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Latest News on Pulmonary Fibrosis


Biomarkers identified for idiopathic pulmonary fibrosis

The first evidence of a distinctive protein signature that could help to transform the diagnosis and improve the monitoring of the devastating lung disease idiopathic pulmonary fibrosis (IPF) is being reported by University of Pittsburgh School of Medicine researchers in this month’s edition of PLoS Medicine, an open-access journal of the Public Library of Science.

In the paper, Naftali Kaminski, M.D., director of the Dorothy P. & Richard P. Simmons Center for Interstitial Lung Disease in the Division of Pulmonary, Allergy and Critical Medicine at the University of Pittsburgh School of Medicine, and his colleagues describe a unique combination of blood proteins that appears to distinguish IPF patients from normal controls with extraordinary sensitivity and precision.
“Our findings suggest that we may be able to monitor what is happening in the lungs by measuring certain proteins in the peripheral blood,” explains senior author Dr. Kaminski, who also is associate professor of medicine. “More study is needed to confirm whether these biomarkers might be useful as a clinical blood test to detect lung fibrosis. But right now, there is no straightforward test for IPF. The lung is not highly accessible; biopsy procedures carry risk, and while imaging is good, it can’t follow the disease biologically.”

IPF is a degenerative illness distinguished by progressive lung scarring and diminished breathing capacity, typically leading to death within about five years of diagnosis. It is estimated that 5 million people worldwide and 130,000 in the United States are affected by pulmonary fibrosis and about 30,000 people die of the disease every year. For this study, researchers analyzed the concentrations of 49 proteins in the plasma of 74 patients with IPF and 53 normal controls. A combination of five proteins related to normal tissue breakdown and remodeling and certain disease processes, including arthritis and cancer, was found to be highly indicative of IPF.

Increases in two of the five, matrix metalloproteinases (MMP) 7 and 1, also were observed in tissue and fluid taken from the lungs of IPF patients. Other proteins in the IPF signature are matrix metalloproteinase 8, insulin-like growth factor binding protein 1 and tumor necrosis factor receptor superfamily member 1A. “These proteins were increased in IPF patients, but not in patients with lung illnesses such as chronic obstructive pulmonary disease,” says Ivan O. Rosas, M.D., first author on the study and assistant professor of medicine, University of Pittsburgh School of Medicine. Elevated MMP1 and MMP7 also distinguished IPF when compared to levels associated with another disease that closely mimics IPF, called subacute/chronic hypersensitivity pneumonia. In particular, increased concentrations of MMP7 “may be indicative of asymptomatic lung disease and perhaps reflect disease progression,” Dr. Rosas says.

“One of the challenges is to know whether a blood protein actually reflects the situation in the lung,” notes Thomas J. Richards, Ph.D., study co-first author and research assistant professor in the Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine. The team evaluated all the genes expressed in IPF-affected lung tissue to determine the proteins in the peripheral blood on which they should focus. Based on their detailed analysis, the team believes that increased levels of these five proteins probably are reflective of the disease. “IPF can have a slow progression, so drug companies may wait a long time to see whether a particular drug is having any effect,” says Dr. Kaminski. “But a blood biomarker could indicate whether a drug is working earlier. The biomarkers also might be used for risk assessment and for evaluation of disease progression.”

Some known causes of pulmonary fibrosis include occupational and environmental exposure to asbestos, metal dust, farming chemicals and mold, an inflammatory disease called sarcoidosis, radiation, drug reactions, autoimmune disorders and possibly a genetic predisposition, according to the American Lung Association. Most cases are considered to be idiopathic, or of unknown origin. There is no proven effective therapy for IPF, and most drug interventions are considered experimental. Long-term benefit may be possible with lung transplantation, a radical approach dependent upon a limited number of donated organs.

Source: University of Pittsburgh, April 29, 2008

 


Former InterMune CEO W. Scott Harkonen Indicted for Wire Fraud and FDA Violations

SAN FRANCISCO, March 18 /PRNewswire-USNewswire/ -- W. Scott Harkonen, M.D., the former CEO of InterMune Inc., was indicted on wire fraud and felony Food, Drug and Cosmetic Act charges for his role in the creation and dissemination of false and misleading information about the efficacy of InterMunes drug Actimmune (Interferon gamma-1b) as a treatment for idiopathic pulmonary fibrosis (IPF), the Justice Department announced today.

The indictment alleges that Harkonen, a medical doctor, was the chief executive officer of InterMune from February 1998 through June 30, 2003, and a member of InterMunes board of directors from February 1998 through September 2003. Under Harkonen's direction, InterMune marketed and sold Actimmune to treat IPF, a fatal disease, despite the fact that the drug was not approved by the Food and Drug Administration (FDA) as a safe and effective treatment.

According to the indictment, Harkonen promoted and caused the promotion by InterMune of Actimmune as a safe and effective treatment for IPF, despite the lack of FDA approval, in order to sell more Actimmune and to generate revenues and profits from sales of the pharmaceutical for InterMune. The cost of Actimmune for one IPF patient for one year was approximately $50,000 and the vast majority of the companys sales of Actimmune were for the unapproved, off-label use of treating IPF.

The indictment further states that Harkonen devised a scheme to induce doctors to prescribe, and patients to take, Actimmune to treat IPF. As part of that scheme to defraud, on Aug. 28, 2002, InterMune issued a press release publicly announcing the results of a clinical trial of Actimmune for the treatment of IPF. Although the clinical trial in fact failed, Harkonen caused the issuance and distribution of a false and misleading press release to portray that the results of the trial established that Actimmune helped IPF patients live longer. Specifically, the press release's headline falsely stated that, InterMune Announces Phase III Data Demonstrating Survival Benefit of Actimmune in IPF, with the subheading Reduces Mortality by 70% in Patients With Mild to Moderate Disease.

According to the indictment, it was part of the scheme to defraud that the information in the press release be conveyed to pharmacies that sold Actimmune and to patients and doctors. In furtherance of this scheme, defendant Harkonen caused a specialty pharmacy to distribute the misleading information in the press release to more than 2,000 pulmonologists and to patients taking Actimmune.

In October 2006, InterMune agreed to enter into a deferred prosecution agreement and to pay nearly $37 million to resolve criminal charges and civil liability in connection with the illegal promotion and marketing of its drug Actimmune. InterMune also entered into a 5-year Corporate Integrity Agreement with the Office of Inspector General for the Department of Health and Human Services.

When corporate executives provide false and misleading information about pharmaceuticals, they jeopardize the public health and welfare, said Jeffrey S. Bucholtz, acting Assistant Attorney General for the Civil Division. The Department of Justice is committed to ensuring that patients and their doctors receive truthful information about medical products and will hold accountable those individuals who are responsible for sending the public deceptive information.

The U.S. Attorney's Office for the Northern District of California is committed to protecting the public against health care fraud, said Brian J. Stretch, acting U.S. Attorney. Those who unlawfully violate the trust that exists among the biotechnology industry, the FDA, doctors and patients will be prosecuted.

The maximum statutory penalty for wire fraud is 20 years in prison, a $250,000 fine, three years supervised release, and $100 mandatory special assessment. The maximum statutory penalty for acting with intent to defraud and mislead, resulting in drugs being misbranded while held for sale after shipment in interstate commerce, is three years in prison, a $250,000 fine, one year supervised release, and $100 mandatory special assessment. However, any sentence following conviction would be imposed by the court after consideration of the U.S. Sentencing Guidelines and the federal statute governing the imposition of a sentence. Harkonen is scheduled to be arraigned on Friday, March 28, 2008, at 9:30 a.m. before the Hon. Magistrate Judge Joseph C. Spero.

