Hello folks, hope everyone enjoyed a lovely fall weekend. Autumn for me is bittersweet, it's the season I completed treatment. I still remember walking in the woods with the leaves crunching underfoot, my mind racing with each step, knowing the virus was gone. In 2000 the regimen of drugs were unbearable, with less then a desirable chance of reaching SVR.
These days we dare to dream of an interferon free combination to treat hepatitis C. Could it happen? Enter; an all oral regimen, consisting of a few pills, a better cure rate, and less side effects. This month brought exciting news from Pharmasset on PSI-7977, if you missed the update you may want to read up @ The Haystack;
Two HCV Meds are Better than One for Pharmasset .
According to the news this morning over at
TheStreet Roche is hoping to achieve an all oral regimen of its own folks, by buying the pharmaceutical company Anadys, check it out.
SAN DIEGO (TheStreet) -- Roche is buying Anadys Pharmaeuticals for $230 million to bolster its pipeline of experimental hepatitis C drugs, the company said Monday.
By acquiring Anadys, Roche hopes to develop safer, convenient and all-oral treatments for hepatitis C that do not the use of injectable interferon -- a goal shared by all of the major drug makers pursuing new hepatitis C therapies. Continue reading
More from
Adam Feuerstein, TheStreet Senior Columnis
t published @ Fidelity
Roche's All-Oral Hep C Therapy Could Be First, Not Best, to Reach Market
Roche's purchase of Anadys provides the third drug in what may be the first all-oral hepatits C regimen to start late-stage trials.
By Adam Feuerstein, TheStreet Senior Columnist THESTREET.COM — 25 MINUTES AGO
BOSTON (TheStreet (Symbol : TST
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) purchase of Anadys likely provides the third drug in what might be the first (but not necessarily best) all-oral, interferon-free therapy for hepatitis C to begin phase III studies.
Being first to market with an all-oral Hep C therapy is important to Roche (Symbol : RHHVF
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) because the company has a lot to lose by lagging behind. Roche (Symbol : RHHVF
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) sells Pegasys, the leading interferon used to treat hepatitis C today, with sales of 1.1 billion Swiss francs through the first nine months of the year. Roche (Symbol : RHHVF
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) executives aren't stupid; they look ahead a few years and see Pegasys sales going away, similar to the patent cliffs hitting other Big Pharma drug blockbusters. If Roche (Symbol : RHHVF
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) wants to maintain or grow its Hep C franchise, it has to figure out a way to develop an all-oral (interferon-free) therapy -- and fast.
One way of doing this is by acquiring or partnering Hep C drugs others consider to be weak or non-competitive on their own. That description fits Anadys' lead drug setrobuvir, which for $230 million, Roche (Symbol : RHHVF
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) is acquiring at a relatively low price.
InterMune's (Symbol : ITMN
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) danoprevir, which Roche (Symbol : RHHVF | |
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) acquired last year, is also seen as a weak Hep C drug.
Roche (Symbol : RHHVF
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) could start relatively quickly a phase III study against Hep C that combines three oral drugs -- setrobuvir (from Anadys), RG7128 (partnered with Pharmasset (Symbol : VRUS
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)) and Merck's currently approved Hep C drug Victrelis, predicts Brian Skorney, biotech analyst at Brean Murray, Carret & Co. Roche (Symbol : RHHVF | |
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Another potential Roche (Symbol : RHHVF
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) all-oral regimen could include setrobuvir, RG7128 and danoprevir (acquired from InterMune (Symbol : ITMN
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These Roche (Symbol : RHHVF
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) triple combinations may require longer 24-week dosing (instead of faster 8 or 12 week dosing) and may not be as potent or effective as all-oral regimens being developed by Pharmasset (Symbol : VRUS
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) and others, but Roche (Symbol : RHHVF
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) may figure that being first is more important than being best, adds Skorney... Continue Reading
Also In The News This October Monday Letters are in the mail to almost 7,000 people who had procedures at an Ottawa medical facility to warn them they may have been exposed to hepatitis B, hepatitis C and HIV.
Ottawa's chief medical officer Dr. Isra Levy announced Saturday that Ottawa Public Health has been
investigating an unnamed non-hospital facility for the past several months because of "lapses in infection control" that may have led to some 6,800 people being exposed.
