Wednesday, January 26, 2011

In The News; Liver Health/Hepatitis C Compensations and More

PMQs: Labour ask about Hepatitis C compensations
Labour are asking the coalition what they are doing about the long running Hepatitis C debacle. Where have Labour been for the past 13 years when they were in government - they did nothing?Recorded from BBC's The Daily Politics showing of PMQs, 26 January 2011

Off The Cuff
A third of the physicians in the United States are over 65, and many continue to work with competence into their 70s and beyond. Yet what happens if a doctor’s cognitive or physical skills begin to slip because of early Alzheimer’s, a subtle stroke or another illness, putting the patient at risk? That’s a question explored by Laurie Tarkan in this week’s Science Times.
In regenerative medicine, large supplies of safe and reliable human embryonic stem (hES) cells are needed for implantation into patients, but the field has faced challenges in developing cultures that can consistently grow and maintain clinical-grade stem cells.Standard culture systems use mouse "feeder" cells and media containing bovine sera to cultivate and maintain hES cells, but such animal product-based media can contaminate the cells. And because of difficulties in precise quality control, each batch of the medium can introduce new and unwanted variations.Now, a team of stem cell biologists and engineers from UCLA has identified an optimal combination and concentration of small-molecule inhibitors to support the long-term quality and maintenance of hES cells in feeder-free and serum-free conditions. The scientists used a feedback system control (FSC) scheme to innovatively and efficiently select the small-molecule inhibitors from a very large pool of possibilities.The research findings, published recently in the journal Nature Communications, represent a major advance in the quest to broadly transition regenerative medicine from the benchtop to the clinic."What is significant about this work is that we've been able to very rapidly develop a chemically defined culture medium to replace serum and feeders for cultivating clinical-grade hES cells, thereby removing a major roadblock in the area of regenerative medicine," said Chih-Ming Ho, the Ben Rich-Lockheed Martin Professor at the UCLA Henry Samueli School of Engineering and Applied Science and a member of the National Academy of Engineering.........
Posted by: Scott Read more Source
Patient Voices: Rare Diseases
Six men and women speak about their experience facing a rare disease: the difficulty of diagnosis, limited treatment options
January 22, 2011, 6:32 AM CT
Under standard laboratory conditions, the human beta-defensin 1 (hBD-1), a human antibiotic naturally produced in the body, had always shown only little activity against microbes. Nevertheless the human body produces it in remarkable quantities. The solution to the puzzle was the investigation process itself, as the research group led by Dr. Jan Wehkamp at the Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology of the Stuttgart-based Robert Bosch Hospital found out.Before the research group took a new approach to this research, defensins were commonly tested in the presence of oxygen, eventhough little oxygen is present, for example, in the human intestine. Starting out from the discovery that a special antibiotic-activating protein of the human body is diminished in patients with inflammatory bowel diseases, Crohn's Disease and Ulcerative Colitis, the working group investigated how defensins act under low-oxygen conditions. During their investigations the researchers found out that under these conditions hBD-1 unfolds a strong antibiotic activity against lactic acid bacteria and yeast.Furthermore the scientists discovered that another human protein, thioredoxin, is able to activate beta-defensin 1 even in the presence of oxygen. Moritz Marcinowski and Professor Johannes Buchner from the Department of Chemistry at the Technical University of Munich, used circular dichroism spectroscopy to elucidate the differences between the folded inactive and the unfolded active form of the protein......... Posted by: Mark Read more Source
The FDA And Its Pilot Pharma Fraud Program
January 26, 2011
Earlier this week, the US Department of Health Human Services trumpeted its efforts to root out healthcare fraud and recover 4 billion for taxpayers, including about 2.

