciences, and Cytometry Associates laboratories. LabCorp conducts clinical trials testing through its Esoterix Clinical Trials Services division. LabCorp clients include physicians, government agencies, managed care organizations, hospitals, clinical labs, and pharmaceutical companies. To learn more about our organization, visit our Web site at: www.labcorp.com.
*Genzyme Genetics and its logo are trademarks of Genzyme Corporation and used by Esoterix Genetic Laboratories, LLC, a wholly-owned subsidiary of LabCorp, under license. Esoterix Genetic Laboratories and LabCorp are operated independently from Genzyme Corporation.
This press release contains forward-looking statements. Each of the forward-looking statements is subject to change based on various important factors, including without limitation, competitive actions in the marketplace and adverse actions of governmental and other third-party payors. Actual results could differ materially from those suggested by these forward-looking statements. Further information on potential factors that could affect LabCorp's financial results is included in the Company's Form 10-K for the year ended December 31, 2010, and subsequent SEC filings.
Laboratory Corporation of America® Holdings (LabCorp®)
Investor/Media Contact:
Stephen Anderson, 336-436-5274
Company Information: www.labcorp.com
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