Pharmaceutical executives who promote drugs using false and misleading information should not be allowed to hide behind a corporate shield, said Kim Rice, Special Agent in Charge of FDA's Office of Criminal Investigations, Washington Field Office. Pharmaceutical companies do not run themselves, and those who engage in criminal conduct will be held personally accountable.

We have an obligation to pursue and bring to justice those who prey on the vulnerable and place profits before public health, said FBI Special Agent in Charge Charlene B. Thornton. This four-year investigation reflects the seriousness with which the FBI takes violations of the law by those entrusted to safeguard the health of the public.

The results of this criminal investigation show our commitment to protect the Veteran Administrations healthcare system from deceptive and fraudulent practices by pharmaceutical companies, said Special Agent in Charge Douglas J. Carver of the U.S. Department of Veterans Affairs, Office of Inspector General. These charges are the result of a multi-year investigation by the Federal Bureau of Investigation; the Food and Drug Administration's Office of Criminal Investigations; the Department of Veterans Affairs' Office of Investigations; and the Office of Personnel Management's Office of Investigations.

This case is being prosecuted by Assistant U.S. Attorney Ioana Petrou of the Northern District of California and trial Attorneys Sondra Mills and Allan Gordus of the Office of Consumer Litigation in the Civil Division in Washington with the assistance of Associate Chief Counsel Anne Walsh of the FDA Office of General Counsel, Paralegal Specialists Maryam Beros and Matthew McCrobie, and Legal Technician Ana Guerra.

An indictment contains only allegations against an individual and, as with all defendants, the defendant in this case must be presumed innocent unless and until proven guilty.

SOURCE U.S. Department of Justice

Contact: U.S. Department of Justice Office of Public Affairs, +1-202-514-2007, TDD, +1-202-514-1888


 

How Can We Develop New Treatments For
Idiopathic Pulmonary Fibrosis?

04 Mar 2008   

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disorder of unknown cause that leads to death in a relatively short time because of the lack of any effective treatment. In an article in this week's PLoS Medicine, a team of researchers from Mexico and the US discusses how a better understanding of the molecular pathways involved in causing IPF may lead to the development
of new therapies.

Moisés Selman (Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico) and colleagues say that the lungs of patients with IPF are enriched with genes associated with lung development in the embryo. In healthy adults, these genes are switched off but they appear to
be abnormally switched on in IPF. "Dysfunctional activation of embryological pathways regularly repressed in the adult life may explain the persistent nature of the disease," say the authors.

"Designing and implementing interventions that target these embryological pathways may be required to develop novel anti-IPF therapies and to significantly improve the outcome of IPF patients."

Citation: Selman M, Pardo A, Kaminski N (2008) Idiopathic pulmonary fibrosis: Aberrant recapitulation of developmental programs? PLoS Medicine 5(3): e62.

Link to the published article.

CONTACT:
Moisés Selman
Instituto Nacional de Enfermedades Respiratorias
Tlalpan 4502
Mexico City, DF 14080
Mexico
 

 


New organ-transplant method
could eliminate rejection drugs


Jan. 24, 2008: LOS ANGELES - In what is being called a major advance in organ transplants, doctors say they have developed a technique that could free many patients from having to take anti-rejection drugs for the rest of their lives.

The treatment involved weakening the patient's immune system, then giving the recipient bone marrow from the person who donated the organ. In one experiment, four of five kidney recipients were off immune-suppressing medicines up to five years later.

"There's reason to hope these patients will be off drugs for the rest of their lives," said Dr. David Sachs of Massachusetts General Hospital in Boston, who led the research published in today's New England Journal of Medicine.

Since the world's first transplant more than 50 years ago, scientists have searched for ways to trick the body to accept a foreign organ as its own. Immune-suppressing drugs that prevent organ rejection came into wide use in the 1980s. But they raise the risk of cancer and kidney failure. And they have side effects such as excessive hair growth, bloating and tremors.

 


Acid Reflux Study Looks At Lifespan Of Sufferers

 Jan. 4th, 2008: Gastroesophageal reflux disease (GERD), often known as acid reflux, is a common problem that has been associated with cancers, asthma, recurrent aspiration and pulmonary fibrosis. A new study published in The American Journal of Gastroenterology examines whether GERD sufferers may have shorter lifespans than those without the disease.

Drawing on over 50,000 person-years of data, the study provides reassuring evidence that people with acid reflux symptoms do not have an increased risk of death, finding no difference in survival rates between sufferers and non-sufferers.

In fact, the study finds that people with infrequent acid reflux may actually have better survival rates than those with either daily symptoms, or none at all. "It may be that occasional reflux symptoms are a reflection of potential protective behaviors that are associated with reflux, such as regular exercise or modest amounts of alcohol ingestion," suggest Nicholas J. Talley and G. Richard Locke, III, co-authors of the study.

The study adds perspective to the risk of acid reflux symptoms. While there are a large number of acid reflux sufferers in the U.S., incidences of related cancer are extremely rare. "Although extraesophageal manifestations occur in some people with reflux disease, our results suggest that this disease is a benign condition in the vast majority of sufferers," say the authors.
This study is published in The American Journal of Gastroenterology.

Nicholas J. Talley, M.D., Ph.D., is Editor-in-Chief of The American Journal of Gastroenterology; a Professor of Medicine and Epidemiology at the Mayo Clinic College of Medicine; and Chair of the Department of Internal Medicine at the Mayo Clinic, Jacksonville.

G. Richard Locke, III, M.D., is a Professor of Medicine at the Mayo Clinic College of Medicine; Consultant, Division of Gastroenterology and Hepatology, Department of Internal Medicine; and Consultant, Division of Health Care Policy & Research, Department of Health Sciences Research at the Mayo Clinic.

 

Translational research patented first experimental treatment against idiopathic pulmonary fibrosis

Innovative pneumocytes transplantation has reverted the disease for the first time in rats

21-Dec-2007 Barcelona, Spain: Idiopathic pulmonary fibrosis is a disease with unknown cause with a very severe prognosis; when detected, it is already in an advanced stage. Patients suffering from it cannot develop with normality pulmonary gas exchange, and have a very reduced quality of life. Because of lack of an effective treatment, they rarely survive 5 years after being diagnosed. Idiopathic pulmonary fibrosis affects 13 out of 100,000 men and 7 out of 100,000 women, normally over 40 years of age. Researchers from the Biomedical Research Institute of Barcelona CSIC (IIBB-CSIC), a centre developing research in the framework of the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), have discovered and patented a method to stop and revert this disease in an animal model. A clinical study will be soon conducted in humans in the Hospital Clínic de Barcelona.

Results of their research work are published in the last issue of the American Journal of Respiratory and Critical Care Medicine (176(12):1261-8). This study has had the collaboration of basic researchers, such as Dr. Anna Serrano-Mollar, and Dr. Oriol Bulbena, first and last signatories of the study; and researchers with a clinical background, such as Dr. Antoni Xaubet, from the Unit of Pneumology of the Hospital Clínic de Barcelona. This turns this work into a paradigm of translational research promoted in IDIBAPS and through other initiatives such as the Network of Centres of Biomedical Research (CIBERs). This research work has been financed through a contribution from the Fondo de Investigaciones Sanitarias (FIS) from the Instituto de Salud Carlos III.

