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Week Ending: August 12th , 2006
Alan Franciscus
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August 7, 2006
Risk Factors for Infection and Pathogen Transmission from Liver Donors
SourceURL:http://www.gastrohep.com
This month's issue of Liver Transplantation shows that prolonged intensive care unit stay increases infection risk, while older donor age is associated with recipient pathogen transmission.
Infection transmission from donor to recipient is a dreadful complication in transplantation.
Bacteremia was previously detected in 5% of donors without negative impact on recipient outcome.
The current expansion of graft pool requires consideration of the infectious risk associated with suboptimal donors.
Dr Elisabetta Cerutti and colleagues from Italy evaluated the incidence and risk factors of infection in unselected cadaveric liver donors.
In addition, the investigative team assessed the occurrence of microorganism transmission to recipient and its influence on patient survival.
Results of microbiologic cultures obtained before harvesting in intensive care unit and routinely at harvesting from 610 consecutive liver donors were retrospectively analyzed.
Evidence for bacterial and fungal transmission to the recipient was searched for in each culture-positive donor.
1 or more cultures were positive in 48% of donors -- Liver Transplantation
The investigators found that 1 or more cultures were positive in 48% of donors.
Bacteremia was present in 21%.
The team observed that culture-positive and bacteremic donors were of significantly older age and had longer intensive care unit stays.
At multivariate analysis, an intensive care unit stay of 3 or more days was the only significant predictor of donor infection.
The investigators noted that 1-year patient/graft survival rates were not influenced by donor culture positivity.
However, pathogen transmission occurred in 45% of cases with high recipient 1-year mortality.
The investigators found that in those cases, median donor age was 74 years, significantly much older than that of the other culture-positive donors.
Dr Cerutti's team concludes, "Donors with a prolonged intensive care unit stay are at increased risk of infection, while older donor age is associated with pathogen transmission to the recipient."
"Adequate donor maintenance and careful microbiologic surveillance and treatment, especially of elderly donors, may limit transmission of donor infection."
Liver Transplant 2006: 12(8): 1253-59
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Transition's Hepatitis Drug Shows Potential
SourceURL:http://www.pharmaceutical-business-review.com
By Tom Neilson
An interferon enhancer being developed by Transition Therapeutics has shown signs of efficacy after 12 weeks of a phase I/II trial in the treatment of patients with hepatitis C who have not responded to treatment with the current gold standard therapy for the disease.
The product, HCV-IET, combines Transition's interferon enhancer, EMZ702, with the current standard of care for hepatitis C, a combination therapy of pegylated interferon alpha and ribavirin.
The study data demonstrated that six of 21 (28%) of the hepatitis C non-responder patients that were treated for 12-weeks had a greater than 99% reduction of virus levels (2 log10 decrease).
The preliminary safety data collected to date reveals no serious safety concerns with EMZ702. The type of side effects observed in the study were consistent with expected adverse events for interferon and ribavirin treatment. However, the highest dose of EMZ702 in combination with interferon and ribavirin appears to increase the incidence rate and/or severity of skin rash.
"This trial showed signs of efficacy in non-responding hepatitis C patients, a patient population without any approved treatments available. Our next steps in the development of the product will be to work with a partner to perform a larger study to identify the optimal dosing regimen for this therapy," said Dr Tony Cruz, chairman and CEO of Transition.
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Dialysis Patients Infected with Hepatitis C
SourceURL:http://www.polskieradio.pl
At least twenty one patients have been infected with the dangerous type C hepatitis virus in a dialysis centre in the western city of Ostrow Wielkopolski. More than a hundred patients are still being tested for the virus. A probe launched by prosecutors revealed that the employees of the dialysis centre were guilty of major negligence, such as using contaminated disposable gloves and syringes.
The justice ministry said Monday that the investigation will be supervised by the National Prosecutors' Office.
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August 8th, 2006
Jonathan Spicehandler Dies
SourceURL:http://www.the-scientist.com
Former chairman of Schering-Plough was one of the first to dive into recombinant DNA technology, helped develop interferon
Jonathan Spicehandler, retired chairman of the Schering-Plough Research Institute, died July 30 from brain cancer. He was 57.
Spicehandler is credited with helping develop a widely-used IV antibiotic and interferon, leading to the first approved drug for hepatitis C. He was both a physician (trained in infectious diseases) and a businessman -- an unusual combination in the pharmaceutical industry, according to mentor and close friend James Rahal, director of the infectious disease section at NY Hospital Queens and a professor of medicine at Weill Medical College at Cornell University.
"At the time the pharmaceutical industry did not attract well trained academic physicians," Rahal told The Scientist. "He went into the pharmaceutical industry almost as a pioneer from the infectious disease world."
Spicehandler brought a great deal to the industry, his friend added. "He had tremendous clinical and scientific insight."
At Hoffman-La Roche, Spicehandler was responsible for the clinical development of intravenous antibiotics. He helped to create ceftriaxone, an IV antibiotic now used widely around the world, according to Rahal. "It's saved hundreds of thousands of lives," he said.
In 1982, Spicehandler joined New Jersey-based Schering-Plough as senior director of immunology. He was appointed president of the company's research division in 1993, advanced to chairman in 2002, and retired only weeks before his death. When he joined the company in 1982, it was a $1.7 billion company. In 2005 Schering-Plough reported net sales of $9.5 billion.
At Schering-Plough, Spicehandler helped develop interferon. The naturally occurring immune protein had been discovered decades before, but wasn't put to therapeutic use until researchers began to cultivate it in large quantities using recombinant DNA technology. "When [Spicehandler] came to Schering-Plough it was in the earliest days of biotechnology, and we were one of the first pharmaceutical companies beginning to get interested in recombinant DNA," Robert Spiegel, Schering-Plough's chief medical officer, told The Scientist.
Schering-Plough's interferon drug, Intron-A, was the first medication approved for hepatitis C, which can lead to cirrhosis or liver cancer. Today interferon is also used to treat some forms of cancer, and eradicates the virus in more than half of patients when taken with the antiviral ribavirin -- a combination Spicehandler helped develop, according to Spiegel. "He believed in that combination and it was developed under his leadership," Spiegel said.
Spicehandler also oversaw the development of Zetia, a drug that blocks absorption of cholesterol from food. While most cholesterol medications work in the liver, Zetia targeted the digestive tract. Enrico Velti, vice president of cardiovascular, dermatology and endocrinology at Schering-Plough, said Spicehandler considered Zetia a great achievement, simply because of the vast numbers of people it could help. "He felt he was doing something that was really going to benefit people," Velti said.
Even though Spicehandler moved from medicine to industry, he never put aside his training as a physician when making business decisions. His first consideration was always what a drug could mean to patients and their doctors, Spiegel said. "As much as Jon understood the commercial side, it meant something extra because he was passionate about what the products could mean to patients."
