Tuesday, April 12, 2011

Hepatitis C News; PPI-437, PPI-668 AND PPI-833 ACTIVITY AGAINST ALL HCV GENOTYPES

Senate hearing on Dayton VA set for April 26

3:40 PM Tuesday, April 12, 2011

DAYTON — A U.S. Senate hearing will be held April 26 in Dayton on problems with the dental clinic at the Dayton VA Medical Center, Sen. Sherrod Brown’s office said Tuesday.

n for Brown said his office didn’t yet have a list of witnesses who will be called to testify at the official hearing. Other details remain to be worked out.

Brown called for the hearing Feb. 11, three days after the Dayton VA offered free screenings to 535 veterans to see if they were infected with hepatitis B, hepatitis C or HIV at the dental clinic between 1992 and July 2010.

The veterans had received invasive dental work from a dentist, Dwight M. Pemberton, who failed to change latex gloves between appointments and did not sterilize dental equipment properly. Two patients have tested newly positive for hepatitis B, and further testing is under way to try to determine if the dental clinic was the source of their infections.

Medical marijuana bill passes in House

OLYMPIA - House lawmakers approved a bill Monday to regulate medical marijuana dispensaries and give greater legal protection to patients with a prescription for cannabis.


The bill, originally sponsored by Sen. Jeanne Kohl-Welles, D-Seattle, aims to bring medical marijuana dispensaries out of the legal gray area in which they operate under current law.

It establishes a licensing process for cannabis producers and sets up regulations for dispensaries, including a provision that they must be located at least 500 feet away from a school.

 
New at NATAP

CHARACTERIZATION AND IDENTIFICATION OF PPI-437, PPI-668 AND PPI-833 AS POTENT AND SELECTIVE HCV NS5A INHIBITORS WITH ACTIVITY AGAINST ALL HCV GENOTYPES

Mechanisms of isolated unconjugated hyperbilirubinaemia induced by the HCV NS3/4A protease inhibitor BI 201335 -

BI 201335 pharmacokinetics and early effect on viral load in HCV genotype-1 patients

SVR and pharmacokinetics of the HCV protease inhibitor BI 201335 with PegIFN/RBV in HCV genotype-1 patients with compensated liver cirrhosis and non-response to previous PegIFN/RBV -

Inhibitex Reports Positive Safety and Antiviral Data from Its Phase 1b Study of HCV Nucleotide Inhibitor INX-189 -

A Study of the Safety and Pharmacokinetics of Single Ascending Oral Doses of INX-08189, a Nucleotide Polymerase Inhibitor, in Healthy Subjects

No resistance to IDX184 was detected in 3-day and 14-day clinical studies of IDX184 in genotype 1-infected HCV subjects -

Idenix NS5A HCV replication inhibitors with low picomolar, pan-genotypicin vitro antiviral activity

CHARACTERIZATION OF NOVEL, HIGHLY POTENT NS5A INHIBITORS WITH QD DOSING POTENTIAL AND ROBUST ACTIVITY IN AN HCV CHIMERIC ANIMAL MODEL

GNS-227: A New Potent and Selective (2nd Gen) HCV NS3 Protease Inhibitor With a High Genetic Barrier to Resistance -

ACH-2928: A NOVEL HIGHLY POTENT HCV NS5A INHIBITOR WITH FAVORABLE PRECLINICAL CHARACTERISTICS

PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY AND TOLERABILITY OF ACH-1625 (HCV NS3 PROTEASE INHIBITOR) IN HCV GENOTYPE 1 INFECTION -


Congress Details Cuts In '11 Budget Deal As Votes Near

More than $1 billion would be cut from programs to prevent sexually transmitted diseases, AIDS, and viral hepatitis. The budget deal would also eliminate a provision of last year's health-care law enabling low-income workers to opt out of employer-offered health insurance and shop for more affordable coverage on insurance exchanges to be created in 2014.

Fragment Of RegeneRx's T(beta)4 Inhibits Activation Of Liver Cells Responsible Fibrosis & Scar Formation

12 April 2011

RegeneRx Biopharmaceuticals, Inc. (OTC Bulletin Board: RGRX) ("the Company" or "RegeneRx") has announced that researchers have found that a fragment of T(beta)4 has the ability to inhibit a type of liver cell responsible for...