Gas exchange is developed in lungs thanks to type 1 pneumocytes in alveoli, cells recovering the inner walls of the alveolar cavity. Occupying the same spaces, there are also type II pneumocytes, precursor cells that repair the damaged alveolar tissue. When idiopathic pulmonary fibrosis appears, this regeneration process cannot be developed correctly and fibrosis advances until respiration is impossible. The technique developed by researchers from the IIBB-CSIC-IDIBAPS consists in a transplantation of type II pneumocytes via intratracheal. In order to monitor correctly the transplanted cells with genetic and fluorescence techniques, sexual chromosomal differences were used. Thus, the disease was induced in female rats, and cells from male rats were transplanted. This is a lowly invasive technique which has permitted to regenerate, for the first time, rat fibrotic alveoli where idiopathic pulmonary fibrosis was induced.

CSIC has patented as a treatment the cell suspension transplanted with this innovative strategy. The world patent will be proved in humans with a clinical study, soon conducted in the Hospital Clínic de Barcelona thanks to the financing of the Fundación Genoma España and CSIC This study will have the participation of 6 recently diagnosed patients who will receive a suspension of type II pneumocytes coming from a dead donor, since these cells cannot be cultured in the laboratory. All this events throw new and hopeful light into basic and clinical research lines. One of the following steps of researchers will be to try to obtain type II pneumocytes from adult stem cells.

Further information:

Communication Area IDIBAPS
Marc de Semir, Head of Communication (mdesemir@clinic.ub.es)
Àlex Argemí, scientific editor (aargemi@clinic.ub.es)
Tel.: 00 34 93 227 57 00



Fibrosis can be Stopped,

Cured and Reversed

Tue 18-Dec-2007, University of California, San Diego researchers have proven in animal studies that fibrosis in the liver can be not only stopped, but reversed. Their discovery, to be published in PLoS Online on December 26, opens the door to treating and curing conditions that lead to excessive tissue scarring such as viral hepatitis, fatty liver disease, cirrhosis, pulmonary fibrosis, scleroderma and burns.

University of California, San Diego researchers have proven in animal studies that fibrosis in the liver can be not only stopped, but reversed. Their discovery, to be published in PLoS Online on December 26, opens the door to treating and curing conditions that lead to excessive tissue scarring such as viral hepatitis, fatty liver disease, cirrhosis, pulmonary fibrosis, scleroderma and burns. Six years ago, the UC San Diego School of Medicine research team discovered the cause of the excess fibrous tissue growth that leads to liver fibrosis and cirrhosis, and developed a way to block excess scar tissue in mice. At that time, the best hope seemed to be future development of a therapy that would prevent or stop damage in patients suffering from the excessive scarring related to liver or lung disease or severe burns.

In their current study, Martina Buck, Ph.D., assistant professor of medicine at UCSD and the Veterans Affairs San Diego Healthcare System, and Mario Chojkier, M.D., UCSD professor of medicine and liver specialist at the VA, show that by blocking a protein linked to overproduction of scar tissue, they can not only stop the progression of fibrosis in mice, but reverse some of the cell damage that already occurred.In response to liver injury – for example, cirrhosis caused by alcohol – hepatic stellate cell (HSC) activated by oxidative stress results in large amounts of collagen. Collagen is necessary to heal wounds, but excessive collagen causes scars in tissues. In this paper, the researchers showed that activation of a protein called RSK results in HSC activation and is critical for the progression of liver fibrosis. They theorized that the RSK pathway would be a potential therapeutic target, and developed an RSK inhibitory peptide to block activation of RSK.

The scientists used mice with severe liver fibrosis – similar to the condition in humans with cirrhosis of the liver – that was induced by chronic treatment with a liver toxin known to cause liver damage. The animals, which continued on the liver toxin, were given the RSK-inhibitory peptide. The peptide inhibited RSK activation, which stopped the HSC from proliferating. The peptide also directly activated the caspase or “executioner" protein, which killed the cells producing liver cirrhosis but not the normal cells.“All control mice had severe liver fibrosis, while all mice that received the RSK-inhibitory peptide had minimal or no liver fibrosis,” said Buck. Buck explained that the excessive collagen response is blocked by the RSK-inhibitory peptide, but isn’t harmful to the liver. “The cells continue to do their normal, healing work but their excess proliferation is controlled,” Buck said. “Remarkably, the death of HSC may also allow recovery from liver injury and reversal of liver fibrosis.”

The researchers found a similar activation of RSK in activated HSC in humans with severe liver fibrosis but not in control livers, suggesting that this pathway is also relevant in human liver fibrosis. Liver biopsies from patients with liver fibrosis also showed activated RSK. The study expands on work reported in 2001 in the journal Molecular Cell announcing that a team led by Buck had found that a small piece of an important regulatory protein called C/EBP beta was responsible for fibrous tissue growth, or excessive scar tissue following injury or illness. When normal scarring goes awry, excessive build-up of fibrous tissue can produce disfiguring scars or clog vital internal organs and lead to serious complications. Buck and colleagues developed a mutated protein that stopped this excessive fibrous tissue growth.

“Six years ago, we showed a way to prevent or stop the excessive scarring in animal models,” said Buck. “Our latest finding proves that we can actually reverse the damage.” Worldwide, almost 800,000 people die from liver cirrhosis each year, and there is currently no treatment for it. Excessive tissue repair in chronic liver disease induced by viral, toxic, immunologic and metabolic disorders all result in excessive scar tissue, and could benefit from therapy developed from the UCSD researchers’ findings.The research was supported by grants from the National Institutes of Health, the Department of Veterans Affairs and UCSD’s Medical Research Foundation. Buck is the recipient of a Howard Temin Award from the National Cancer Institute.


 

Molecular pathway appears crucial in development of pulmonary fibrosis

Discovery may provide new therapeutic target for dangerous lung disease

 

Massachusetts General Hospital 12-Dec-2007
A study led by Massachusetts General Hospital (MGH) researchers may have found a key mechanism underlying idiopathic pulmonary fibrosis (IPF), a usually fatal lung disease for which transplantation is the only successful treatment. The investigators found that a specific molecular pathway appears responsible for key aspects of the scarring of lung tissue that characterizes IPF, the cause of which is currently unknown. The results will appear in the January issue of Nature Medicine and have received early online release.

“Identifying the key role of this pathway in the development of fibrosis gives us an exciting new target for devising treatments,” says Andrew Tager, MD, of the MGH Pulmonary and Critical Care Unit, who led the study. “An agent that blocks this pathway is already being developed as a potential cancer treatment, and we’re hoping to be able to test it in our animal model of IPF to determine whether it might be a candidate for trials in patients.”

About 50,000 new cases of IPF are diagnosed in the U.S. each year, primarily in people aged 50 to 75. While some patients may survive for extended periods, in others the diseases progresses rapidly, leading to death in an average of 3 to 5 years. Theories about the cause of IPF previously focused on chronic inflammation of the lungs, but recent evidence has suggested that an abnormal healing response to some sort of lung injury may be responsible.

The primary characteristic of IPF is scarring (fibrosis) of the lung surface, rendering it unable to transmit oxygen into the bloodstream. In any part of the body, scarring occurs when cells called fibroblasts, an important part of normal wound healing, make collagen to reinforce the healing matrix that forms over damaged tissue. Normally scarring is limited, but if too many fibroblasts travel to the site of an injury, large amounts of collagen can be deposited, producing excessive, fibrotic scarring. Fibroblasts are known to be present in affected lung tissue in IPF, and previous studies showed that the activity of factors that attract fibroblasts to the site of an injury rises with the severity of the disease. The current study was designed to determine which specific “chemoattractants” were associated with IPF, something not previously known.