Spicehandler earned his medical degree in 1974 from St. Louis University School of Medicine. He trained at New York University and the New York Veterans Administration Hospital under Rahal.
After being diagnosed with a brain tumor in 2001, he began a foundation and raised more than $1 million to support neuro-oncology research at Duke University's Brain Tumor Center. "I think everyone who knew him admired his optimism," Rahal said.
Jonathan Spicehandler is survived by his wife Debra and their four children.
Kirsten Weir
mail@the-scientist.com
Links within this article
"Schering-Plough Corporation mourns death of Jonathan R. Spicehandler, MD, retired R&D head," Schering-Plough press release, July 31, 2006.
http://www.schering-plough.com/schering_plough
/news/release.jsp?releaseID=889740
Best Places to Work in Industry 2006
http://www.the-scientist.com/article/display/23282/
James Rahal
http://www.nyhq.org/posting/rahal.html
Ceftriaxone
http://www.rocheusa.com/products/rocephin/
Intron-A
http://www.introna.com/introna/index.jsp
S. Bunk, "Looming hepatitic C epidemic sparks new research," The Scientist, December 8, 1997.
http://www.the-scientist.com/article
/display/17830/
B. Dixon, "Research opens door for new applications of interferon," The Scientist, April 3, 1989.
http://www.the-scientist.com/article
/display/9255/
Zetia
http://www.zetia.com/ezetimibe/zetia
/consumer/index.jsp
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Weight Loss May Improve the Efficacy of Therapy for Hepatitis C
SourceURL:http://www.xagena.it/
Obese patients chronically infected with the hepatitis C virus ( HCV ) and treated with combination drug therapy may have better outcomes if the underlying abnormalities caused by excessive fat tissue are corrected.
Weight loss, medications to decrease insulin resistance and extending duration or dosage of therapy are strategies that may improve the efficacy of therapy.
Hepatitis C virus is one of the leading causes of chronic liver disease worldwide, affecting 3 percent of the world's population.
In the U.S. alone 4.1 million people have been infected with HCV, and up to 85 percent of those are chronic carriers of the virus.
Up to 70 percent of chronic carriers will go on to develop some other form of chronic liver disease, from mild liver enzyme abnormalities to cirrhosis and liver cancer.
The current optimal treatment for HCV is a combination therapy with Peginterferon alfa, an immune stimulant, and Ribavirin, an inhibitor of viral replication.
One of the risk factors for treatment failure is obesity.
Obesity itself is linked to the disruption of hormone signaling pathways that affect cell function and to abnormal levels of circulating proteins and sugars. In other words, obesity is associated with a wide range of metabolic changes that affect multiple cellular and organ functions. This biochemical disregulation is linked to serious chronic medical conditions, such as heart disease, diabetes, and non-alcoholic fatty liver disease.
Given the association between obesity and metabolic abnormalities, Michael R. Charlton, at the Mayo Clinic and Foundation in Rochester, and coauthors reviewed several mechanisms by which obesity may interfere with the treatment of chronic HCV and recommend management strategies for obese patients.
The authors identify three possible ways by which obesity may interfere with Peginterferon alpha and Ribavirin activity.
First, fat tissue actively secretes hormones that can modulate the immune system. Increases in fat tissue may disregulate immune pathways Peginterferon targets, rendering the drug ineffective.
Second, obesity causes insulin resistance which itself leads to the accumulation of fat in the liver. The greater the accumulation of fat in the liver, the greater the risk of fibrosis, or scar tissue formation, that alters liver function and blood flow, often permanently. Because HCV also causes liver cells to not respond to insulin, obesity may simply compound the problem and worsen liver disease.
Third, fat tissue reduces the amount of Peginterferon circulating in the body. The decreased circulation of the drug may also weaken Peginterferon's stimulation of the immune system against HCV.
To address all of these mechanisms, the authors make three treatment recommendations.
First, weight loss to reduce fat tissue would address all three hypothesized mechanisms. Weight loss in obese HCV patients is already associated with improved liver biopsy results and liver enzyme levels.
Second, treatment with drugs that improve cellular sensitivity to insulin, such as the diabetes drugs Metformin or Pioglitazone ( Actos ), would lead to reduced fat accumulation in liver cells and might reverse disease progression.
Third, increasing the dosages or the duration of combination therapy may increase circulating drug levels and improve drug efficacy.
"Treatment strategies that focus on improving underlying metabolic factors associated with poor response to combination therapy are thus more likely to overcome the low sustained viral response rates often observed in obese patients infected with HCV," conclude the authors.
Source: Hepatology, 2006
XagenaMedicine2006
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August 9th, 2006
Chronic Hepatitis B Sustained Treatment Response Involves Genetic Polymorphisms
SourceURL:http://www.therapeuticsdaily.com
Hepatitis Weekly - Aug. 07, 2006
Aug. 7, 2006--(NewsRx.com) -- Recent research from the People's Republic of China has reported on genetic polymorphisms of interleukin-1-beta in association with sustained response to anti-viral treatment in chronic hepatitis B.
"Interleukin-1 beta is a pro-inflammatory cytokine that may influence host defence against viral infection," wrote H.L.Y. Chan and colleagues, Prince of Wales Hospital.
The researchers continued that the aim of the study was "to investigate the impact of interleukin-1 beta gene polymorphism on the response to anti-viral treatment."
"Hepatitis B e antigen-positive chronic hepatitis B patients who have completed a randomized study of peginterferon alpha-2b and lamivudine combination vs. lamivudine monotherapy were included. Sustained responders were patients who had persistent hepatitis B e antigen loss and less than two occasions with hepatitis B virus DNA >100,000 copies/mL at any time up to week 76 post-treatment.
"Polymorphisms at interleukin-1 beta-511, -31 and -3954 and interleukin-1 receptor antagonist (RN) were studied. Eighty-eight patients were studied and 18 (20%) patients developed sustained response," the scientists explained.
"Near complete linkage disequilibrium was observed between interleukin-1 beta-511 and -31 loci. After adjustment for the potential confounding effects of treatment allocation, hepatitis B virus genotype, pre-treatment Ala aminotransferase and hepatitis B virus DNA levels, genotype C/T at interleukin-1 beta-511 was found to be associated with higher sustained response than genotype C/C (adjusted odds ratio 10.4, 95% CI 1.1, 96.9, p=.040).
"The proportion of sustained responders tend to be higher among patients with allele T at interleukin-1 beta-511 (83%) than those without (70%) (p=.058)," reported the authors.
They concluded, "High interleukin-1 beta production genotype at position -511 has a favourable response to anti-viral treatments."