Liver Cancer

Laparoscopic Liver Resection Headed for Mainstream

By: DIANA MAHONEY, Internal Medicine News Digital Network
SAN ANTONIO – Laparoscopic liver resection provides significant intraoperative and postoperative benefits, compared with open hepatic resection, in patients with benign and malignant tumors and it does not compromise 5-year outcomes in hepatocellular carcinoma or colorectal cancer metastases, said Dr. David A. Geller, codirector of the liver cancer center at the University of Pittsburgh Medical Center.


Not yet considered standard of care, "laparoscopic hepatic resection [LHR] has now been performed in more than 4,000 patients worldwide, and the benefits when compared with open hepatic resection [OHR] include decreased operating room time, less pain, less narcotic use, shorter length of stay, less blood loss when matched for size of tumor and extent of the operation performed, faster oral intake, and a Band-Aid–sized incision," Dr. Geller concluded from a review of the available literature. The studies included meta-analyses, case cohort matched series, and single-center series from more than 20 centers.

"Most importantly, there are no oncologic disadvantages," he said. "If we were giving patients a small incision and shortening their recovery but sacrificing margins or recurrences, then it wouldn’t be worthwhile."

The first comprehensive literature review on the LHR procedure was published in the Annals of Surgery in 2009; it showed the procedure to be "safe with acceptable morbidity and mortality for both minor and major hepatic resections," said Dr. Geller, who coauthored the study (Ann. Surg. 2009;250:842-8).

Of 2,804 minimally invasive liver resections included in that analysis, the overall mortality was 0.3%, and "morbidity was 10.5% with no intraoperative deaths," Dr. Geller reported at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

For cancer resections, which constituted 50% of the total resections, "negative surgical margins were achieved in 82%-100% of the reported series, and the overall and disease-free survival at 3 years in the colorectal metastasis patients and at 5 years in the hepatocellular carcinoma patients matched – or was better than – that seen in open liver resection series," he said.

Acknowledging the likelihood of a bias for carefully selected patients with laparoscopic procedures, "the results still confirm that in well-selected patients, and in the hands of technically skilled surgeons who have training in both minimally invasive surgery and formal liver procedures, it is a safe operation," Dr. Geller concluded.

The following studies corroborate and extend the early findings, he said:

• An updated meta-analysis of relevant studies evaluating long-term outcomes of LHR and OHR for benign and malignant tumors demonstrated that patients undergoing LHR for malignant tumors had a significantly reduced hazard ratio for death, less operative blood loss, and fewer postoperative complications than did patients in the OHR group, with no significant difference in the rate of recurrence compared with the OHR patients (Arch. Surg. 2010;145:1109-18).

• In a review of 31 case-cohort matched studies that directly compared LHR with OHR in nearly 2,500 patients, and an institutional series of 314 patients, Dr. Geller and colleagues showed that, in addition to the previously reported safety and efficacy findings and patient benefits, the minimally invasive approach was economically advantageous, despite the increased cost associated with disposable instruments, because of the reduced incidence of complications and significantly shorter hospital stays (Arch. Surg. 2011;146:348-56).

There are currently no level 1, randomized, controlled trials comparing LHR and OHR, "and there probably never will be, both because it would be difficult to accrue enough patients to detect a difference in the complications and because it’s very much patient driven, and patients are unlikely to choose to undergo the open procedure when the reported outcomes of the minimally invasive procedure have been so positive," said Dr. Geller.

"The body of literature available to date indicates that, in experienced hands, [LHR] for both benign and malignant lesions is safe and feasible, is associated with significant short-term patient benefits, is economically reasonable, and does not compromise oncologic principles." As such, he noted, "laparoscopic hepatic resection should be considered an important tool in the liver resection armamentarium."

Dr. Geller reported having no relevant financial conflicts of interest

Transplant

Liver transplantation using donor organs with markedly elevated liver enzymes: how far can we go?

Sonia Radunz, Andreas Paul, Knut Nowak, Jürgen W. Treckmann, Fuat H. Saner, Zoltan MathéArticle first published online: 5 APR 2011

DOI: 10.1111/j.1478-3231.2011.02525.x

© 2011 John Wiley & Sons A/S

Issue Liver International

Early View (Online Version of Record published before inclusion in an issue)

Abstract

Background: The disparity between the demand for solid organs and the current supply is a growing problem for patients with end-stage liver disease. To overcome organ shortage, extended criteria donor organs are also accepted for liver transplantation.

Aims: We here unprecedentedly report the clinical course of patients receiving livers with markedly elevated liver enzymes.

Methods: Between November 2007 and December 2010, 15 donor livers with markedly elevated liver enzymes [median aspartate aminotransferase (AST) 1400 (500–7538) U/l, median alanine aminotransferase (ALT) 1026 (308–9179) U/l] were offered to our transplant centre. Based on elaborate judgment, seven of these donor livers were rejected and eight donor livers were transplanted.