Anti-Notch therapies are being evaluated for cancer. When Washington University scientists disrupted Notch1 signaling in mice, they developed vascular tumors, primarily in the liver, which filled with blood (shown) and eventually led to massive hemorrhages and death.
Credit: Washington University in St. Louis ---
Posted on: Wednesday, 26 January 2011, 10:27 CST
By Caroline Arbanas
Washington University in St. Louis Widespread vascular tumors, massive hemorrhage and death reported in mice A study by researchers at Washington University School of Medicine in St. Louis has raised safety concerns about an investigational approach to treating cancer. The strategy takes aim at a key signaling pathway, called Notch, involved in forming new blood vessels that feed tumor growth. When researchers targeted the Notch1 signaling pathway in mice, the animals developed vascular tumors, primarily in the liver, which led to massive hemorrhages that caused their death. Their findings were reported online Jan. 25 in The Journal of Clinical Investigation and will appear in the journal’s February issue.
A number of anti-Notch therapies now are being evaluated in preclinical and early clinical trials for cancer. They target Notch1 as well as the three other signaling pathways in the Notch receptor family. The current research did not study any of these specific therapies in mice but instead focused on the potential side effects of chronically disrupting the Notch1 signal in individual cells. “Our results suggest that anti-Notch1 strategies are bound to fail,” says Raphael Kopan, PhD, professor of developmental biology and of medicine at the School of Medicine. “Without the Notch1 signal, cells in the vascular system grow uncontrollably and produce enlarged, weakened blood vessels. Eventually, the pressure within those vessels exceeds their capacity to hold blood, and they rupture, causing a dramatic loss of blood pressure, heart attack and death.” Notch plays a crucial role in determining a cell’s fate and is active throughout a person’s life.
In recent years, the pathway has emerged as a target to block the formation of blood vessels – called angiogenesis – in solid tumors. Kopan says he is not advising that anti-Notch clinical trials already under way be halted. These early trials generally involve short-term use of the drugs and are designed to assess safety. However, he says patients who take anti-Notch therapies for extended periods should receive MRI scans to check for liver abnormalities.

In the new research, Kopan and his colleagues engineered mice to develop random but progressive disruptions in the Notch1 gene in cells that depend on its signal. This model mimics a scenario that may occur in cancer patients receiving anti-Notch therapies for extended time periods. Then, the researchers monitored the mice for any potential negative consequences and compared the outcomes of 41 mutant mice to 45 normal “control” mice. Within several months, the experimental mice developed opaque corneas, which were already known to be associated with a loss of Notch1 signaling. Otherwise, for more than a year, the genetically engineered mice appeared to grow and develop normally. Then, for no apparent reason, they started dying suddenly. The researchers conducted autopsies on 13 pairs of experimental and control mice.
They noted vascular tumors and/or abnormal collections of blood vessels called hemangiomas in 85 percent (11/13) of the mutant mice, primarily in the liver. Some of the mice developed additional tumors in the uterus, colon, lymph nodes, skin, ovary and testis. None of the control animals developed vascular tumors or hemangiomas. On average, the experimental mice lived 420 days compared with 600 days for the control mice. “It is highly unlikely that mice in the experimental group would randomly die so soon,” Kopan explains. “When we examined the mice, we found evidence of ruptured blood vessels and pooling of blood in their body cavities along with an odd-looking liver pathology.”

The investigators then conducted MRI scans on living experimental mice. They noted that their livers had holes that looked “like a big Swiss cheese instead of having a dense, reddish, featureless landscape,” Kopan says. “This is highly abnormal.” All the evidence pointed to abnormalities in the endothelial system in the experimental mice. Endothelial cells line blood vessels, allowing them to expand and contract as blood is pumped through the body. For reasons the researchers don’t yet understand, endothelial cells in the liver were most affected. Ninety percent of the proliferating liver endothelial cells in the experimental mice had lost the Notch1 signal. Notch plays many roles in the body, depending on the cellular context. In some instances, Notch can spur tumor growth and in others suppress it.

The researchers suspect that loss of the Notch1 signal in the experimental mice releases the brakes on endothelial cell division, allowing the cells to proliferate uncontrollably, particularly in the liver. Anti-notch compounds now in preclinical and clinical trials include gamma secretase inhibitors, originally developed to treat Alzheimer’s disease.

These drugs block an enzyme all Notch receptors rely on. Other drugs in the pipeline are called DLL4 antibodies, which also disrupt Notch signaling and blood vessel formation. Anti-Notch1 antibodies are also being developed. Kopan, however, says he is not optimistic about the prospects for any of them. “The therapeutic window for any kind of anti-Notch1 therapy – that’s the dosage of a drug that is both safe and effective – is extremely small, perhaps even nonexistent, for these compounds in their current form," he says. "We need to do additional research to try to find out how we can open that window."

The research was funded by the National Institutes of Health, the National Cancer Institute and the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis. Liu Z, Turkoz A, Jackson EN, Corbo JC, Engelbach JA, Garbow JR, Piwnica-Worms DR, Kopan R. Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. The Journal of Clinical Investigation. February 2011.
Healthy You
New evidence shows a possible link between too much sugar and high blood pressure, high cholesterol and liver disease. The Dr. Oz Show dedicated a portion of Thursday's show to the issue. Host and doctor Mehmet Oz called it the No. 1 substance that should be removed from households...Keep reading...
Discovery of a biochemical basis for broccoli's cancer-fighting ability
Scientists are reporting discovery of a potential biochemical basis for the apparent cancer-fighting ability of broccoli and its veggie cousins. They found for the first time that certain substances in the vegetables appear to target and block a defective gene associated with cancer. Their report, which could lead to new strategies for preventing and treating cancer, appears in ACS' Journal of Medicinal Chemistry.