Chan and colleagues published their study in Alimentary Pharmacology & Therapeutics (Genetic polymorphisms of interleukin-1-beta in association with sustained response to anti-viral treatment in chronic hepatitis B in Chinese. Aliment Pharmacol Ther, 2006;23(12):1703-1711).
For additional information, contact H.L.Y. Chan, Prince of Wales Hospital, Department of Medicine & Therapeutics, 30-32 Ngan Shing St., Shatin, Hong Kong, People's Republic of China.
Publisher contact information for the journal Alimentary Pharmacology & Therapeutics is: Blackwell Publishing, 9600 Garsington Rd., Oxford OX4 2DQ, Oxon, England.
This article was prepared by Hepatitis Weekly editors from staff and other reports.
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Diabetes May Worsen Liver Encephalopathy
SourceURL:http://news.yahoo.com
NEW YORK (Reuters Health) - In patients with cirrhosis of the liver due to infection with hepatitis C virus (HCV), the presence of diabetes is associated with earlier onset and greater severity of liver or "hepatic" encephalopathy, according to results of a prospective study.
Hepatic encephalopathy is a complication of cirrhosis of the liver. Toxic substances like ammonia that accumulate in the blood and impair the function of brain cells are believed to be contributing factors.
Dr. Samuel H. Sigal and colleagues theorize that diabetes predisposes a cirrhotic patient to hepatic encephalopathy and its exacerbation by increasing ammonia levels as a result of delayed emptying of contents of the stomach and slowed intestinal motility contributing to bacterial overgrowth. Constipation often precedes the development of hepatic encephalopathy.
Sigal, from the New York Weill Cornell Medical Center, and colleagues at the Mount Sinai School of Medicine in New York, tested their theory in 65 patients from a liver transplant program, who had HCV-related cirrhosis.
Eleven (17 percent) had no evidence of hepatic encephalopathy, 33 had mild hepatic encephalopathy, and 21 had severe hepatic encephalopathy.
Twenty patients had diabetes, including one (5 percent) who had no hepatic encephalopathy, seven (35 percent) who had mild hepatic encephalopathy, and 12 (60 percent) who had severe hepatic encephalopathy.
Sigal and colleagues found that diabetics had significantly more severe hepatic encephalopathy, at earlier stages of liver dysfunction, compared with nondiabetic subjects. However, the investigators discerned no relationship between cirrhosis severity and hepatic encephalopathy.
These findings "emphasize the importance of optimizing diabetic control," Sigal's group writes in the American Journal of Gastroenterology.
They caution that their study included only cirrhotic patients with HCV and so it "should not be interpreted to imply that the presence of diabetes is invariably associated with hepatic encephalopathy."
SOURCE: American Journal of Gastroenterology July 2006.
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ViRexx Completes Treatment in HepaVaxx B Vaccine Phase I Study
http://www.ccnmatthews.com
EDMONTON, ALBERTA--(CCNMatthews - Aug. 9, 2006) - ViRexx Medical Corp. (TSX:VIR) (AMEX:REX) a company focused on immunotherapy treatments for certain cancers, chronic hepatitis B & C and embolotherapy treatments for tumors, announced today that enrolment and treatment has been completed in the Phase I trial for HepaVaxx B Vaccine, the lead candidate from ViRexx's novel ChimigenTM vaccine platform. The trial has enrolled and vaccinated its target of 15 healthy volunteers with a subcutaneous injection of HepaVaxx B Vaccine. There were no significant adverse events associated with the treatment.
"Establishing a strong safety profile for this novel therapeutic vaccine is critical to the advancement of our ChimigenTM platform. We intend to continue to monitor volunteers in order to complete the safety assessment for this study." commented Dr. Lorne Tyrrell, Chief Executive Officer and Chief Scientific Officer of ViRexx Medical Corp. "Existing hepatitis B antiviral therapies are effective in only approximately 20 to 30 percent of chronic carriers. The therapeutic potential of HepaVaxx B Vaccine, used alone or in combination with existing anti-viral therapies could have an enormous impact for these chronic carriers."
HepaVaxx B
HepaVaxx B Vaccine consists of a recombinant chimeric molecule containing a hepatitis B viral antigen and a portion of a murine monoclonal antibody. The molecule is designed to target dendritic cells, which play a significant role in antigen presentation and initiation of an immune response. In preclinical testing, HepaVaxx B Vaccine has produced both cellular and humoral immune responses. ViRexx believes that the development of humoral and cellular responses may be effective in clearing the virus from patients with chronic hepatitis B infection.
Hepatitis B
Hepatitis B is a serious public health problem worldwide. The World Health Organization estimates that one out of every three people globally has been infected with the hepatitis B virus. Individuals that develop chronic infections are at increased risk of death from cirrhosis of the liver, liver failure and liver cancer. On average, 15% to 25% of chronically infected persons die from chronic liver disease, with approximately 1.2 million hepatitis B virus-related deaths worldwide occurring each year.
About ViRexx Medical Corp.
ViRexx is an Edmonton, Alberta based biotechnology company focused on the development of novel therapeutic products for the treatment of certain cancers and specified chronic viral infections. ViRexx's most advanced programs include drug candidates for the treatment of ovarian cancer, chronic hepatitis B, and solid tumors.
ViRexx's lead product candidate, OvaRex® MAb, a therapy for the treatment of late-stage ovarian cancer, is currently the subject of two phase III clinical trials being funded by ViRexx's licensing partner Unither Pharmaceuticals, Inc., a subsidiary of United Therapeutics Corporation. For additional information about ViRexx, please see www.virexx.com.
This news release contains certain forward-looking statements that reflect the current views and/or expectations of the Company with respect to its performance, business and future events. Such statements are subject to a number of risks, uncertainties and assumptions. Actual results and events may vary significantly.
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August 10th, 2006
Viral Load May Be a Prognostic Tool in Hep B Infection
Source: www.gastrohep.com
Viral load is associated with increased mortality from hepatocellular carcinoma, and chronic liver disease in Hep B, finds this month's American Journal of Gastroenterology.
Dr Gang Chen and colleagues assessed the relationship between past Hepatitis B virus viral load and mortality.
Surviving cohort members of the 11 year follow-up study were evaluated for current liver disease.
The team measured Hepatitis B virus viral load by real-time polymerase chain reaction.
Stored samples from cohort entry in 2763 Hepatitis B surface antigen-positive adults were used for the analysis.
Major end points were death from hepatocellular carcinoma or chronic liver disease.
The researchers reported that there were 447 deaths.
In the 1683 survivors, the research team assessed severity of liver disease on a return visit in 2003.
Relative risk for hepatocellular carcinoma was 11 with a high viral -- American Journal of Gastroenterology
Viral load was divided into 3 categories, including undetected, low titer, and high titer.