Results: All eight transplanted patients showed a liver enzyme peak on the day of surgery (AST 2076±1808 U/l, ALT 1087±833 U/l) and a statistically significant decrease from day 0 to day 7 post-liver transplantation. INR decreased and platelet count increased statistically significantly within 1 week after liver transplantation. The patients were discharged from the hospital 28±11 days after liver transplantation in good clinical condition.

Conclusions: These data demonstrate that using donor livers with markedly elevated liver enzymes may be an acceptable option to expand the donor pool. Universal objective parameters for acceptance should be defined in future studies.


Uptake of hepatitis C antibody testing in patients with end-stage liver disease

A study in this month's issue of the Journal of Viral Hepatitis investigates the uptake of hepatitis C antibody testing in patients with end-stage liver disease in Glasgow.

Individuals infected with hepatitis C virus (HCV) need to be diagnosed well before developing end-stage liver disease to benefit from treatment.

Dr McDonald and colleagues from the United Kingdom ascertained what proportion of cases had been tested for HCV to inform on the effectiveness of current guidelines.

Record linkage between national databases of HCV tests, hospital discharges and deaths identified 10,645 persons who were hospitalized or had died with mention of end-stage liver disease in Glasgow, Scotland, between 1993 and 2007.

The research team estimated HCV test uptake and prevalence of HCV infection within the study population.

Test uptake in those hospitalized increased to 58% in 2003–2007

Journal of Viral Hepatitis

The associations between both HCV test uptake and HCV-antibody status and sex, age group and deprivation quintile were estimated using logistic regression.

The research team found that 43% of those hospitalized, and 23% of those who otherwise died with first-time mention of end-stage liver disease had been tested for HCV during this period.

Test uptake in those hospitalized increased from 13% in 1993–1997 to 58% in 2003–2007.

The adjusted odds of being tested for HCV were significantly higher for men, for ages 25–54 compared with 55+ years, and for those residing in the 2 most deprived quintiles.

The research team observed that 28% of the HCV testees aged 25–44 years were HCV infected.

Dr McDonald's team concluded, "These results highlight the continuing need for raising awareness among medical professionals for comprehensive HCV testing in patients with liver disease."


Distribution of Hepatitis C virus (HCV) genotypes in patients with chronic infection from Rondonia, Brazil

Hepatitis C virus (HCV) is an important human pathogen affecting around 3% of the human population. In Brazil, it is estimated that there are approximately 2 to 3 million HCV chronic carriers.


There are few reports of HCV prevalence in Rondonia State (RO), but it was estimated in 9.7% from 1999 to 2005. The aim of this study was to characterize HCV genotypes in 58 chronic HCV infected patients from Porto Velho, Rondonia (RO), Brazil.

Methods: A fragment of 380bp of NS5B region was amplified by nested PCR for genotyping analysis. Viral sequences were characterized by phylogenetic analysis using reference sequences obtained from the GenBank (n=173).

Sequences were aligned using Muscle software and edited in the SE-AL software. Phylogenetic analyses were conducted using Bayesian Markov chain Monte Carlo simulation (MCMC) to obtain the MCC tree using BEAST v.1.5.3.

Results: From 58 anti-HCV positive samples, 22 were positive to the NS5B fragment and successfully sequenced. Genotype 1b was the most prevalent in this population (50%), followed by 1a (27.2%), 2b (13.6%) and 3a (9.0%).

Conclusions: This study is the first report of HCV genotypes from Rondonia State and subtype 1b was found to be the most prevalent.

This subtype is mostly found among people who have a previous history of blood transfusion but more detailed studies with a larger number of patients are necessary to understand the HCV dynamics in the population of Rondonia State, Brazil.

Author: Deusilene VieiraMonica Alvarado-MoraLivia BotelhoFlair CarrilhoJoao PinhoJuan Salcedo

Credits/Source: Virology Journal 2011, 8:165

Pharmaceutical

Clinical Outsourcing Is Up… And So Is The Cost
For those who had any doubt about where R and;D money is headed…look east. As in the Far East. A recent survey of 241 execs from drugmakers and biotechs finds that R&D budgets are rising just 1 percent overall this year. Meanwhile, outsourcing is expected to rise 11 percent, to 41 percent of the R&D undertaken, and most companies favor investing more of their clinical work in China.