Many Children Suffer From Hepatitis C Without Diagnosis And TreatmentMany Children Suffer From Hepatitis C Without Diagnosis And Treatment. Many children with hepatitis C go undiagnosed and untreated, which can cord to unbending liver impair later in life, a new study warns. Researchers from the University of Miami Miller School of Medicine well-known that national data shows that between 0,2 percent and 0,4 percent
continue reading..A Doctor For Legalization, But Against Medical Marijuana
By Lindsay BeyersteinSkylandia, a doctor and guest blogger at the feminist Echnide of the Snakes,
argues for marijuana legalization and against medical marijuana.
As a physician who practices evidence-based medicine, Skylandia is committed to prescribing based on research, not anecdotes. Yet, she faces a Catch-22: Since marijuana is a Schedule I drug, there there's a dearth of research on its safety and efficacy for most of the conditions that it is recommended for....continue reading..
FDA
By Lori Clapper, Editor
This year, the FDA says it has seen an improved quality of new drug submissions, having approved several scientific breakthroughs, including the first new treatment for Lupus in 50 years, two new therapies for Hepatitis C, and the first drug shown to be an effective treatment for Melanoma.
However, the agency is concerned with the low quantity of submissions. Investors spent nearly $95 billion for R&D in 2010 alone, and this money has not translated into a parallel increase in submissions. In fact, last year the agency received the lowest number of applications for novel drugs in nearly two decades. No single cause can be blamed for this slump in innovation, but the global economy, more complex science and products, and product safety and efficacy are all contributing factors. .. continue reading..
ResearchRisk factors associated with symptomatic cholelithiasis in Taiwan: a population-based studyShih-Chang Hung , Kuan-Fu Liao , Shih-Wei Lai , Chia-Ing Li and Wen-Chi Chen
BMC Gastroenterology 2011, 11:111doi:10.1186/1471-230X-11-111
Published:
17 October 2011
The risk factors for Gallstones were obesity, hyperlipidemia, hepatitis B infection, hepatitis C infection, and cirrhosis in both genders, and menopause in females.
Abstract (provisional)
Background
Cholelithiasis has become a major health problem in Taiwan. The predominant type of gallstone found in Asian populations differs from that in the West, indicating possible differences in the etiology and risk factors for cholelithiasis. The aim of this study is to investigate the risk factors for cholelithiasis using data representative of the general population.
Methods
We performed a population-based, case-control study in which we analyzed medical data for 3725 patients newly diagnosed with cholelithiasis and 11175 gender- and age-matched controls with no history of cholelithiasis, using information obtained from the 2005 Registry for Beneficiaries of the National Health Insurance Research Database. Coexisting medical conditions were included in the analysis. Relative risks were estimated by adjusted odds ratio (OR) and 95% confidence interval (CI) using a multivariate logistic regression analysis.
Results
After controlling for the other covariates, multivariate logistic regression analysis identified the following as risk factors for cholelithiasis (in descending order of contribution): Among all patients - hepatitis C (OR=2.78), cirrhosis (OR=2.47), hepatitis B (OR=2.00), obesity (OR=1.89), and hyperlipidemia (OR=1.54); Among women - hepatitis C (OR=3.05), cirrhosis (OR=1.92), obesity (OR=1.91), menopause (OR=1.61), hepatitis B (OR=1.54), and hyperlipidemia (OR=1.49). Diabetes mellitus appeared to have a marked influence on the development of cholelithiasis but was not identified as a significant independent risk factor for cholelithiasis.
Conclusions
The risk factors for cholelithiasis were obesity, hyperlipidemia, hepatitis B infection, hepatitis C infection, and cirrhosis in both genders, and menopause in females. Despite differences in the predominate type of gallstone in Asian versus Western populations, we identified no unique risk factors among the population of Taiwan.
The complete article is available as a
provisional PDF.
Targeting STAT3 in hepatocellular carcinoma: Sorafenib again… published online 28 June 2011.
See Article, pages 1041–1048
Article Outline
Sorafenib is the first drug of proved clinical efficacy on hepatocellular carcinoma (HCC) as it provides a modest but significant increase in survival rate in patients with advanced HCC
[1]. Initially developed as a Raf-1 kinase inhibitor, sorafenib also targets other Raf kinase isoforms (wild-type B-Raf and oncogenic B-Raf V600) and receptor tyrosine kinases such as vascular endothelial growth factor receptors (VEGFR-2 and -3), platelet-derived growth factor-β (PDGFR-β), Flt-3, and c-Kit. More recently, the BCR/ABL kinase has been also identified as a sorafenib target
[2]. The broad spectrum of actions of sorafenib against kinases involved in neovascularisation and tumor progression is supposed to contribute to its potent activity towards tumor angiogenesis and tumor growth in a variety of tumors including HCC
[3]. Accordingly,
in vitro and
in vivo studies have shown that sorafenib promotes antiproliferative and proapoptotic effects in tumor cells as well as in endothelial cells. However, it appears that the molecular mechanisms underlying the direct effects of sorafenib in these cells are not completely understood and they probably involve additional pathways.