The researchers found that for hepatocellular carcinoma, there was a significant increase in mortality across viral load categories.
Compared to the Hepatitis B virus undetected category, the relative risk for hepatocellular carcinoma mortality in the low viral load group was 2.
The research team found that the relative risk for hepatocellular carcinoma was 11 in the high viral load group.
For chronic liver disease mortality, the relative risks were 1.5 and 15, respectively for both groups.
The researchers observed that the relative risk associated with high viral load did not change with increased follow-up time.
In surviving cohort members evaluated for liver disease in 2003, there was also a significant association of viral load with disease severity.
Dr Chen's team concludes, “In this prospective study, viral load is associated with increased mortality from hepatocellular carcinoma, and chronic liver disease in Hepatitis B virus-infected subjects.”
“Viral load may be a useful prognostic tool in Hepatitis B virus infection, and interventions aimed at its reduction should be explored.”
Am J Gastroenterol 2006:101(8):1797
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New Hope for Hepatitis C Research
http://www.eurekalert.org
The mystery surrounding Hepatitis C, a disease that affects millions of people worldwide, is one step closer to being solved.
In a paper published in the August edition of Journal of Virology, scientists describe how they replicated, or reproduced the hepatitis C virus (HCV) in mouse cells. Working with different models, they showed a gene called protein kinase R (PKR) blocked the replication of HCV in mice.
"When a person becomes infected with HCV, the immune system produces a protein called interferon to fight the infection," said co-author and Director of the Monash Institute of Medical Research, Professor Bryan Williams.
"We now know genes interferon stimulates PKR to try to stop the virus spreading throughout the body."
HCV replicates at a very high rate – approximately one trillion viral particles are produced each day in an infected person. Professor Williams' research will provide a better understanding of how this replication occurs and how and why PKR blocks the production of the virus.
Hepatitis C affects 210,000 Australians. Worldwide, it is estimated more than 170 million people suffer from the disease. The virus attacks the liver, causing flu-like symptoms, fevers, abdominal pain, depression, and for two-thirds of patients, chronic liver disease.1
The discovery may also shed light on why some hepatitis C patients respond better to treatment than others.
"As there is no vaccine or cure for HCV, the only treatment on offer for patients is interferon therapy, which aims to slow the progression of the disease. However, there are six different genotypes, or strains of HCV, which all react differently to treatment," Professor Williams said.
"We can now explore why some strains are more sensitive to interferon therapy, and how we can adapt treatment to the different strains of the disease."
"Our research is still in the early stages, but the research model we have created will be a valuable tool in understanding the underlying mechanisms of chronic HCV infection, and how the virus responds to interferon treatment" said Professor Williams.
###
Research collaborators were the Monash Institute of Medical Research, the Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Kentucky, USA and the Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, USA.
A full copy of the research paper is available at: http://jvi.asm.org/current.dtl#VIRUS
_CELL_INTERACTIONS
1Hepatitis C Council of Victoria:
http://www.hepcvic.org.au
More information / interview opportunities:
Contact Julie Jacobs
Public Relations Manager:
(+61 3) 9594 7109
0408 135 256.
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MP: Have Special Dialysis Machines for Hepatitis Patients
http://thestar.com.my/
DIALYSIS treatment centres should have dedicated dialysis machines to treat renal patients who suffer from hepatitis, Padang Serai MP Datuk Lim Bee Kau said.
She said many centres did not treat hepatitis patients because they were afraid that their machines would get contaminated.
She said this at the presentation of a new dialysis ma-chine by The Star to the Fo En Charitable Haemodialysis Centre in Kulim on Tuesday.
Lim praised the centre's operator, Pertubuhan Bakti Fo En Bandar Kulim, for allocating five out of its 19 dialysis machines for patients with hepatitis B and hepatitis C.
She also thanked The Star for its contribution of the RM44,000 Fresenius 4008S dialysis machine that came with an online clearance monitor (OCM).
“This is a very meaningful contribution. It shows The Star's social responsibility towards the people,” she said.
Star Publications regional director (North) Datuk Seri Kamal Hashim said the money for the purchase of the machine came from the RM100,000 raised at a charity concert held during Starwalk Carnival 2005.
“In May, we used RM44,000 from the fund to buy a similar dialysis machine, which we gave to the Province Wellesley Renal Medifund in Bukit Mertajam. We are now identifying other suitable charitable organisations to give out the remaining RM12,000 from the fund,” he said.
Organisation vice-chairman Wan Tiam Chooi said the centre now had 51 renal patients, who came for treatment three times a week.
“We are thankful to The Star for donating this machine. We will keep it as a spare unit, as we are now running all 19 machines at full capacity,” he said.
Wan said the shelf-life of a dialysis machine was six years, adding that the centre spent about RM1,500 a month to maintain its machines.
He said the organisation recently spent RM847,000 to buy a 4,165 sq m plot of land including a light industrial unit in Taman Cendana II, as a permanent site for its dialysis and recycling centres.
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Young Mom Reaches Womanhood in a Shadow of Addiction
http://www.centredaily.com/
By Sara Solovitch
Public Access Journalism
At 28, Holly is a cute blond who most people would never guess was once a serious drug addict. But until last year, when it came to drugs and alcohol, Holly was an omnivore. She did everything that came her way; as a result of her drug use, she has hepatitis C.
For the first time in her life, Holly is on track. Last September, she graduated from Fayette County Drug Court in Lexington, Ky., as well as from a women's aftercare program. Holly was willing to tell her story in her own words, but requested that her full name not be used, citing the stigma of substance abuse.
*****
I was raised in an alcoholic home. My dad was very abusive to my mother growing up. I remember him one time pulling her hair out and me, being waist-high to him, hitting him as hard as I could. I was full of anxiety as a child.
After my dad left the house, I was abused and raped by a friend of the family.
I started smoking marijuana when I was 12 years old. It escalated to drinking, tripping on acid and taking speed by the time I was 14. I had my first job when I was 16, and that's when I started doing pain-killers then cocaine. I went from snorting to smoking to shooting; heroin; ecstasy. I did whatever was available.
I was a blackout drinker, anything to numb out. It helped temporarily. But when I came back off the high, the pain would be there and it would be even more intense.
I overdosed several times. I had seizures, my lungs collapsed, my kidneys failed. But I kept doing it. I was 16 when my first child was born. I was in an abusive relationship with her father. I smoked marijuana the whole time I was pregnant with her. I quit drinking when I was pregnant with her -- not that smoking marijuana is OK. But she wasn't born addicted.
My second child was born a week after I turned 18. I had started doing pills and my drinking really picked up after I had him. The kids lived with me for a short period of time, until my mother suggested that she take them 'til I got on my feet, which was her way of saying I had a problem. But I wanted my freedom. I was young, I didn't have a husband now.