Analysis of fluid from the lung surfaces of a mouse model of pulmonary fibrosis suggested that the activity of lysoposphatidic acid (LPA), acting through its receptor LPA1, was responsible for attracting fibroblasts in the disorder. This association was supported by the fact that a strain of mice lacking the gene for LPA1 did not develop pulmonary fibrosis when treated with a compound that usually causes the disease in the animals. Lung fluid samples from human IPF patients not only had significantly higher levels of LPA than control samples, laboratory tests showed that patient samples attracted fibroblasts while fluid from controls did not. In addition, an agent that blocks the LPA1 receptor eliminated the ability of fluid from IPF patients to attract fibroblasts.

“These results indicate that the LPA-LPA1 pathway is responsible for the abnormal migration of fibroblasts into the lungs in IPF, an absolutely crucial step in the development of fibrosis,” says Andrew Luster, MD, PhD, senior author of the study. “This pathway appears to be involved in several steps in the development of fibrosis, including the leaking of blood vessels, which is why the LPA1 knockout mice are so dramatically protected. If we’re right, then targeting this pathway should be a very exciting new therapeutic strategy for IPF.” Luster is director of the MGH Center for Immunology and Inflammatory Disease (CIID) and a professor of Medicine at Harvard Medical School (HMS). Tager is also associated with the MGH CIID and has opened a clinic focused on pulmonary fibrosis and related lung diseases. He is an assistant professor of Medicine at HMS.

Additional co-authors of the study are Peter LaCamera, Barry Shea, Gabriele Campanella, John Wain, Banu Karimi-Shah, Nancy Kim, and William Hart, of the MGH; Moises Selman, National Institute for Respiratory Disorders, Mexico; Zhenwen Zhao, and Yan Xu, Indiana University School of Medicine; Vasiliy Polosukhin, and Timothy Blackwell, Vanderbilt University School of Medicine; Annie Pardo, National Autonomous University of Mexico; and Jerold Chun, Scripps Research Institute. The study was supported by grants from the Pulmonary Fibrosis Foundation, the American Lung Association, the Nirenberg Center for Advanced Lung Disease, the National Autonomous University of Mexico, and the U.S. National Institutes of Health.



Breakthrough brings hope to Seattle scientists

UW to get cells early next year

Seattle Wednesday, November 21, 2007
Tuesday's announcement that scientists have created the equivalent of embryonic stem cells without using an embryo has Seattle researchers cautiously optimistic about the future of stem cell research in the area. The research was published online by two journals, Cell and Science. The Cell paper is from a team at Kyoto University in Japan; the team published by Science was from the University of Wisconsin-Madison.

Dr. Chuck Murry, a pathology professor at the University of Washington, said he wrote to both groups asking for cells to be sent to the university. The Wisconsin scientists agreed to send them, probably by the first of the year, he said. Murry's protocol for regenerating damaged hearts in rats using embryonic stem cells was used by the Japanese scientists whose work was reported in Cell, he said.

"My intention is to get these cells in Seattle and do what we want to do with them," Murray said. "I'm cautiously enthusiastic ... things have been wrong before and if it's not reproducible it's not science ... but two very good labs have published (the same findings) in two very good journals." Dr. Beverly Torok-Storb, a stem cell scientist at the Fred Hutchinson Cancer Research Center, said she and many other scientists have been expecting this announcement for some time. She pointed out that scientists still must prove the cells are as good as embryonic stem cells over the long haul. She cautioned against the public expecting immediate cures and said the next step will be to try to make certain the cells are safe for humans. "Will they really be as good and as long-lived as an embryonic stem cell? We don't know that yet," she said.

Seattle was home many years ago to the first successful medical use of stem cells, a kind of master cell that can grow into any one of the body's more than 200 cell types. This allows them to replace cells that have died and they have been used to replace defective cells and tissues in patients who have certain diseases or defects. Scientists at the Hutch are conducting similar research using canine cells, Torok-Storb said. Virginia Mason Medical Center also is involved in stem cell research. Torok-Storb said the findings, which used human skin cells, eliminate the ethical and moral dilemma of using human embryonic stem cells for research and makes every patient his or her own donor with no worries of rejection. The findings also could mean that someday two separate lab designs would no longer be needed at the University of Washington's Institute for Stem Cell and Regenerative Medicine, Murray said. Scheduled to open in July 2008, one side would be used to work only on the federally approved, non-embryonic, stem cells; the other side for any kind of stem cells. The findings also increase the potential for more federal funding, which now is restricted for embryonic stem cell research, Murray said. "If these cells are the real deal, which I think they are, there's no reason why anyone could object to them," he said. "We'll see how this plays out."


 

Eli Lilly Issues post marketing warning that cancer drug Gemzar may result in Pulmonary Fibrosis

May 31, 2007

The following adverse events have been identified during post-approval use of Gemzar. These events have occurred after Gemzar single-agent use and Gemzar in combination with other cytotoxic agents. Decisions to include these events are based on the seriousness of the event, frequency of reporting, or potential causal connection to Gemzar.

Cardiovascular — Congestive heart failure and myocardial infarction have been reported very rarely with the use of Gemzar. Arrhythmias, predominantly supraventricular in nature, have been reported very rarely.

Vascular Disorders — Clinical signs of peripheral vasculitis and gangrene have been reported very rarely.

Skin — Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported very rarely.

Hepatic — Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and death has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs.

Pulmonary — Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely following one or more doses of Gemzar administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last Gemzar dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy.

Renal — Hemolytic-Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS.

 

 
 
 
 

Rapid Progressors Speed to End-Stage Pulmonary Fibrosis

 
MEXICO CITY, May 31 -- A difference in genetic patterns may explain why some idiopathic pulmonary fibrosis patients, especially men who smoke, die more quickly after diagnosis than others do. These rapid progressors were 6.5-fold more likely to be men and seven-fold more likely to have been smokers than slow progressors, found Moisés Selman, M.D., of the Instituto Nacional de Enfermedades Respiratorias here, and colleagues. In the retrospective study, gene expression patterns differed between fast and slow progressors, implying biologically-distinct phenotypes of the disease, they wrote online in the journal Public Library of Science ONE. The findings suggest that physicians should pay more attention to the time of onset of symptoms to identify these patients who are at greater risk, they said. Most idiopathic pulmonary fibrosis patients have symptoms long before diagnosis, then slowly progress, with death coming within five years of diagnosis, they noted. But, they said, distinct patterns of disease progression have become increasingly clear clinically.

To characterize these patterns, the researchers reviewed the charts of 167 consecutive patients with the disease who were evaluated at a single center between 1995 and 2004. Seven healthy volunteers as well as lung samples from autopsies were also studied as controls for immunohistochemistry, cellular and genetic profiling. Rapid progressors were defined as those with no more than six months of symptoms before seeking medical attention. From symptom onset, these 26 patients had a median follow-up of 13.5 months and median survival of 27 months. From diagnosis, median follow-up was 10 months and survival was 25 months. Slow progressors were defined as those with at least 24 months of symptoms before presentation. From symptom onset, these 88 patients had a median follow-up of 60.5 months and median survival of 93 months. From diagnosis, median follow-up was 17 months and median survival was 32 months. In a multivariate analysis, significant factors in survival among the overall cohort included time from symptom onset to first consult, smoking, male gender, and lung function as measured by forced vital capacity.