Fung-Lung Chung and colleagues showed in previous experiments that substances called isothiocyanates (or ITCs) — found in broccoli, cauliflower, watercress, and other cruciferous vegetables — appear to stop the growth of cancer. But nobody knew exactly how these substances work, a key to developing improved strategies for fighting cancer in humans. The tumor suppressor gene p53 appears to play a key role in keeping cells healthy and preventing them from starting the abnormal growth that is a hallmark of cancer. When mutated, p53 does not offer that protection, and those mutations occur in half of all human cancers. ITCs might work by targeting this gene, the report suggests.

The scientists studied the effects of certain naturally-occurring ITCs on a variety of cancer cells, including lung, breast and colon cancer, with and without the defective tumor suppressor gene. They found that ITCs are capable of removing the defective p53 protein but apparently leave the normal one alone. Drugs based on natural or custom-engineered ITCs could improve the effectiveness of current cancer treatments or lead to new strategies for treating and preventing cancer.
Painkillers fuel growth in drug addiction, from the Harvard Mental Health Letter
January 2011

Prescription painkillers kill about twice as many people as cocaine and five times as many as heroin. Nearly two million Americans are dependent on or abusing narcotic (opioid) pain relievers — nearly twice as many as are addicted to cocaine. Because opioid painkillers target the same brain receptors as heroin, causing euphoria, they carry the risk of addiction.
On television shows, drug addicts are often depicted as criminal characters making deals on dark street corners. In fact, people abusing opioid painkillers are most likely to obtain them from friends or family members rather than from any other source, reports the January 2011 issue of the Harvard Mental Health Letter.

Dr. Michael Miller, editor in chief of the Harvard Mental Health Letter, explains that treatment for a painkiller addiction is most successful when it consists of two phases: detoxification to reduce or eliminate withdrawal symptoms after opioid use stops, followed by a longer (and sometimes indefinite) maintenance phase. Although counseling is an important part of treatment, most people addicted to painkillers require treatment a medication such as methadone or buprenorphine during both detoxification and maintenance therapy. Although most people addicted to opioids make multiple attempts to kick the habit, it can be done.
Read the full-length article: "Painkillers fuel growth in drug addiction"

Drugs That Harm The Liver : Worldwide News
Medical Officers Caution Against "Nimesulide"
Wednesday, 26 January 2011 08:15
Medical Officers have been asked to be more cautious in the prescription and dispensing of "Nimesulide" to patients, especially children.

This comes amidst growing global concern about the harmful and damaging effect of the drug on the liver.