Consistent with its inhibitory activity towards Raf kinases, sorafenib impairs the ERK signaling pathway in diverse tumor cell types and this effect has been linked to the antiproliferative action of sorafenib. However, there are also substantial data showing that sorafenib antiproliferative activity does not fully correlate with the inhibition of ERK phosphorylation and with the downregulation of cyclin D1. This discrepancy was observed in different tumor cell types including HCC cells [4], [5], [6]. Regarding apoptosis, sorafenib treatment is frequently associated with the downregulation of the anti-apoptotic Bcl-2 family member Mcl-1 and survivin. Several studies have shown that Mcl-1 and survivin downregulation occurs through a MEK/ERK-independent mechanism [7], [8], [9]. As compelling data continue to accumulate, it now appears that STAT3 inhibition may be responsible for the ERK-independent effects of sorafenib.
STAT3 (for Signal Transducer and Activator of Transcription 3) represents a key transducer in signaling pathways involved in the injury-inflammation-regeneration response associated with chronic liver diseases and human HCC development [10]. STAT3 is inactive in non-stimulated cells but is rapidly activated by various cytokines and growth factors such as interleukin-6 (IL-6), epidermal growth factor (EGF) family members or hepatocyte growth factor and acts as a nuclear transcription factor. STAT3 activation requires Tyr705 phosphorylation by different kinases such as Janus kinases, Src, EGFR, or MEK kinase 1, which results in STAT3 dimerization, nuclear translocation, DNA binding, and gene transcription. STAT3-stimulated genes promote angiogenesis, proliferation, and survival and include genes coding for cyclin D1, Mcl-1 and survivin. STAT3 activation also turns on strong negative feedback loops involving tyrosine phosphatases (SHP1 and SHP2) and suppressors of cytokine signaling (SOCS). By reducing the levels of phospho-STAT3, phosphatases block STAT3 dimerization and transcriptional activity, thus insuring that STAT3 activation is a transient event in normal cells.
STAT3 is constitutively activated (i.e. phosphorylated) in most cancers, including 60% of HCC as a result of inflammation, oxidative stress, growth factor stimulation, epigenetic silencing of SOCS, and low expression levels of phosphatases [10]. IL-6 and STAT3 are required for tumorigenesis in the mouse liver. IL-6- or STAT3-deficient mice exhibit a marked reduction of diethylnitrosamine (DEN)-induced liver carcinogenesis in comparison to wild-type mice [11], [12]. SHP2 ablation enhances DEN-induced HCC development which is abolished by concurrent deletion of SHP2 and STAT3 in hepatocytes [13].
It has been recently observed that sorafenib inhibits Tyr705 STAT3 phosphorylation in a variety of tumor cells including medulloblastoma [5], cholangiocarcinoma [14], and HCC [15]. The inhibition of STAT3 signaling and the subsequent downregulation of Mcl-1 play a prominent role in sorafenib-induction of apoptosis in these cells. The mechanism whereby sorafenib prevents STAT3 activation has been addressed by Gores’s laboratory in cholangiocarcinoma cells [14]. Their study showed that sorafenib promotes Tyr705 STAT3 dephosphorylation by stimulating phosphatase SHP2 activity since the knockdown of SHP2 using siRNA technology abrogated sorafenib-stimulated Tyr705 STAT3 dephosphorylation. As the Raf kinase inhibitor ZM336372 also resulted in Tyr705 STAT3 dephosphorylation, this result led the authors to conclude that sorafenib promotes Tyr705 STAT3 dephosphorylation by inhibiting Raf-1 kinase activity in cholangiocarcinoma.