 

Among the 80% to 85% of patients with known vital status, rapid progressors had significantly lower survival rates than slow progressors (hazard ratio 9.0, 95% confidence interval 4.48 to 18.3, P<0.001) or intermediate progressors (P=0.045). Mortality determined from the time of diagnosis also tended to be higher in the rapid progressors (HR 1.5, 95% CI 0.81 to 2.87, P=0.18). Among rapid progressors, significantly more patients were:

  • Male (odds ratio 6.5, 95% CI 1.4 to 29.5, P=0.006).
  • Ever smokers (OR 3.04, 95% CI 1.1 to 8.3, P=0.04).
  • Current smokers (OR 7.1, 95% CI 1.2 to 40.9, P=0.02)

These rapid progressors, though, were not simply patients presenting at a different stage of disease or an acute exacerbation, the researchers said. Their physiologic, radiologic, and histopathologic parameters were similar to those of slow progressors. Socioeconomic and educational background -- which can influence when patients seek treatment -- as well as initial treatment were similar between groups, they said. And there were no differences between rapid and slow progressors in pack-years smoked. Nor were there baseline differences in age, lung function alterations, oxygen saturation, extent of changes seen on high resolution computed tomography, or bronchoalveolar lavage cellular profile, the researchers noted.

 

Lung biopsies done on 31% of patients showed no differences in baseline morphology for interstitial inflammation, pulmonary hypertension changes, smooth muscle hyperplasia, type 2 cell hyperplasia, or extent of fibrosis or honeycombing. However, Dr. Selman wrote, there were important differences showing that "rapid progressors appear to represent a distinct biological phenotype among patients with idiopathic pulmonary fibrosis." In a global gene expression analysis in a subset of patients, the researchers found that 437 genes were expressed differently between groups. Rapid progressors overexpressed genes involved in morphogenesis, oxidative stress, migration and proliferation, and fibroblast and smooth muscle cell function. This upregulation was seen on immunohistochemistry for the adenosine-2B receptor, which is involved in a key process of fibrotic remodeling, and prominin-1/CD133, which is found in hematopoietic stem cells and embryonic epithelium. Furthermore, bronchoalveolar lavage showed that rapid progressors had more than a twofold increase in active matrix metalloproteinase-9, which may contribute to abnormal tissue repair and remodeling, compared with slow progressors.

 

Rapid progressors also had higher fibroblast migration than slow progressors (238% versus 123%, P<0.05) or controls (238% versus 30%, P<0.01). While these subgroup studies were of limited size, "the relatively stringent selection of genes, the protein verification by immunohistochemistry on additional samples, and the biological relevance of the genes suggest that our results are biologically meaningful," the investigators wrote. They also noted, however, that their study was preliminary and limited by retrospective data collection and dependence on patient recall of symptom duration. However, "taken together with reports of the impact of acute exacerbations of idiopathic pulmonary fibrosis on morbidity and mortality, our results further highlight the variability in the progression and outcome of [the disease]," they concluded. "These findings may explain, in part, the difficulty in obtaining significant and reproducible results in studies of therapeutic interventions in patients with idiopathic pulmonary fibrosis," they added.

The study was partially supported by a grant from the Universidad Nacional Autónoma de México. One of the researchers was supported by grants from the National Institutes of Health and by a donation from the Simmons family. The researchers reported no conflicts of interest.
 
 

Extra-aggressive Form Of Idiopathic Pulmonary Fibrosis Identified

Science DailyMay 29, 2007 - Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disorder from which most patients die within 5 years after diagnosis. The disease is characterized by the insidious onset of dyspnea or cough and usually evolves slowly. Now, Selman and coworkers present strong evidence indicating that a subset of IPF patients has a short duration of symptoms before diagnosis and display an accelerated clinical course to end-stage disease. The authors postulate that these "rapid progressor" patients, predominantly smoking males, represent a distinct clinical phenotype compared with the usual "slow progressors" patients.

"These findings highlight the variability in the progression and outcome of IPF, and may explain, in part, the difficulty in obtaining significant and reproducible results in studies of therapeutic interventions in patients with IPF," said Dr Selman, who is the Director of Research at the National Institute of Respiratory Research in Mexico City and the lead author on this publication. "They also suggest that physicians should pay more attention to the time of onset of symptoms, and to look for other signs that allow the identification of these rapid progressor patients." In this study the authors performed global gene expression analysis and other molecular studies in a subset of patients and identified a number of genes that were differentially expressed in both groups, suggesting that rapid progressors are biologically distinct from slow progressors.

"While preliminary, these results may allow investigators to identify biomarkers of disease progression," said Dr King, who is the Chief of Medicine at San Francisco General Hospital and an internationally renowned expert in research and management of pulmonary fibrosis. The senior author on this paper, Dr Naftali Kaminski, who is the Director of the Simmons Center for Interstitial Lung Disease at the University of Pittsburgh, added that this research highlighted the need to collect as much information on patients with IPF as possible. "We are only now starting to really understand the disease and characterize it," he said, "therefore, it is critical for patients with the disease to be seen in centers that are actively involved in IPF research."Better identification and understanding of these differences may provide insights into the pathogenesis of IPF and assist in the development of therapeutic interventions for this devastating lung disease.


 

Cold War, hellish consequences

Ex-nuke weapons workers caught in medical crossfire

By Laura Frank, Rocky Mountain News - April 7, 2007

Harold Hinton is dying.

He is slowly suffocating from incurable lung disease that the government acknowledges is linked to his work making nuclear bomb fuel during the Cold War. Harold Hinton, 76, gets an insulin shot from his full-time nurse at his Cortez home. Hinton - as a young man he ground up uranium ore that became the feedstock for atomic bombs at a plant in Utah - fears he may lose his around- the-clock health care because the Department of Labor wants to reduce it. Hinton, of Cortez, is eligible for medical care through a federal program designed to compensate ill nuclear weapons workers who weren't fully warned by the government of the dangers they faced. His physician said Hinton needed around-the-clock nursing care at his home in southwestern Colorado, but a government worker reduced the doctor's orders to eight hours a day. Hinton is not alone, says the president of a Denver-based company that provides nursing care to Hinton and about 60 other former nuclear weapons workers across the country.

The U.S. Department of Labor is disregarding doctors' orders and approving less care than doctors say is medically necessary, said Greg Austin, president of Professional Case Management. Department officials have also called family members and doctors, pressuring both to agree to lower levels of care, he said. Labor Department officials said they are simply trying to be good stewards of public funds while getting ill workers the help they need. Assistant Deputy Labor Secretary Shelby Hallmark, who oversees the program, said Professional Case Management is pressuring doctors to prescribe 24-hour home nursing care when less costly care would do. " I think what's going on here is (PCM) wants to maximize cash flow," Hallmark said, adding that he has referred PCM's cases to the Labor Department's Office of Inspector General for review. Austin says the Labor Department's decisions are dangerous. "If we do what the Department of Labor says instead of what the doctors say, literally, lives could be put at risk," he said.

Crying himself to sleep

Verna Keaton, of Ohio, said her husband, Addison, cried himself to sleep Wednesday night after learning that the Labor Department was trying to take away the nursing care that keeps him home with his wife of 44 years. Addison Keaton is dying of cancer that the government says was caused by exposure to radioactive uranium at the Portsmouth Gaseous Diffusion Plant in Portsmouth, Ohio. His colon cancer has spread to his lungs, heart and esophagus.

PCM has served more than 100 ill weapons workers in 11 states during the past five years. The total bill for those five years has approached $30 million, Hallmark said. Austin said Labor Department officials have created such an "adversarial culture" toward ill workers that it is affecting workers' already fragile health. The company is considering assisting some patients with a class-action lawsuit against the Labor Department. The suit would ask a judge to stop officials from ignoring medical directives. On Wednesday, a Labor Department doctor called Addison Keaton's doctor to question his home health-care order, Verna Keaton said. Unbeknownst to the Keatons, the government doctor had already contacted a hospice-care company, which would be less expensive than full-time nursing care, to open a case on Addison Keaton. "I think they want him to hurry up and die because it's costing them too much money," said Verna Keaton. "How can a doctor in Washington, D.C., determine what kind of help my husband needs?"  She said the Labor Department doctor was relying on reports from case managers without medical degrees. "I don't know what's going to happen next because I haven't gotten hold of DOL to answer my questions," she said. "They won't return my calls."

