Germans claim Alzheimer's toxin breakthrough

GERMAN researchers claim they have found a way of blocking the formation of a toxin blamed for the onset of Alzheimer's disease. The researchers from the chemistry department at Berlin's Free University said the discovery could prove useful in the development of medicines to combat the fatal brain disease.

Biochemist Gerd Multhaup said his team had largely managed to inhibit the formation of Amyloid-Beta Asse42, which destroys nerve cells and plays a key role in the onset of Alzheimer's. They have patented the technique which subverts the formation of the toxin, he said.

The group's findings will be published in The Embo Journal science review at the end of April. There is currently no cure for Alzheimer's but there are medicines aimed at mitigating the effects of the debilitating disease.

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Big blow for cholesterol theory

Pfizer spent more than $900 million testing its experimental heart pill, torcetrapib. But in December a 15,000-patient study revealed that this chemical increased death rates, forcing Pfizer to suddenly drop the project. What went wrong? Why torcetrapib failed is the biggest mystery facing the $260 billion global pharmaceutical industry, which has spent years in a research dry spell. On paper, torcetrapib looked like a winner. It boosted levels of good cholesterol, known as HDL, by 50%. It cut bad cholesterol, or LDL, by 20% on top of existing meds like Pfizer's Lipitor. Pfizer had hoped that would lead to a wave of new good-cholesterol-raising drugs that could reduce heart attack rates far beyond what Lipitor can do alone.

But the terrible results have thrown the whole concept of raising HDL via drugs into turmoil. Here at the annual meeting of the American College of Cardiology (ACC), researchers unveiled results of new studies that examined the neck and coronary arteries of patients on the drug using ultrasound imaging. They showed Pfizer's pill did nothing to clear out clogged arteries as had been hoped.

One study used a technique that peers directly inside the coronary arteries using a catheter. It found the drug raise blood pressure by 4.6 points, far more than expected. Two other ultrasound studies even hinted that torcetrapib might have made plaque buildup in the carotid artery in the neck worse. These murky results may not stop other drug companies from testing HDL boosters, but they will significantly delay the development of those drugs. For the foreseeable future, doctors will probably be forced to refocus on getting bad cholesterol down as far as they can. Other HDL-boosting drugs presented at the meeting also failed or yielded mixed results. An Eli Lilly pill to raise HDL and cut triglycerides, or particles of fat in the blood, proved no more effective than older drugs and were potentially dangerous. A method of injecting HDL into patients' veins, developed by Australian flu-shot-maker CSL Limited, failed to confirm the promise of a similar experiment three years ago, although it did hint that the medicine might clear arteries some.

The torcetrapib mystery is deepened because data from the big 15,000-patient trial are not yet available. Study head Philip Barter of the University of Sydney told an overflow crowd at the meeting that it would be the early fall before results of that trial can be fully analyzed to see what went wrong. "Nothing is being hidden," he said. "We still just do not know" what happened. Pfizer Senior Vice President Michael Berelowitz said Pfizer is exhaustively reviewing "every element" of the patient data to figure out what happened.

Cleveland Clinic cardiologist and ACC head Steven Nissen, who conducted one of the ultrasound studies, says there are three possible explanations of how torcetrapib went awry. One is that torcetrapib produced HDL that did not work properly. Another is that the blood pressure side effect made the drug toxic. Experts who still hold out hope for such medicines are betting on a third possibility. The drug might have caused some nasty damage to blood vessel walls, and the increased blood pressure was just a consequence of this more severe damage. The drug "was obviously toxic. It may be doing something bad to blood vessels, and the blood pressure is just a manifestation," Nissen said.

The Pfizer drug worked by blocking the cholesterol ester transfer protein (CETP), and there has long been a controversy among cardiologists whether this approach to raising good cholesterol would be beneficial. If so, then it would mean that similar CETP-blocking drugs in development at Merck and Roche Holding are highly unlikely to work.

But some experts say it's at least possible that the drug's problems were caused by strange side effects linked to torcetrapib's tendency to raise blood pressure. "I realize that it is proposing a lot," says Daniel Rader of the University of Pennsylvania, "but I do think it is possible." He thinks other companies should cautiously continue to test their HDL-raisers. John Kastelein of the University of Amsterdam, who conducted two of the imaging studies, says it is still possible other CETP inhibitors like those from Merck and Roche might work.