"Nimesulide" is an analgesic (pain killer) that is also used to control inflammation and high body temperature.The Drug Information Unit of the Komfo Anokye Teaching Hospital (KATH), in Kumasi in the Ashanti Region in its latest News letter publication, reminded doctors that the Food and Drugs Board (FDB) is currently reviewing the safety of the drug. It made reference to the World Health Organisation's (WHO) "Information Exchange System Alert", which shows that there are a total of 320 reports of liver and biliary disorders in patients, who received "Nimesulide."Out of these cases, 18 have been proved to be the result of the drug's use. It said doctors should make sure that they continuously monitor the function of the liver of patients on such medicines.It must be stopped immediately if patients show the slightest symptom of liver damage. The publication advised the public to also report all adverse reaction on the use of the drug to the FDB.
Source: GNA
(CN) - A child who needed a liver transplant after taking generic ibuprofen and going into organ failure can pursue failure-to-warn claims under state law against the drug manufacturer, the 9th Circuit ruled on Monday.
With the ruling the federal appeals court in San Francisco becomes the third circuit to apply the 2009 U.S. Supreme Court decision Wyeth v. Levine to both name-brand drug manufacturers and those who make and sell the cheaper generic versions.
The high court determined in Levine that approval of medication by the Federal Drug Administration does not preempt or shield a manufacturer of brand-name medications from liability under state law. Since the 2009 ruling, two courts of appeals - the 5th and the 8th Circuits - have applied it to generic drugs as well.
After A.G., a minor child, had two benign moles removed in 2004, his doctor gave him a prescription for ibuprofen for the pain. His parents, the Gaetas, bought an over-the-counter generic ibuprofen manufactured by Perrigo Pharmaceuticals. Later, A.G. developed a high fever and had to be rushed to the hospital and treated for liver failure. A.G. needed a liver transplant less than two weeks after the mole surgery and later had dead tissue from his fingers and toes amputated. Doctors determined that the ibuprofen had clashed with the anesthetic Halothane, which had been administered during the mole-removal surgery. Halothane is hepatotoxic or known to cause liver failure in some circumstances, according to the ruling.
The Gaetas sued Perrigo and other manufacturers of generic ibuprofen, alleging defective design, defective marketing, breach of express and implied warranty, negligence and gross negligence, and deceit by concealment. The family claimed that Perrigo had failed to warn doctors and consumers that ibuprofen could cause liver injury if mixed with other drugs. Perrigo argued that the Gaetas' state-law failure-to-warn claims were preempted by the FDA's labeling and marketing regulations governing generic drugs. The district court agreed, concluding that since federal law required generic drugmakers to conform to the approved labeling of brand-name drugs, Perrigo could not have changed its labeling without violating federal law. While the Gaetas' appeal was pending, the U.S. Supreme Court issued its opinion on Levine, and the family won a limited remand from the 9th Circuit so that the district court could reconsider its decision with the Supreme Court ruling in mind. The district court denied the family's motion for reconsideration, however, and ruled that the high court's decision only applied to brand-name drug manufacturers.
When the Gaetas appealed again, the three-judge panel decided the issue of first impression in favor of the Gaetas and reversed the district court's ruling. In Levine the high court reasoned that manufacturers are primarily responsible for warning consumers about possible drug dangers because they have better access to information about their products than the FDA has, according to the ruling. But there is nothing in the decision that limits this responsibility to brand-name drug manufacturers, the panel found.
"Indeed, the regulatory framework makes clear that generic manufacturers, just like their brand name counterparts, must take specific steps when they learn of new risks associated with their products," Judge David Thompson wrote for the panel. "Thus, both sets of manufacturers must record and report to the FDA certain adverse effects."
Thompson added that Perrigo had at least three "mechanisms to warn consumers and health care professionals of the risks associated with using ibuprofen concurrently with other drugs known to be hepatotoxic," including a "prior approval" process that would have applied the generic manufacturer's proposed changes to the drug's warning label to both the name-brand and generic drugs.
Perrigo would not have run afoul of federal regulations if it simply suggested that the FDA send a "Dear Doctor" letter to heath care professionals, warning them of the risks associated with using ibuprofen concurrently with other drugs, the panel found.
"The state-law duty to warn by an appropriate label on the generic ibuprofen drug was not preempted by federal law," the ruling states. "Compliance with both state and federal law was not 'impossible.' Additional warnings would not stand as an obstacle to the accomplishment of purposes and objectives of Congress. Perrigo failed to present clear evidence that the FDA would have rejected the specific hepatotoxicity warnings proposed by the Gaetas."
Published: January 26th, 2011
Canadian health officials are joining the growing number of countries that are monitoring the potential side effects of Multaq, a relatively new heart drug, for links to liver failure and other liver problems.
Health Canada began a review of Multaq after the FDA announced earlier this month that it is requiring the drug to carry new warnings about the possibility of severe liver problems with Multaq.
Although there have been at least two reported cases of liver failure requiring a transplant among users of Multaq and several other reports of liver injury in the United States, there have been no adverse reaction reports in Canada involving Multaq liver problems.
The European Union is also reviewing Multaq for liver damage links, and last week Sanofi-Aventis sent letters to healthcare providers in Europe detailing the two cases of acute liver failure which played a crucial role in the FDA’s decision to add new label warnings to the drug.
Multaq (dronedarone) was approved in July 2009 for the treatment of patients who have had abnormal heart rhythms in the last six months. In less than two years since its approval, there have been at least 492,000 Multaq prescriptions in the United States filled by about 147,000 patients at outpatient pharmacies across the country. In addition, the drug can be given to patients being treated in hospitals.
The two cases of acute Multaq liver failure and transplantation that preceded these warnings in the United States and Europe both occurred in women about 70 years of age. One suffered liver failure after six months on Multaq and another after only four and a half months. Both had atrial fibrillation problems. In both cases, doctors found signs of extensive cellular death in the liver, and in both cases they ruled out other possible causes of liver failure.
Canadian health officials reported they have only received about 40 adverse event reports concerning Multaq between its launch and October 31, 2010. None of those cases involve liver damage from Multaq.
..Keep reading..
On the 45th anniversary of the first kidney transplant in Poland we talk to Professor Wojciech RowiƄski, a member of the team of doctors who performed the surgery in 1966.



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