Study reveals new target for antidepressants

Study finds antidepressants affect key stress protein

* Glucocorticoid receptor useful new target for future drugs

By Kate Kelland

LONDON, April 12 (Reuters) - British scientists using human stem cells say they have found out how antidepressants make new brain cells -- a finding that should help drug researchers develop better and more efficient medicines to fight depression.

Previous studies have shown that antidepressants such as tricyclics and selective serotonin reuptake inhibitors (SSRIs) generate new brain cells, but until now scientists had not been clear how they did it.

In a study published in the journal Molecular Psychiatry that used Pfizer's (PFE.N) Zoloft and other antidepressants, researchers from King's College London's Institute of Psychiatry found that the drugs regulate the glucocorticoid receptor (GR) -- a key protein involved in the stress response.

The study also showed that all types of antidepressant are dependent on the GR to create new cells, the scientists said.

"Having identified the glucocorticoid receptor as a key player in making new brain cells, we will now be able to use this novel stem cell system to model psychiatric illnesses in the laboratory, test new compounds and develop much more effective, targeted antidepressant drugs," said Christoph Anacker, a doctorate student at the IoP who led the study.

Depression is common, affecting some 121 million people worldwide, according to the World Health Organisation. It is among the leading causes of disability worldwide and less than 25 percent of sufferers have access to effective treatments.

Recent studies have demonstrated that depressed patients show a reduction in a process called neurogenesis -- the development of new brain cells. Researchers believe this reduced neurogenesis may contribute to the debilitating psychological symptoms of depression, such as low mood or impaired memory.

Anacker's team used human hippocampal stem cells, the source of new cells in the human brain, to investigate the effects of antidepressants on brain cells in a lab dish.

They treated the cells with Zoloft, known generically as sertraline -- an SSRI used to treat depression.

The SSRI class also includes Eli Lilly's (LLY.N) Prozac and GlaxoSmithKline's (GSK.L) Paxil. Carmine Pariante, who worked with Anacker on the study, said the findings would also hold true for a newer class of antidepressants known as serotonin and norepinephrine reuptake inhibitors (SNRIs), which include Pfizer's Effexor and Eli Lilly's Cymbalta.

"For the first time in a clinically relevant model, we were able to show that antidepressants produce more stem cells and also accelerate their development into adult brain cells," Anacker said in a statement about the findings.

"We discovered that a specific protein in the cell, the glucocorticoid receptor, is essential for this to take place," he explained. "The antidepressants activate this protein which switches on particular genes that turn immature stem cells into adult brain cells."

Pariante said it might be some time before new types of antidepressants could be developed to the stage of testing in patients, but he reckoned it could happen within five years.

"We have some tools with which we can probe the glucocorticoid receptor but... we don't yet have a drug which is ready to be tested. What we do have, however, is a specific target on which drug companies... can dedicate their attention," he said in a telephone interview. (Reporting by Kate Kelland; Editing by Mike Nesbit)


Off The Cuff

Evangelical Christian uses 'The Language of God' to Diagnose and Treat Atheist's Cancer

By: Michele R. Berman, MD

April 11, 2011

Last year, English-American author and journalist Christopher Hitchens published his memoir Hitch-22 which begins with a sad and dark "Prologue with Premonitions" describing a magazine article that, due to a proofreading error, referred to him as "the late Christopher Hitchens." In his prologue, Mr. Hitchens goes on to describe examples of other people in similar situations such as Mark Twain who famously stated that "reports of my death have been greatly exaggerated."
Sometime later, physical exam revealed palpable right clavicular lymph nodes which were then biopsied with a resulting diagnosis of Stage IV squamous cell carcinoma of the esophagus, a tumor that Mr. Hitchens' father had died from at age 79. As Hitchens put it, "And the thing to note about stage four is that there is no stage five."

A Ray of Hope from an Unlikely Source

Christopher Hitchens is the author of God Is Not Great: How Religion Poisons Everything and is one of the New Atheists, a group that also includes Sam Harris, Daniel Dennett and Richard Dawkins. Therefore it was striking when Hitchens decided to become a self-described "guinea pig" in an "n of one" experiment proposed by an evangelical Christian who believed that personalized treatment for Mr. Hitchens' tumor might be revealed through .......


Multitasking Takes Toll on Memory, Study Finds

By MATT RICHTEL

A growing body of research shows that juggling many tasks, as so many people do in this technological era, can divide attention and hurt learning and performance. Does it also hinder short-term memory?

That’s the implication of a study being published on Monday in Proceedings of the National Academy of Sciences, a respected journal. The research shows that multitasking takes a significantly greater toll on the working memory of older people.

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