My mother had the kids for three or four years, and then, when I was 21, I had another child. By that last pregnancy, I couldn't stop using for anything: cocaine, heroin, Dilaudid, OxyContin, you name it.
Here I was doing all these drugs, but afraid that if I drank, my baby would be born with alcohol fetal syndrome. So I didn't drink. I never had any prenatal care, but my daughter was OK.
In 2003, I went into treatment at the Women's Health Center in Lexington and relapsed eight months later. Then in June 2004, the police came to arrest me (for a probation violation). Jail was a better option than what I was doing. At least there, I would sleep, I would eat. I started going to AA meetings while I was there, and then I asked to go to drug court. I had made up my mind. I knew that if I didn't make it work, I was going to die out there.
The judge ordered me to another women's residential facility -- Chrysalis House. I completed the residential part in June 2005, and I'm finishing the aftercare part on the 22nd (of March). I will definitely stay grounded in AA. I've got a sponsor, I work the (12) steps with the community I'm in, and I love the 12-Step program. It's changed me.
I think the reason it worked this time, the main difference, was because Chrysalis House gave me parenting skills and job skills. I had never worked a full-time job. I had never been accountable like that.
When they told me I would have to work a 40-hour-a-week job, I broke down crying. I said I didn't know how to do that. They showed me that it took skills to survive out there, that it was a full-time job being an addict and I could turn around those skills -- like creativity, the constant hustle and energy we needed to come up with drugs -- to help society.
Chrysalis House got me a temporary position that turned into a full-time job. I've been there a year now. I never worked anywhere for a year. It shows I'm capable of doing anything I turn my mind to.
I'm a staff support administrator and I love what I do. I love the people I work with. Being accountable to society, getting up and going to work -- I love it.
I was diagnosed with depression when I was 12 years old. Chrysalis House made sure that that I saw a psychiatrist and got medicated. It turns out I was self-medicating for many years.
I have a conscience today, I'm aware of who I am. I have self-respect. I have all three of the kids occasionally. My youngest daughter -- her aunt was awarded temporary custody, and at this point she's not comfortable spending the night with me. If it's meant for them to be in my life full time, it will happen."
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Sacramento Proposes Needle Purchase Program
(News in brief from Northern California)
http://www.dailycomet.com
By The Associated Press
A proposed city ordinance in Sacramento would create a needle-purchase program in local pharmacies to help stop the spread of HIV, hepatitis C and other diseases among drug users.
The City Council voted 7-2 this week to draft the ordinance. If it is adopted, pharmacies within city limits that voluntarily register would be able to sell needles without a prescription.
There are about 15,000 daily intravenous drug users in Sacramento County, according to county health department estimates. Those users have a 90 percent chance of being infected with hepatitis C within one year because of used and shared syringes, the department said.
Forty-six states allow the sale of syringes without a prescription.
California law permits the sale of up to 10 needles to an adult at one time without a prescription. But the local government where the pharmacy is located must approve the practice. Sixteen counties and nine cities in California have done so.
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Cincinnati Surgeon's Pediatric Laparoscopic Liver Surgery a World First
http://www.medicalnewstoday.com/
A University of Cincinnati (UC) surgeon recently performed what is believed to be the world's first pediatric laparoscopic liver surgery, a specialized procedure for removing cancerous liver tumors without the need for a major incision.
Mark Thomas, MD, an assistant professor and transplant surgeon at UC, performed the operation in a 2-year-old boy with liver cancer on May 24 at La Raza Pediatric Medical Hospital in Mexico City.
Liver cancer is rare in children--less than 150 cases are diagnosed each year compared to more than 18,000 in adults--so the disease often misdiagnosed as constipation, food intolerance or anorexia until it is in an advanced and difficult-to-treat stage.
This patient's symptoms had been dismissed as such for several months before physicians confirmed he had hepatoblastoma of the liver, a type of cancer that starts in the organ's cells (hepatocytes) and develops into one or multiple tumors. Thomas was invited to the La Raza Pediatric Medical Hospital to perform the patient's surgery and teach two lectures on the specialized minimally invasive procedure.
Laparoscopic (minimally invasive) surgery is a method of operating inside the abdomen through small, tube-like ports using a fiber-optic light source, camera and specialized instruments. Known as laparoscopic liver resection, this procedure requires incisions so small (about three-inches) that they leave only minimal scarring.
Two months post-surgery, the patient is doing well and is expected to have a full recovery after several additional rounds of chemotherapy.
Thomas says the procedure is a safe, effective alternative to traditional "open" surgery for liver cancer--which requires up to a 30-inch incision. It also is available for patients with advanced liver disease who cannot tolerate the standard operation. The minimally invasive laparoscopic approach is most often used to remove liver tumors and treat other liver diseases.
"Laparoscopic liver resection results in less pain and faster recovery times for patients," Thomas explains. "Adult patients can usually start eating again a day after surgery and are back to work within one or two weeks."
"Now we've shown that the same procedure can improve survival for patients with childhood liver cancer," he adds.
Thomas says the laparoscopic liver procedure has the same success rates as traditional open surgery and the patient usually goes home within two days.
The liver, one of the body's largest organs, helps metabolize food and medicine absorbed from the intestines in the blood supply, produces bile to help digest fats, and stores energy-producing glycogen (sugar).
Primary liver cancer--which grows from within the organ as opposed to spreading there from another area of the body--is rare. In adults, the most common type of primary liver cancer is hepatocellular carcinoma (HCC) and in pediatric patients it is hepatoblastoma. Both develop from hepatocytes and can occur as one or multiple tumors. HCC accounts for 80 percent of all primary liver cancers. Colorectal, breast and gastric cancers also commonly spread to the liver.
To perform the laparoscopic liver procedure, carbon dioxide gas is pumped into the patient's abdomen to increase the operative area and improve visualization of the tumor. The surgeon then makes two to four small incisions on the right side of the rib cage to accommodate the laparoscope, a tiny "telescope" equipped with a camera, and other specialized surgical instruments. The surgeon then severs and ties off tumor's blood supply, cuts out the tumor itself, places it inside a sealed bag, and removes it through one of the incisions.
"The liver is a self-healing organ," explains Thomas, "so once the cancerous tumor is removed the area typically heals within two to four weeks."
Research suggests that cirrhosis, a condition that results in scarring of the liver tissue and long-term hepatitis B and C infections, can increase the risk for liver cancer. People who abuse alcohol, smoke cigarettes or are obese are also at an increased risk for the disease.
Thomas and his team perform about 250 laparoscopic liver cases a year. According to a literature review, there are no published reports of laparoscopic liver resection in a pediatric patient with cancer.