The Labor Department runs the program that Congress created in 2001 to compensate nuclear weapons workers whose toxic exposures made them ill, including those from the now-defunct Rocky Flats weapons plant northwest of Denver. The program includes coverage of medical bills for illnesses linked to those exposures. The Labor Department and the White House have come under fire recently from the ill, their advocates and several federal lawmakers. The critics say recently released internal communications show the Bush administration has been more concerned about containing costs than helping the ill workers, whom they call Cold War veterans. "These brave Americans are suffering, and in some cases, dying, because of the hazardous service they performed for their country," said U.S. Rep. Zoe Lofgren, D-Calif., who heads the congressional committee with oversight of the Labor Department program. "These people deserve better, and I will work with my colleagues in Congress to ensure that they receive the benefits that they were promised."

Producing yellowcake

As a young man during the Cold War, Harold Hinton ground up uranium ore and moved it from one chemical solution to another until it was a fine yellow powder that became the feedstock for atomic bombs. His bosses at the mill just over the Colorado border in Utah told him the radioactive ore was safe. His only protective gear was a hard hat, as he toiled at the mill, coming home covered in yellow uranium dust. The product of the mill - uranium 308, or yellowcake as it was known for its appearance - was shipped to nuclear facilities at Oak Ridge, Tenn., and later to Portsmouth. Hinton knew that Portsmouth workers such as Addison Keaton were turning the yellowcake into fuel for atomic bombs. But he and his fellow workers didn't know the yellowcake itself was radioactive. "We were never warned," he said. Oak Ridge workers recalled being told in the 1950s that yellowcake was safe enough to eat. "Remember, at that time, they were trying real hard to get the warheads on the missiles," Hinton said. "They needed it real bad to protect the nation."

In 1986, two decades after he left the mill, Hinton began having trouble breathing. The radioactive uranium dust had scarred his lungs. He developed pulmonary fibrosis, a disease with no cure and no effective treatment. "I have anywhere from six months to two or three years (to live)," Hinton said. "To me, believe me, (the home health care) is a godsend. I have thanked God for it many times." On the last Friday of February, Hinton's doctor was ready to discharge him from the hospital after a particularly severe episode of breathing difficulty. But there was no one to care for Hinton once he got home. His wife is on oxygen and struggles to care for their son's children, a teenager and a disabled 21-year-old. The Hintons' son is in a Tulsa, Okla., hospital fighting lung cancer. Harold Hinton believes his wife's and son's lung problems resulted from contamination he brought home from the uranium mill. At the request of Professional Case Management, Hinton's doctor delayed his discharge until the next Monday in hopes of getting quick approval for Hinton's home care. But the Department of Labor took two weeks to approve the care and reduced the order to eight hours a day instead of the 24 hours ordered by the doctor.

E-mail and voice-mail messages provided by PCM indicate a case manager in Denver made the decision to offer less care without consulting Hinton's doctor.

Dr. Leonard Cain, Hinton's doctor in Cortez, said ordering 24-hour nursing care is not an easy decision. "It's complicated," Cain said. "If I put a home-health aide (instead of a nurse) in the home and the patient has a medical need during the night, that can't be handled by a home-health aide." Such aides, known as certified nursing assistants, are qualified to help patients bathe or move from a bed to a chair, PCM's Austin said. But they legally cannot administer medications, draw blood, change oxygen levels or do many other things that these patients might require at any time. "Yes, this program covers more than Medicare or some other social safety net," Austin said. "But this isn't a social program - it's a compensation program. These workers' illnesses were caused by their work for this country. They can never get their health back, but they can get some relief and be with their families until they pass away."

Caught in the middle

As a doctor, Cain said he feels caught between Professional Case Management advocating for patient care and the Labor Department trying to save money. "I'm going to err on the side of providing the most care for the patient," Cain said. "This level of care is not provided to anyone else in our health-care system. But (the law creating the workers' compensation program) says we're going to provide this level of care for these people who need it."  Cain said he resents being put in the middle. "There should be negotiation and communication on this," he said. PCM's Austin agreed, saying his company has requested that the Labor Department participate in discussing patients' care with health professionals. "They have said they are not interested," Austin said. Hallmark said he was not aware that PCM had asked the Labor Department to participate in patient case conferences. However, he said, PCM complained when the department talked directly with the physicians. Austin said PCM nurses should always be involved in decisions because they see the patients more than their doctors do. Meanwhile, PCM has been providing full-time nursing care to Hinton since Feb. 26 with no guarantee of payment. "There would be a huge liability for us if we didn't do what the doctor ordered," Austin said. "But we can't afford to do that forever."

How it happened

At the height of the Cold War, thousands of Americans were busy at urgent work they couldn't discuss with their neighbors: building atomic bombs for the arms race with the Soviet Union. At the Rocky Flats plant northwest of Denver - and at scores of other sites across the nation - workers were exposed daily to myriad poisons. Radiation. Exotic heavy metals. Chemicals in uncommon variety and quantity. The government routinely withheld information about the risk workers faced. Records of exposures were often incomplete; others were later destroyed. Today, more than 60,000 former nuclear weapons workers are ill and believe that their ailments are linked to their Cold War work. The government denied almost all such links until 2000. The next year, Congress created a compensation program to give lump-sum payments and medical coverage to workers whose illnesses were likely caused by workplace exposures.

 


Forbes.com Commentary
A Paradigm Shift For Medical Research
Michael J. Fox 05.07.07, 6:00 AM ET

The U.S. was founded on the radical notion that by independently pursuing our dreams we can build a future that's better for everyone. That's why it's always been home to great thinkers and doers, risk-takers and entrepreneurs--people who insist on questioning the status quo and finding a better path forward. That insistence, individual and collective, has made this country a world leader in many fields, including science and technology.

Yet when it comes to the vast enterprise of biomedical research, there's room to question how well the system we've created serves our needs. Do we put enough emphasis on producing new therapies and cures for disease? Are we making progress fast enough in the eyes of the millions touched by illness or injury?

Over $100 billion is spent on biomedical research each year. Roughly a third of that money goes toward expanding our understanding of the basic mechanisms of life. That seems reasonable: Basic research is vital to advancement over the long haul. The other two-thirds goes to the business end of things, where venture capitalists and the pharmaceutical industry are mostly concerned with making a profit for their shareholders. To patients observing from the sidelines, it can feel--on our cynical days--as if the lion's share of today's commercial investment focuses on tweaking innovations from a decade ago.

So we burn through this pile of cash, yet we're left with a major problem: Who's investing in innovation right now? Only a minuscule fraction of our current efforts are strategically allocated to converting basic discoveries into truly new therapies. This is a higher-risk and higher-reward investment arena--for my money, a classic challenge for American ingenuity. Bold action today will pay off for years to come in the form of improved, practical treatments with a chance to benefit people living with disease now.

I'm certain we can achieve tangible results faster. In fact, that's the premise on which I set up my foundation, where we come to work every day to accelerate the best ideas on their path from the labs to the patients. Our goal is to improve the daily lives of people with Parkinson's disease today and find a cure within the decade. But this is a complex problem that requires a better strategy than throwing billions more dollars at biomedical research and hoping for the best.