With two big studies indicating no positive effect on arteries, "it starts to increase the evidence that this may not have been a good idea at all, and that the whole concept is just not the right approach," says Baylor College of Medicine cardiologist Christie Ballantyne, who noted that there had long been "a major debate" about whether CETP inhibitors could work.

The genetic evidence about CETP inhibitors was always murky, says Evan Stein, director of the Metabolic and Atherosclerosis Research Center in Cincinnati. He says doctors should focus as much as possible on reducing bad cholesterol, which has proven benefits.

Nissen argues that the potential of CETP inhibitors is too great to abandon, even given the risks. But he says that the failure of torcetrapib is a setback that will cost drug developers many years. "You cannot kill the whole class just because the first drug has an unusual toxicity," he says.

Experts agree that to test new HDL-boosters or other drugs designed to prevent or reverse the build-up of artery plaque, drug companies are going to have to take a much more cautious approach. Pfizer plunged ahead with all its studies at once. Now drug companies will have to do imaging studies like those conducted by Kastelein and Nissen first, before plunging into larger, more definitive trials. These take at least three years.

Allen J. Taylor, chief of cardiology at Walter Reed Army Medical Center, says it is "reassuring" that imaging studies were consistent with the large torcetrapib trial and would have prevented torcetrapib from being developed if they were done first. But Pfizer's Berelowitz warns he would derive "no certainty" based on imaging studies, given that they have not always delivered clear results.

For the moment, doctors who are treating heart disease may find themselves going back to the future. They will treat bad cholesterol as well as they can with medicines like Lipitor and Zocor, which have been around since the introduction of Merck's Mevacor 20 years ago. HDL-boosting drugs are "not ready for prime time," says Sanjay Kaul, of Cedars-Sinai Medical Center in Los Angeles. He believes that developing HDL drugs is going to be a long and difficult road. "The next 10 to 15 years will be a fertile time for research on HDL. And sooner or later we will get there."

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Just some problems with the "Obesity" war:

1). It tries to impose behavior change on everybody -- when most of those targeted are not obese and hence have no reason to change their behaviour. It is a form of punishing the innocent and the guilty alike. (It is also typical of Leftist thinking: Scorning the individual and capable of dealing with large groups only).

2). The longevity research all leads to the conclusion that it is people of MIDDLING weight who live longest -- not slim people. So the "epidemic" of obesity is in fact largely an "epidemic" of living longer.

3). It is total calorie intake that makes you fat -- not where you get your calories. Policies that attack only the source of the calories (e.g. "junk food") without addressing total calorie intake are hence pissing into the wind. People involuntarily deprived of their preferred calorie intake from one source are highly likely to seek and find their calories elsewhere.

4). So-called junk food is perfectly nutritious. A big Mac meal comprises meat, bread, salad and potatoes -- which is a mainstream Western diet. If that is bad then we are all in big trouble.

5). Food warriors demonize salt and fat. But we need a daily salt intake to counter salt-loss through perspiration and the research shows that people on salt-restricted diets die SOONER. And Eskimos eat huge amounts of fat with no apparent ill-effects. And the average home-cooked roast dinner has LOTS of fat. Will we ban roast dinners?

6). The foods restricted are often no more calorific than those permitted -- such as milk and fruit-juice drinks.

7). Tendency to weight is mostly genetic and is therefore not readily susceptible to voluntary behaviour change.

8). And when are we going to ban cheese? Cheese is a concentrated calorie bomb and has lots of that wicked animal fat in it too. Wouldn't we all be better off without it? And what about butter and margarine? They are just about pure fat. Surely they should be treated as contraband in kids' lunchboxes! [/sarcasm].

Trans fats:

For one summary of the weak science behind the "trans-fat" hysteria, see here. Trans fats have only a temporary effect on blood chemistry and the evidence of lasting harm from them is dubious. By taking extreme groups in trans fats intake, some weak association with coronary heart disease has at times been shown in some sub-populations but extreme group studies are inherently at risk of confounding with other factors and are intrinsically of little interest to the average person.

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