"Only a handful of centers in the world perform the number of specialized laparoscopic liver surgeries that we do in Cincinnati," adds Thomas.
The American Cancer Society estimates that about 18,000 new cases of primary liver cancer and bile duct cancer will be diagnosed in the United States during 2006. Because of a higher incidence rate of hepatitis B and C, liver cancer is more common in developing countries in Africa and East Asia than in the United States.
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For more information on laparoscopic liver surgery, visit http://www.lapliver.com/
Contact: Amanda Harper
University of Cincinnati
http://www.uc.edu/news
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Researchers from the United States and Spain Provide Details of New Studies and Findings in the Area of Hepatitis C Virus
http://www.therapeuticsdaily.com/
Health & Medicine Week - Aug. 14, 2006
New findings from the United States and Spain describe advances in hepatitis C virus.
Study 1: According to recently published research from the United States, hepatitis C virus (HCV) quasispecies variability is influenced by human immunodeficiency virus (HIV) infection and antiretroviral therapy.
"HCV quasispecies variability has been associated with liver disease progression. The effects of HIV coinfection and highly active antiretroviral therapy (HAART) on HCV quasispecies variability have not been firmly established," wrote M.C. Shuhart and colleagues, Harborview Medical Center.
"We determined HCV quasispecies complexity and diversity in 69 subjects, 28 of whom were HIV infected, using clonal frequency analysis via heteroduplex mobility analysis of the second envelope gene hypervariable region. Nucleotide sequencing was performed for a small subset of subjects.
"HIV-positive, HAART-naive subjects had significantly lower HCV quasispecies complexity and diversity than did both HIV-negative and HIV-positive HAART-treated subjects. In multivariate analysis, HIV infection predicted decreased complexity (p<.0001) and diversity (p=.001) of HCV quasispecies, whereas HAART predicted increased complexity (p=.013) and diversity (p=.013)," wrote the researchers.
"For 4 of 6 patients, sequence analysis yielded data supporting the model that positive host pressure drives HCV quasispecies heterogeneity, although data favoring the hypothesis of selective outgrowth of the most fit variants were also observed," the scientists wrote.
The investigators concluded, "HIV coinfection is associated with decreased HCV quasispecies variability, which appears to be reversed by effective HAART. Although HIV- and HAART-related effects on host immune pressure are likely to play a role in the observed differences in HCV genetic heterogeneity, other mechanisms may be operative."
Shuhart and colleagues published their study in the Journal of Infectious Diseases (HIV infection and antiretroviral therapy: Effect on hepatitis C virus quasispecies variability. J Infect Dis, 2006;193(9):1211-1218).
For more information, contact M.C. Shuhart, Harborview Medical Center, 325 9th Avenue, Box 359773, Seattle, WA 98104, USA.
Study 2: According to recently published research from Spain, occult hepatitis C virus (HCV) infection is affected by anti-viral therapy.
"Occult hepatitis C virus infection is defined by the presence of hepatitis C virus-RNA in liver but with undetectable anti-hepatitis C virus and serum viral RNA," wrote M. Pardo and colleagues, Fundacion para el Estudio de las Hepatitis Virales.
They continued that the study was done "to study the response to anti-viral therapy in occult hepatitis C virus infection to assess the pathogenic effect of occult hepatitis C virus."
"Ten patients with occult hepatitis C virus infection were treated with pegylated-interferon plus ribavirin for 24 weeks and were followed-up 24 weeks after therapy. All patients had abnormal Ala aminotransferase, hepatitis C virus-RNA positive in peripheral blood mononuclear cells and liver necroinflammation.
"At the end of treatment and follow-up, the percentage of patients with normal Ala aminotransferase was 80% (95% CI: 48-96%) and 60% (95% CI: 31-84%) respectively, and hepatitis C virus-RNA in peripheral blood mononuclear cells was negative in 80% (95% CI: 48-96%) and 70% (95% CI: 40-90%) cases. At the end of follow-up sustained response was observed in 30% (95% CI: 11-61%) of cases," the authors reported.
"Five patients underwent a second liver biopsy. In all cases, liver hepatitis C virus-RNA persisted, although hepatitis C virus-RNA load was significantly lower (3.2 x 104±5.1 x 104 copies/mcg RNA) than in the basal biopsy (2.4 x 105±3.8 x 105 copies/mcg RNA); (p=.043). Necroinflammation and fibrosis decreased in three cases," the scientists wrote.
The researchers concluded, "The biochemical, virological and histological response to therapy achieved in patients with occult hepatitis C virus infection demonstrates the pathologic effects of occult hepatitis C virus."
Pardo and colleagues published their study in Alimentary Pharmacology & Therapeutics (Effect of anti-viral therapy for occult hepatitis C virus infection. Aliment Pharmacol Ther, 2006;23(8):1153-1159).
Additional information can be obtained by contacting V. Carreno, Fundacion para el Estudio de las Hepatitis Virales, Madrid 28015, Spain.
Study 3: According to recent research published in the journal Clinical Infectious Diseases, hepatitis C virus (HCV) liver fibrosis can be predicted in patients coinfected with human immunodeficiency virus (HIV).
"Liver fibrosis is accelerated in patients coinfected with HCV and HIV. The reasons for this faster liver disease progression are unclear, although higher plasma HCV RNA levels and distinct HCV genotype distribution in this population, compared with in HCV-monoinfected subjects, could play a role," wrote P. Barreiro and colleagues, Hospital Carlos III.
The authors continued, "Liver fibrosis was assessed using elastometry in all consecutive HIV-infected patients with chronic hepatitis C who attended our institution (Hospital Carlos III, Madrid) during the past 12 months. Hepatic stiffness was measured in kiloPascal units (kPa) and was interpreted on the basis of Metavir score: no or mild fibrosis (score, F0 -F1) when liver stiffness is less than or equal to7.1 kPa, and fibrosis with septa or cirrhosis (F2 -F4) when >7.1 kPa."
"A total of 283 patients (71% were male; mean age, 42 years; 94% were injection drug users and 94% were receiving antiretrovirals; mean CD4 cell count, 554 cells/mcL; 72% with plasma HIV RNA level of greater than or equal to50 copies/mL) were analyzed. The mean Ala aminotransferase level was 68 IU/L, and the mean plasma HCV RNA level was 5.9 log IU/mL. HCV genotype distribution was as follows: genotype 1, 60% of patients; genotype 2, 2%; genotype 3, 26%; and genotype 4, 12%.