In the present issue of the Journal of Hepatology [16], the study by Tai and colleagues provides new insights regarding the mechanism whereby sorafenib affects STAT3 activity in HCC cells. The authors have developed a series of sorafenib analogs whose characteristics are reported elsewhere [17]. Among them, SC-1 is a sorafenib derivative lacking inhibitory activity towards Raf-1 and VEGFR-2 kinases. Interestingly, SC-1 was as potent as sorafenib in the inhibition of cell viability and the induction of apoptosis in vitro in human HCC cell lines and endothelial cells. Antiproliferative and proapoptotic effects of SC-1 and sorafenib were both associated with a marked decrease of STAT3 phosphorylation and transcriptional activity and the downregulation of Mcl-1, cyclin D1, and survivin. The antitumoral effect of SC-1 was confirmed in vivo by using a subcutaneous xenograft model of HCC into nude mice and was comparable to that obtained with sorafenib. Based on these results, these authors propose that sorafenib mediates cell growth arrest and apoptosis through a Raf-1- and VEGFR2-independent mechanism in HCC and endothelial cells and that STAT3 dephosphorylation is a major signaling event involved in these effects. Further support for this contention was obtained with experiments showing that Raf-1 silencing with small interference RNA had no impact on SC-1 and sorafenib repression of Tyr705 STAT3 phosphorylation. Rather, the authors report that SC-1 and sorafenib potently stimulated in vitro and in vivo the activity of the phosphatase SHP1, probably through direct binding to the phosphatase. SHP1 activation was required for SC-1 and sorafenib induction of apoptosis and STAT3 dephosphorylation.
This study therefore highlights the major contribution of STAT3 in sorafenib-mediated antitumoral effects on HCC cells and demonstrates that Raf-1 and VEGFR2, the main classical targets of this drug, seem paradoxically to play a negligible role (Fig. 1). In addition, this study reinforces the necessity of testing inactive analogs -when available- to precise the main (and true) molecular mechanisms of antitumoral activity of new pharmacological compounds (as another example, LY303511, the “inactive analog” of the widely used phosphatidylinositide-3-kinase inhibitor LY294002, presents an antitumoral activity by itself [18]). This paper raises also important questions. It is still unclear whether SC-1 has no kinase inhibition activity or if it still maintains some inhibitory effects on other sorafenib targets such as Raf isoforms and PDGFR-β. The present study was largely conducted in vitro and the subcutaneous xenograft model has some limitations regarding the contribution of the immune system and the tumor microenvironment to HCC development. It is not excluded that SC-1 and sorafenib may present some different effects in vivo, in particular on tumor angiogenesis.
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Fig. 1.
Role of STAT3 inibition in sorafenib-mediated antitumoral effects. In cancer cells, STAT3 can be activated by overactive receptor (such as IL-6R and EGFR) and constitutively active non-receptor tyrosine kinases (such as Src and ABL). After tyrosine phosphorylation on residue 705, STAT3 molecules dimerize and translocate to the nucleus, where they directly regulate the expression of genes involved in proliferation, survival, and angiogenesis. In HCC and endothelial cells, sorafenib is a very potent inhibitor of STAT3 phosphorylation which plays a major role in sorafenib-mediated antitumoral effects. This effect involves the direct activation of the tyrosine phosphatase SHP1 and is independent of Raf-1 and VEGF-R2 inhibition since it is mimicked by SC-1, a sorafenib analog devoided of inhibitory activity towards these two kinases.
This paper clearly reinforces the interest of STAT3 as a new potential therapeutic approach for HCC. Indeed, studies using STAT3 inhibitors show that STAT3 is not required for the survival of differentiated cells and may be therefore targeted in human cancers. Different STAT3 inhibitors have been designated to directly target STAT3 mainly by inhibiting its dimerization, DNA binding, or nuclear entry [19], [20]. However, of these inhibitors, a few show good activity in terms of inhibition of STAT3 biological functions and associated antitumor effects in murine models. The need remains therefore high for suitable and effective STAT3 inhibitors for clinical application in cancer. The ultimate and obvious question is how well (and how long) patients will respond to specific STAT3 inhibitors.
Conflict of interest
The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
References
Largest Ever Genetic Study of Liver Function Could Point the Way to New Treatments ScienceDaily (Oct. 16, 2011) — Researchers have identified a large number of areas in the human genetic code that are involved in regulating the way in which the liver functions, in a new study of over 61,000 people, published October 14 in the journal Nature Genetics.The work is an international collaboration led by Imperial College London and it identifies 42 genetic regions associated with liver function, 32 of which had not been linked to liver function before. The work should lead to a better understanding of precisely what goes wrong when the liver ceases to work normally. Ultimately, it could point the way to new treatments that can improve the function of the liver and help to prevent liver damage.
The liver is the body's largest internal organ and the British Liver Trust estimates that around two million people in the UK have a liver problem at any one time. The liver carries out hundreds of different tasks, including making proteins and blood clotting factors, and helping with digestion and energy release. It also purifies the blood of bacteria, and of the by-products of digestion, alcohol and drugs.