It's time for a broad-based paradigm shift, one that reflects what America is all about: rapid innovation toward practical results that we can feel in our everyday lives. The good news: This actually isn't a question of throwing more money at the problem. (Not hitting up the taxpayers for more money--how's that for a radical notion?) It is a question of deploying our financial, scientific and intellectual capital differently, creatively and urgently and designing new solutions to complex challenges. Where we go from here is up to all of us.

Through our experience at the foundation, we know firsthand that America is home not only to many of the most talented and innovative people in the world, but also to some of its most generous. We must figure out how to hold onto the best of what we have--infrastructure and resources that attract the best and brightest scientists; the benefits that accrue from basic research--while pushing ourselves to go still further. Let's think big about new ways to stimulate innovation and seed the drug development pipeline with the next generation of therapies assuring investors of transformative results--high returns on financial capital, yes, but also on human health.

It may be a tall order, but I'm optimistic. When we work together and use our talents and resources for the collective good, everything is possible. To me, that's the core of the American Dream.

Michael J. Fox


Gene Mutations Linked To Hereditary Lung Disease

Article Date: 01 Apr 2007 - 5:00 PDT

Scientists at Johns Hopkins have identified the genetic culprits that trigger a hereditary form of a fatal lung disease. The findings, published in the March 29, 2007 issue of the New England Journal of Medicine, may provide new directions in diagnosis and treatment for families that inherit genes for the disease, as well as for those that develop non-inherited forms of the illness. A progressive scarring of the lungs with no effective treatment, idiopathic pulmonary fibrosis (IPF) affects approximately 50,000 Americans annually, and like some cancers often is fatal within three years. As many as 20 percent of IPF sufferers are thought to have inherited genetic mistakes that predispose them to the disease; and until now, these gene flaws remained unknown.

To locate the genetic problem, Hopkins investigators screened DNA from blood samples of 73 people with inherited IPF and discovered that six of them (eight percent) had mutations in two genes that produce an enzyme which helps lengthen the fragile ends of chromosomes. Chromosome ends, or telomeres, contain repetitive bits of DNA code that wear down each time a cell divides. The mutations were spotted in two genes that regulate the enzyme telomerase, which keeps telomere length extended just beyond the borders of needed genes. With mutations in telomerase, however, chromosome ends fray and wear down far more quickly, which can trigger cell death.

The scientists' first hint that telomerase plays a role in IPF came from studying the genetic traits of a family with a rare, premature-aging disorder caused by short telomeres. Many of the family members were suffering from the disorder's second-leading cause of death -- pulmonary fibrosis. "We thought that perhaps there might be a link between telomerase mutations and IPF," says Mary Armanios, M.D., assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center.

In the current study, mutation carriers had telomeres about one-third the length of those in family members with no gene mistakes. Short telomeres also were found in seven younger relatives who had gene mutations but not IPF. Gene tests are currently not available for IPF, but scientists are evaluating ways to assess risk of disease by screening telomere length. "If we follow the genetic threads of families that inherit IPF, it may lead us to understand the genetic properties causing more common forms of the disease," says Armanios. Patients with non-inherited IPF also may have short telomeres, so, says Armanios, "there may be other causes for short telomeres, such as older age and smoking, which also happen to be the main risk factors for IPF."

To determine the link between short telomeres and non-inherited IPF, investigators will need to study a larger group of these patients. If studies reveal a solid link between the two, Armanios says that it may change the way IPF is treated. "For many years, we've thought that IPF is caused by an immune attack against the lungs, even though current therapies aimed at dampening the immune system don't work," she explains. "If we're not so tied to immune suppression therapies, we could eventually tailor drugs to a different target."

 

  Government makes investment to improve respiratory health of Canadians

OTTAWA - April 26, 2007 - Federal Health Minister Tony Clement today joined the Canadian Lung Association to announce the development of a national action plan to improve the respiratory health of Canadians.
           
The National Lung Health Framework represents a coordinated approach to prevent and manage respiratory diseases in Canada.  The framework will lead to better policy, leadership, research, innovation and education on lung health. Over the next two days, 175 stakeholders representing a wide range of interests will discuss an outline for the
action plan and establish priorities and goals for going forward.

Canada’s New Government is investing more than $1 million in financial and technical support to enable the development of the framework, including $350,000 to the Canadian Lung Association for consultations across Canada, including meetings with provincial and territorial government representatives.

“Respiratory diseases affect more than 3.5 million Canadians, some of whom end up in Canadian emergency rooms,” said Minister Clement.  “Today, Canada’s New Government is taking action with the Canadian Lung Association to improve the lung health of all Canadians.”

“Through partnership with the Government of Canada and stakeholders nationwide, we are building an Action Plan on Lung Health that will make a significant improvement to the health of Canadians and their families,” said Nora Sobolov, Chair of the Interim Steering Committee for the National Lung Health Framework. “It is simply not acceptable that one Canadian dies every 20 minutes from lung disease, or that rates of lung disease continue to grow at a staggering rate.  The time for action is now: and that is exactly what this is all about.”  

Serious lung diseases include asthma, chronic obstructive pulmonary disease, lung cancer, influenza and pneumonia, bronchiolitis, tuberculosis, pulmonary fibrosis, and respiratory distress syndrome.  According to the World Health Organization, lung disease will be the third leading cause of death in the world by 2020.

The Public Health Agency of Canada works to prevent and control the health effects of chronic respiratory diseases.  For more information, visit www.phac-aspc.gc.ca.

 


Gene Mutations Linked To Hereditary Lung Disease

01 Apr 2007: Scientists at Johns Hopkins have identified the genetic culprits that trigger a hereditary form of a fatal lung disease. The findings, published in the March 29, 2007 issue of the New England Journal of Medicine, may provide new directions in diagnosis and treatment for families that inherit genes for the disease, as well as for those that develop non-inherited forms of the illness. A progressive scarring of the lungs with no effective treatment, idiopathic pulmonary fibrosis (IPF) affects approximately 50,000 Americans annually, and like some cancers often is fatal within three years. As many as 20 percent of IPF sufferers are thought to have inherited genetic mistakes that predispose them to the disease; and until now, these gene flaws remained unknown.

To locate the genetic problem, Hopkins investigators screened DNA from blood samples of 73 people with inherited IPF and discovered that six of them (eight percent) had mutations in two genes that produce an enzyme which helps lengthen the fragile ends of chromosomes. Chromosome ends, or telomeres, contain repetitive bits of DNA code that wear down each time a cell divides. The mutations were spotted in two genes that regulate the enzyme telomerase, which keeps telomere length extended just beyond the borders of needed genes. With mutations in telomerase, however, chromosome ends fray and wear down far more quickly, which can trigger cell death.

The scientists' first hint that telomerase plays a role in IPF came from studying the genetic traits of a family with a rare, premature-aging disorder caused by short telomeres. Many of the family members were suffering from the disorder's second-leading cause of death -- pulmonary fibrosis. "We thought that perhaps there might be a link between telomerase mutations and IPF," says Mary Armanios, M.D., assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center.

In the current study, mutation carriers had telomeres about one-third the length of those in family members with no gene mistakes. Short telomeres also were found in seven younger relatives who had gene mutations but not IPF. Gene tests are currently not available for IPF, but scientists are evaluating ways to assess risk of disease by screening telomere length. "If we follow the genetic threads of families that inherit IPF, it may lead us to understand the genetic properties causing more common forms of the disease," says Armanios. Patients with non-inherited IPF also may have short telomeres, so, says Armanios, "there may be other causes for short telomeres, such as older age and smoking, which also happen to be the main risk factors for IPF."