"Overall, 164 (58%) of the patients had scores indicating advanced liver fibrosis (F2-F4), as determined using elastometry. In the univariate and multivariate analyses, respectively, a significant odds ratio (OR) for score F2-F4 was found for HCV genotype 3, compared with the other genotypes (OR, 1.9 [95% confidence interval {CI}, 1.1-3.4] vs. 4.3 [95% CI, 1.4-13.3]); for older age (OR, 1.1 [95% CI, 1.03-1.17] vs. 1.1 [95% CI, 1.01-1.25]); and for elevated Ala aminotransferase levels (OR, 1.02 [95% CI, 1.01-1.03] vs. 1.03 [95% CI, 1.01-1.04])," wrote the investigators.
They concluded, "Although patients with HCV genotype 1 had higher mean serum HCV RNA levels than did those with HCV genotype 3 (6.1 log IU/mL vs. 5.7 log IU/mL;), patients with HCV genotype Pp. 01 3 tended to have F2 -F4 scores more frequently than did those with HCV genotype 1 (69% vs. 58%; p=not significant). HCV genotype 3, older age, and elevated Ala aminotransferase levels are independent predictors of advanced liver fibrosis in HCV-HIV-coinfected patients."
Barreiro and colleagues published their study in Clinical Infectious Diseases (Predictors of liver fibrosis in HIV-infected patients with chronic hepatitis C virus (HCV) infection: Assessment using transient elastometry and the role of HCV genotype. Clin Infect Dis, 2006;42(7):1032-1039).
For additional information, contact V. Soriano, Hospital Carlos III, Department of Infectious Disease, Calle Sinesio Delgado 10, E-28029 Madrid, Spain.
This article was prepared by Health & Medicine Week editors from staff and other reports.
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August 11th, 2006
Hep C Is Associated with Depression in Adults with HIV
www.gastrohep.com
Doctors report in August's American Journal of Gastroenterology that Hep C/HIV coinfected persons with a history of alcohol problems have more depressive symptoms than those without Hep C.
Depression is common in persons with HIV infection and with alcohol problems, and it has important prognostic implications.
Neurocognitive dysfunction has been reported with chronic Hepatitis C virus infection.
Dr Howard Libman and colleagues hypothesized that Hepatitis C infection is associated with more depressive symptoms in HIV-infected persons with a history of alcohol problems.
The team of doctors performed a cross-sectional analysis of baseline data from a prospective cohort study of 391 HIV-infected subjects with a history of alcohol problems.
Of these, 59% were Hepatitis C antibody positive and 49% were Hepatitis C RNA-positive.
The team assessed depressive symptoms, and past month alcohol consumption.
In the primary analysis, the doctors evaluated whether there were more depressive symptoms in Hepatitis C antibody-positive and RNA-positive subjects in unadjusted analyses.
Hep C may have a direct effect on neuropsychiatric function -- American Journal of Gastroenterology
The team also adjusted for alcohol consumption, gender, age, race, CD4 count, homelessness, drug dependence, and medical comorbidity.
Mean Center for Epidemiologic Studies Depression scores were higher in subjects who were Hepatitis C antibody-positive vs those who were antibody-negative.
In adjusted analyses, the team noted that the difference in depression scores between Hepatitis C antibody-positive and antibody-negative subjects persisted.
Unadjusted mean Center for Epidemiologic Studies Depression scores were also higher in Hepatitis C RNA-positive subjects compared with those who were RNA-negative.
The doctors observed that the difference remained significant in adjusted analyses.
Dr Libman's team concludes, “Hepatitis C/HIV coinfected persons with a history of alcohol problems have more depressive symptoms than those without Hepatitis C, and this association is unexplained by a variety of population characteristics.”
“These data suggest that Hepatitis C may have a direct effect on neuropsychiatric function.”
Am J Gastroenterol 2006: 101(8): 1762
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Delivering on Promise of RNAI Therapeutics
http://www.dddmag.com
Carolyn Riley Chapman, PhD
RNAi therapeutics are in phase I and II clinical trials, but systemic delivery remains the primary challenge for harnessing their full potential.
In 1998, scientists discovered that RNA not only acts as a simple intermediary between genes and proteins, but that it also carries out regulatory activities of its own. The discovery of RNA interference (RNAi) by Fire and Mello was breathtaking for two reasons: first, researchers hadn’t known about it before, and second, it had amazing potential as a research tool and even as a new class of therapeutics. With the sequence of the human genome in hand, RNAi essentially allows scientists to knock down the activity of any protein at will by causing mRNA degradation.
Indeed, RNAi has become a standard technique for basic and drug discovery research (see July DD&D). Today, it seems probable that RNAi drugs will eventually make it to the market. While there is no question the mechanism works, “it is not yet a clinically validated technology,” cautions Paul Johnson, PhD, senior vice president of research and development and chief scientific officer at Nastech Pharmaceutical Co., Bothell, Wash.
To receive approval from the FDA, small interfering RNA (siRNA) drugs still need to demonstrate efficacy and safety in humans, even those that take advantage of local administration and delivery paradigms. But for RNAi to become a broader platform applicable to all therapeutic areas, the systemic delivery challenge, or getting siRNAs into appropriate cells within humans, must be solved.
A small group of biotech companies, both public and private, is actively pursuing the discovery and development of RNAi therapeutics, and some pharmaceutical companies have allied with them. For example, Novartis, Basel, Switzerland, and Merck, Whitehouse Station, N.J., have partnered with Alnylam Pharmaceuticals, Cambridge, Mass. And Eli Lilly, Indianapolis, Ind., and GlaxoSmithKline, London, are working with Sirna Therapeutics, San Francisco. But while there is a great deal of work going on, perhaps the biggest barrier to new entrants in the field is the intellectual property associated with RNAi technologies, an area of considerable complexity. “Usually those issues don’t get resolved until a drug comes to market,” says Steven Kriegsman, president and chief executive officer of CytRx Corp., Los Angeles.
Despite the intellectual property issues, there is now substantial progress in the development of RNAi therapeutics. There are currently three RNAi drug candidates in the clinic. One is Bevasiranib, Cand5, from Acuity Pharmaceuticals, Philadelphia, which is in phase II trials for age-related macular degeneration (AMD) and diabetic macular edema. In addition, there are Sirna-027 from Sirna, which is also for macular degeneration, and Alnylam’s ALN-RSV01 for pediatric RSV. Acuity’s Bevasiranib, which targets vascular endothelial growth factor (VEGF), was the first siRNA to enter both phase I and II clinical trials. “The challenge of being first is like being the first person in a bike race, or the first person breaking through snow if you’re hiking through snow,” says Sam Reich, co-founder and vice president of research and development at Acuity.
