AstraZeneca's Crestor doubles side effects-study (Full Article)f1

By Maggie Fox, Health and Science Correspondent
Mon May 23, 6:26 PM ET

WASHINGTON (Reuters) - AstraZeneca's cholesterol-lowering drug Crestor has more than double the side effects of rival statin drugs, including deaths, U.S. researchers reported on Monday.

Adverse effects include muscle damage known as myopathy, including a severe form known as rhabdomyolysis; proteinuria or protein in the urine; nephropathy, a reduced ability of the kidneys to filter toxins from the blood; and kidney failure.

American Heart Association, which published the study in its journal Circulation, said the drug was still generally safe if prescribed properly and urged patients not to panic or stop taking the drug.

And AstraZeneca said it strongly disagreed with the study's conclusions.

Dr. Richard Karas of the Tuft-New England Medical Center in Boston, who led the study, said his team found a rate of 28 adverse events per million prescriptions of Crestor, known generically as rosuvastatin.

That was about 2.2 times more than the adverse events seen with simvastatin, made by Merck and Co. under the brand name Zocor and 6.8 times higher than atorvastatin, made by Pfizer Inc. under the brand name Lipitor, he said...

Karas said there were 6 per million deaths on Crestor as compared to 3 per million for Zocor, 1 per million with Bristol Myers Squibb's Pravachol and 2 per million for Lipitor.

"It would seem prudent at the current time for healthcare providers to consider other statins as first-line therapy, to initiate therapy in appropriate patients at lower doses, to consider combination LDL-C lowering therapy (eg, statin combined with ezetimibe), and to vigilantly monitor for adverse events if rosuvastatin is used," they concluded.

REFUSAL TO BAN

"We strongly disagree with the conclusions of this study," the company said in a statement.

"The study implies that because post-marketing rates of spontaneous adverse event reports were higher, the risk is also higher. This is factually incorrect,' it added.

" ... These reports are just that, reports, not medically confirmed cases."

In March, the U.S. Food and Drug Administration denied a petition by the consumer group Public Citizen to ban Crestor, saying it disagreed with arguments that Crestor was more dangerous than other statins.

For the study, Karas and colleagues looked at adverse events reported to the FDA between October 2003 and the end of September 2004.

They broke the data down in several ways but found that overall, Crestor was associated with many more adverse event reports than its rivals.

Nonetheless, several heart experts said the drug was safe overall and should be prescribed for some patients.

"Importantly, most side effects, including myopathy, disappear upon withdrawal of medication," said Dr. Scott Grundy, director of the Center for Human Nutrition at the University of Texas Southwestern Medical Center in Dallas, who wrote a commentary on the report in Circulation.

Karas said it was important to note that there is no way to prove Crestor caused the side effects reported to the FDA.

"One of the limitations is that the current surveillance system does not require the reporting of all the drugs that patients are taking," he told reporters in a telephone news briefing.

Crestor is considered a more powerful statin than the others and Karas and other experts said it may be the only way to get cholesterol down to desirable levels in some people. But he also noted that 62 percent of the adverse events were seen at the very lowest dose of the drug.

Statin drugs lower low density lipoprotein or LDL -- the so-called bad cholesterol that clogs arteries. Patients who take them lower their risk of heart attacks, stroke and also some cancer such as breast and prostate cancer, as well as Alzheimer's disease.

Another statin, Bayer AG's Baycol, was pulled from the market in 2001 after it was linked to more 100 deaths, many of them from rhabdomyolysis.

Karas said Crestor did not seem to cause as much muscle damage as Baycol.

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 Mechanism for green tea's anti-cancer action revealed (Full Article)f2

5/17/2005 - Green tea appears to protect against cancer by affecting a 'promiscuous' protein that pharmaceutical experts are already targeting in their work on anti-cancer drugs, according to new research.

The study, by PhD student Christine Palermo at the University of Rochester Medical Center, reveals a potential new mechanism to explain the tea, and particularly its active compounds' action against cancer. While many studies suggest that green tea protects people against some forms of cancer, such as breast and liver cancer, exactly how it does so has been difficult to pinpoint.

"It's important to find out the source of green tea's protective effects," said toxicologist Thomas A Gasiewicz, whose work on the harmful effects of dioxin led the Rochester group to explore the protective effects of green tea.

"What is exciting here is that a completely new mechanism has been found that very well could be responsible for its protective effects, and that could help us find a compound that is much more potent."

Palermo, Gasiewicz, and current undergraduate Claire Westlake discovered that a chaperone protein known as HSP90 is involved in conferring green tea's protective effects. Other researchers have shown that many cancer cells have an increase in the level of HSP90 compared to healthy cells, and that when HSP90 is blocked, levels of proteins that make cancer cells grow drop.

Drug makers are currently working on ways to block HSP90, which is known as a promiscuous chaperone protein because it binds to many different cells and receptors in the body. It turns out that those researchers are trying to duplicate what green tea does naturally. Gasiewicz says green tea might modulate HSP-90 in a way that researchers have not seen before.

Gasiewicz and his group have shown how dioxin and other substances like cigarette smoke manipulate a major cancer-causing molecule, the aryl hydrocarbon (AH) receptor, which frequently plays a role in turning on genes that are oftentimes harmful.

Two years ago the team discovered that AH activity is inhibited by a chemical found in white and green teas, epigallocatechingallate or EGCG, now being produced and marketed as a supplement by DSM.

"We initially hypothesized that EGCG would work in the same way as other AH antagonists, by binding directly to it. We were completely surprised that this isn't the case," said Gasiewicz, whose work was funded by the National Institute of Environmental Health Sciences and the American Institute for Cancer Research.

Instead, the team found that EGCG binds to HSP90, a protein that helps other proteins stay stable, serving the same role as a tail on a kite. When the two bind, HSP90 no longer turns on the AH receptor, stopping the cascade of events that would lead to the activation of several harmful genes.

Another potential mechanism for green tea's action was outlined recently by a team at the University of Wisconsin and Case Western Reserve University in Cleveland, Ohio. The found that green tea polyphenols reduce levels of insulin-like growth factor-1 (IGF-1) in prostate tumour cells in a mouse model for human prostate cancer. Increased levels of IGF-1 are associated with higher risk of several cancers, such as prostate, breast, lung and colon.

Meanwhile, researchers at Kyushu University in Japan reported last year that EGCG appears to inhibit tumour cell growth by binding to a receptor on cells called the 67-kDa laminin receptor. A variety of tumours produce abnormally high levels of 67 LR, and the receptor is thought to be involved in the spread of cancers through the body.

The new research was published in the 5 April issue of Biochemistry.

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