To determine the link between short telomeres and non-inherited IPF, investigators will need to study a larger group of these patients. If studies reveal a solid link between the two, Armanios says that it may change the way IPF is treated. "For many years, we've thought that IPF is caused by an immune attack against the lungs, even though current therapies aimed at dampening the immune system don't work," she explains. "If we're not so tied to immune suppression therapies, we could eventually tailor drugs to a different target."



Viagra May Help Improve Exercise Capacity in Pulmonary Fibrosis Patients
Monday, March 12, 2007
University of California Los Angeles

UCLA researchers have found that Viagra may help patients with idiopathic pulmonary fibrosis, an incurable disease characterized by progressive scarring in the lungs, which often leads to a lung transplant. Published in the March issue of the journal Chest, the research shows that more than half of the patients treated with Viagra, also known medically as Sildenafil, improved their walking distance by at least 20 percent during a standard test to measure lung function.

"Over five million worldwide suffer from this devastating disease, so we are hopeful that this drug may prove an effective therapy for pulmonary fibrosis," said the study's principal investigator, Dr. David A. Zisman, medical director of UCLA's Interstitial Lung Disease Program and assistant professor of pulmonary and critical care medicine at the David Geffen School of Medicine at UCLA. Many patients with pulmonary fibrosis also have pulmonary hypertension, which constricts arteries and lessens blood flow to the lungs, resulting in diminished lung capacity and breathing difficulties. According to Zisman, Sildenafil may help breathing by opening or dilating blood vessels to allow more blood flow to the lungs.

In this pilot study, 14 idiopathic pulmonary fibrosis patients initially took a standard six-minute walking test. All patients were then given oral Sildenafil therapy for three months, followed by a second walking test to gauge performance changes. Researchers noted that 57 percent of the patients improved their walking distance by 20 percent or more. The average improvement in walking distance was 49 meters (161 feet).

Eleven patients completed the study. Only two patients experienced side effects and had to stop the medication - one due to diarrhea and the other due to abnormally low blood pressure. "In this small pilot study, the drug was well-tolerated," said Zisman. "The next step is to confirm this finding in a large, randomized clinical trial." The study was funded by the National Institutes of Health.

Other authors include: Dr. Harold R. Collard, department of medicine, San Francisco General Hospital, University of California, San Francisco; Kevin J. Anstrom, Ph.D., Duke Clinical Research Institute, Duke University; and Dr. Marvin I. Schwarz, department of medicine, University of Colorado Health Sciences

 

InterMune Discontinues Phase 3 INSPIRE Trial of Actimmune in Idiopathic Pulmonary Fibrosis

BRISBANE, Calif., March 5, 2007 /PRNewswire-FirstCall via COMTEX News Network/ -- InterMune, Inc. today announced that it has discontinued the Phase 3 INSPIRE clinical trial evaluating Actimmune(R) (interferon gamma-1b) in patients with idiopathic pulmonary fibrosis (IPF) based upon the recommendation of the study's independent data monitoring committee (DMC). In a planned interim analysis that included a total of 115 deaths, the DMC found the overall survival result crossed a predefined stopping boundary for lack of benefit of Actimmune(R) relative to placebo. Among the 826 randomized patients, there was not a statistically significant difference between treatment groups in overall mortality (14.5% in the Actimmune group as compared to 12.7% in the placebo group). Based on a preliminary review of the interim safety data, the adverse events associated with Actimmune(R) therapy appear generally consistent with prior clinical experience, including constitutional symptoms, neutropenia and possibly pneumonia.

INSPIRE was a randomized, double-blind, placebo-controlled Phase 3 study designed to evaluate the safety and efficacy of Actimmune(R) in IPF patients with mild to moderate impairment in lung function. The primary endpoint was survival time. The lack of benefit stopping boundary was developed to allow for early study termination in the event interim data were statistically inconsistent with a clinically meaningful treatment effect of Actimmune(R). InterMune plans to submit the data from the Phase 3 INSPIRE trial for presentation at an appropriate medical meeting and for publication in a peer-reviewed journal.

"The interim results of the INSPIRE trial and our decision to discontinue the trial are disappointing," said Steve Porter, M.D., Ph.D., Chief Medical Officer at InterMune. "We are extremely grateful for the strong support we received from physicians, healthcare providers and especially the patients who participated in the clinical evaluation of Actimmune(R). The overall conduct of the study by investigators and the participation by patients were exemplary."

Dan Welch, President and Chief Executive Officer of InterMune, said, "Although we are disappointed by this result with Actimmune(R), we remain committed to addressing the significant unmet medical need in IPF with pirfenidone through our Phase 3 CAPACITY program. A positive treatment effect of pirfenidone on lung function has been supported in several Phase 2 studies and in a Phase 3 study as recently reported by Shionogi & Co., Ltd. We also are focused on advancing our novel hepatitis C virus drug candidate, ITMN-191. In collaboration with our partner Roche, our Phase 1a study of ITMN-191 is proceeding as planned."

Mr. Welch continued, "We will promptly evaluate the implications of the INSPIRE study termination on our corporate strategy and our infrastructure. We expect to provide an update on this evaluation, including revised financial guidance, in the near future."

Actimmune(R) is a synthesized version of interferon gamma, a naturally occurring protein believed to stimulate the immune system. InterMune markets Actimmune(R) for the treatment of two life-threatening congenital diseases: chronic granulomatous disease and severe, malignant osteopetrosis. The most common side effects are flu-like symptoms, including headache, fatigue, fever, chills and rash. Physicians and patients can obtain additional prescribing information regarding Actimmune(R) including the product's safety profile, by visiting www.actimmune.com.


FivePrime Enters Osteoarthritis and Pulmonary Fibrosis Collaboration With Centocor

 

 Wednesday January 3, 2007 SAN FRANCISCO--(BUSINESS WIRE)--Five Prime Therapeutics, Inc. today announced a worldwide collaborative research and license agreement with Centocor Research and Development Inc. The collaboration will focus on novel therapeutic products to treat osteoarthritis and pulmonary fibrosis. Under the collaboration, FivePrime will screen its comprehensive protein library against cell-based assays directed to osteoarthritis and fibrosis and Centocor will have exclusive rights to the proteins and targets identified in these screens.

FivePrime will receive an upfront payment of $15 million, comprised of cash and an equity investment by Johnson and Johnson Development Corporation (JJDC), and two years research funding from Centocor. Centocor will have exclusive worldwide rights to develop and commercialize products and targets discovered during the research term in exchange for future milestones and royalties. Further details of the agreement have not been disclosed. "With Centocor as a partner in these disease areas, we should be able to move the products of our discovery platform into clinical trials faster and more effectively," commented Lewis T. "Rusty" Williams, FivePrime's founder and Executive Chairman.

"Centocor has a long-standing commitment to innovative biotherapeutics," added Gail Maderis, President and CEO of FivePrime. "We are extremely pleased to be working with a group that shares our enthusiasm for the tremendous potential of novel biologic therapies. Additionally, we welcome JJDC to our premier group of investors." A key component of the collaboration is FivePrime's comprehensive, rapid protein discovery system. FivePrime's protein screening library contains essentially all human secreted proteins and their receptors, including many that are unavailable in public collections. FivePrime screens its protein library in complex, primary cell assays with a level of precision, speed and thoroughness previously achievable only in small molecule screening. Using technologies for rapid in vivo validation of hits from its screens, FivePrime aims to reduce time from idea to an Investigational New Drug to less than three years.


KIN SUING CITY OVER 'WTC TOXIN' DEATH

By CARL CAMPANILE

New York: January 29, 2007 -- The wife of a utility repairman who restored essential cellphone service at Ground Zero - and died last year of a rare lung disease - has filed a $20 million wrongful-death claim against the city, The Post has learned. Mark