Targeting VEGF
Dale Pfost, PhD, Acuity’s chairman, president and chief executive officer, says his company’s approach was to use the breakthrough technology of siRNA to silence a clinically-validated target. “VEGF, the protein, is central to the angiogenesis and the leakage that causes these diseases. We have seen time and again now that an anti-VEGF approach is a fruitful one to pursue. So, therefore, translating that into an siRNA strategy was really quite appropriate,” says Pfost. For example, Macugen and Lucentis, drugs for AMD from OSI Pharmaceuticals, Melville, N.Y., and Genentech, San Francisco, respectively, are both VEGF antagonists. Macugen is a pegylated aptamer and Lucentis is a humanized therapeutic antibody. In that respect, it is important to recognize that siRNA drugs will compete not only with other siRNA drugs, but with many different types of therapies, including small molecules and antibodies.
So far, results with Bevasiranib have been promising. In phase I trials, more than 100 patients were exposed to the drug, and Reich points out that the approval of two phase II protocols is validation of the safety findings from phase I. But he adds that “one of the safety advantages we have is lack of systemic exposure to a potent VEGF inhibitor.” Bevasiranib is administered by intravitreal injection, and without modifications to increase its stability, it quickly degrades in serum.
Sirna, in collaboration with Allergan, Irvine, Calif., is also pursuing a siRNA drug, Sirna-027, for the treatment of AMD, and it is now in phase I clinical trials. But Roberto Guerciolini, MD, the company’s chief medical officer, expresses even more excitement about Sirna-034, “because we switch now from local administration to systemic administration.” Sirna expects to file an IND for intravenous administration of Sirna-034 for the treatment of chronic hepatitis C by the end of 2006. Guerciolini believes Sirna-034 meets the chemical stabilization, modification, and delivery challenges associated with a systemic RNAi therapy. He says Sirna-034 combines two different RNA sequences in a proprietary nanoparticle formulation that preferentially delivers RNA into hepatocytes.
One way Sirna improves the stability of its siRNA drugs is by removing ribose from the molecules so they become “siNAs” or small interfering nucleic acids instead of ribonucleic acids. Sirna-034 has been significantly modified to maintain stability in extracellular and intracellular environments, says Guerciolini, but it still retains some riboses so it is not a complete siNA molecule. He says Sirna has also been able to chemically modify their oligonucleotides in such a way as to avoid triggering an immune response. Guerciolini says Sirna’s success with targeting Sirna-034 to hepatocytes will allow the company to evaluate a variety of endogenous targets in the liver for future systemic siRNA therapeutics. The next systemic program at Sirna may be aimed at phosphatase 1B, a major regulator of insulin signaling. “That is probably the one that will be evaluated in animal models of disease in the next few months.”
In contrast to Sirna, Alnylam is focusing its near-term efforts on developing siRNAs that can be delivered by direct application or local administration, thereby minimizing the need to address the challenges posed by systemic siRNA delivery, according to Barry Greene, the company’s chief operating officer. “We could, through inhalation, target drugs to the respiratory system; through injection, target drugs to the eyes for ocular disease; and through interthecal or infusion pump technology, target drugs to the CNS [central nervous system].” Alnylam has published on systemic delivery of cholesterol-conjugated and liposome-encapsulated siRNAs in rodents and primates, respectively, but Nagesh Mahanthappa, PhD, senior director of business development and strategy, emphasizes that “siRNA technology today is ready to go for these local administration paradigms” in humans.
Alnylam’s lead clinical candidate, ALN-RSV01, is an siRNA drug targeting the conserved N protein of the RSV genome. It has completed phase I trials in the United States and Europe. Alnylam’s goal with ALN-RSV01 is to develop a drug that will be administered directly to the lungs of a patient using a nebulizer. “siRNAs, for reasons that are not clear, when administered directly to the airway epithelium, are taken up very effectively, even in the absence of complicated formulation approaches,” Mahanthappa, says.
RNAi for flu
Based on their experience developing ALN-RSV01, Alnylam’s next program seeks to develop a drug to treat pandemic flu. Like ALN-RSV01, an RNAi therapeutic against flu would target a gene or genes required for viral replication, and would be delivered to the lungs via inhalation. “We have an opportunity to actually develop a drug targeting a sequence within a gene required for viral replication that’s consistent across flu viruses. We can develop a drug before the actual virus that becomes a pandemic emerges,” says Greene. Alnylam will partner with Novartis to move candidates to and through clinical development.
Nastech is also aiming to develop RNAi therapeutics for influenza. This February, the company announced its acquisition of the RNAi assets of Galenea Corp., Cambridge, Mass., in the areas of respiratory viral infections, including influenza, rhinovirus, and other respiratory diseases. Galenea’s G00101 represents one of four lead compounds for influenza, which Johnson expects Nastech to bring to the clinic in 2007.
Johnson says their lead influenza siRNAs have a spectrum across all avian and human sequences, and are particularly insensitive to mutational change. He believes Galenea’s intellectual property relating to the use of RNAi against flu is strong, and also cites Nastech’s expertise in solving drug delivery problems for macromolecules as one of the strengths of their RNAi program. “siRNAs are not easy to deliver to the sites and cells of action and get them into cells in high enough amounts so that they have a strong therapeutic effect, and that’s our specialty,” says Johnson.
Like others, Johnson believes full clinical validation of RNAi therapeutics rests on overcoming delivery issues. Nastech is investigating several different agents that may help siRNAs be delivered to and into cells, including peptides, lipids, and lipid-peptide combinations. Like Alnylam, Nastech is initially focusing on indications that allow
click to enlarge
FNAi Molecules in Clinic
therapeutics to be administered by inhalation through the lung or nose, but Johnson believes that siRNAs need a delivery agent to get into cells efficiently. Nastech has a “pretty major effort on the identification of small, cost-effective peptides with properties that help siRNA be delivered into cells,” he says, adding that peptides can also have a stabilizing effect on the siRNAs. Johnson also notes that studies performed at Nastech have shown that peptide delivery agents can have lower toxicity and off-target profiles as compared to lipid-based delivery agents.
Calando Pharmaceuticals, Duarte, Calif., is another siRNA company that has been built “on the delivery vehicle as opposed to the siRNA technology per se,” says John Rossi, PhD, co-founder of Calando and chair and professor of the division of molecular biology at the Beckham Research Institute of the City of Hope. Calando’s technology incorporates two components, a linear, cyclodextrin-containing polycation and an siRNA. When the two are mixed together, they self-assemble into nanoparticles that are less than 100 nanometers in diameter.
Rossi says siRNAs delivered with cyclodextrins do not activate the interferon immune response in the same way that lipid-delivered siRNAs do. Because of the way they enter and exit the cell, Rossi says, the cyclodextrin siRNAs escape toll-like receptor encounters. Another advantage is that ligands can be added to the carriers to direct tissue-specific or cell-specific uptake. Calando’s goal is to move a lead candidate into clinical trials for cancer in 2007. Earlier this year, Calando announced it will collaborate with the National Cancer Institute to develop RNAi therapeutics for pediatric neuroblastoma.
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