In the new genome-wide association study, the researchers compared the genetic makeup of over 61,000 people, in order to identify areas of the genetic code that were associated with liver function.
The team assessed the function of the volunteers' livers by looking at the concentrations of liver enzymes in their blood. People who have liver damage have high concentrations of these enzymes, which are associated with an increased risk of conditions such as cirrhosis, type 2 diabetes and cardiovascular disease.
Dr John Chambers, the lead author of the study from the School of Public Health at Imperial College London, said: "The liver is a central hub in the body and because it has so many diverse functions, it is linked to a large number of conditions. Our new study is a big step towards understanding the role that different genes play in keeping the liver working normally, and towards identifying targets for drugs that can help prevent the liver from functioning abnormally or becoming susceptible to disease."
The researchers identified 42 areas on the genetic code associated with liver function and they then went on to pinpoint 69 associated genes within these areas. Some of the genes are known to play a part in other functions in the body, including inflammation and immunity, and metabolising glucose and carbohydrates.
Professor Jaspal S Kooner, the senior author of the study from the National Heart and Lung Institute at Imperial College London, said: "This massive international research effort provides in-depth new knowledge about the genes regulating the liver. We are particularly excited about the genes whose precise role we don't yet know. Investigating these further should help us to fill in the gaps in our understanding about what happens when the liver ceases to function normally and how we might be able to tackle this."
Professor Paul Elliott, also a senior author of the study, from the School of Public Health at Imperial College London, said: "Liver problems affect a huge number of people and they can have a devastating effect on a person's quality of life. This study represents a vast discovery that opens up multiple new avenues for research."
The research was funded by the Imperial Comprehensive Biomedical Research Centre award from the National Institute for Health Research; the Medical Research Council; the Wellcome Trust; and other sources.
The latest issue of the Alimentary Pharmacology & Therapeutics investigates computerised adaptive tests to measure health-related quality of life in patients with cirrhosis.
Cirrhotic patients have an impaired health-related quality of life, which is usually analysed using static paper-pencil questionnaires.
The Patient Reported Outcomes Measurement Information System (PROMIS) computerized adaptive testing (CAT) are flexible, freely available, noncopyrighted, health-related quality of life instruments with US-based norms across 11 domains.
CAT presents 5 to 7 questions/domain depending on the patient’s response, from large validated question banks.
This provides brevity and precision equivalent to the entire question bank.
Dr Bajaj and colleagues from Virginia, USA evaluated PROMIS CAT tools against ‘legacy instruments’ for cirrhotics and their informal caregivers.
The team evaluated a total of 200 subjects, of which 100 cirrhotics and 100 caregivers were administered the PROMIS and legacy instruments [Sickness Impact Profile (SIP), Beck depression/anxiety inventories, Pittsburgh Sleep-Quality Index (PSQI) and Epworth Sleepiness scale (ESS)] concurrently.
Both legacy and PROMIS results for patients were compared with caregivers and US norms.
The research team also compared compensated and decompensated patients.
Preference for SIP or PROMIS was inquired of a selected group.
Test – retest reliability was assessed in another group of 20 patients.
The team found that patients had significant impairment on all PROMIS domains apart from anger and anxiety compared with caregivers and US norms.
Decompensated patients had significantly worse sleep, pain, social and physical function scores compared with compensated ones, similar to legacy instruments.
The research team observed a statistically significant correlation between PROMIS and their corresponding legacy instruments.
The team found that 71% preferred PROMIS over SIP.
PROMIS tools had significant test – retest reliability when administered 12 days apart.
Dr Bajaj's team commented, "PROMIS computerised adaptive testing tools had significant concurrent and discriminant validity, test – retest reliability and subject preference for assessing health-related quality of life in cirrhotic patients."
Aliment Pharmacol Ther 2011: 34(9): 1123–113217 October 2011
Healthy YouLaura Landro
(The Wall Street Journal, New York)
"When it comes to medicine, as many as half of Americans don't stick to their regimens. They fail to fill about 20% to 30% of prescriptions written by doctors, don't take drugs as directed, and don't refill medications when they run out. Now, health-care providers have new strategies to increase medication adherence, as concerns rise about health risks and the high costs of treating noncompliant patients who have chronic illnesses. Prescriptions that don't get picked up or refilled can be tracked using electronic medical records and prescribing technology. Clinical pharmacy specialists, case managers and other team members follow up with reminders, phone calls and counseling to get patients back on the wagon."
