PharmaLive.com, March 17, 2009 — The Food and Drug Administration says an experimental drug from Sanofi-Aventis could significantly decrease hospitalizations caused by irregular heart rhythms.

Sanofi has asked the FDA to approve its drug Multaq to treat atrial fibrillation, a condition in which the upper chambers of the heart quiver instead of beating effectively, potentially causing blood clots.

On Wednesday an outside panel of cardiologists will give their opinion of the drug’s safety and effectiveness. But regulators signaled Monday they already favor approval for the drug, also known as dronedarone, in briefing documents posted online.

The positive assessment marks a significant comeback from Multaq, which was rejected by FDA in 2006 after a study linked the medication to higher death rates.

But the head of FDA’s heart drug division said more recent results from the company “define a population which derives benefit from dronedarone use and in whom safety was demonstrated.”

The study that showed a higher death rate with Multaq included patients with severe heart failure, who already face higher mortality risks.

A more recently completed trial, focused on patients with less severe health problems, showed Multaq significantly reduced the need for hospitalization due to atrial fibrillation when compared with placebo.

The same trial, which included more than 4,600 patients, also showed Multaq slightly reduced the risk of death, though the change was not significant. As a result, FDA heart division leader Abraham Karkowsky said he does not support a claim that the drug can reduce risk of death.

“The results are not convincing that, aside from hospitalization for atrial fibrillation, dronedarone prevents other morbid or mortal outcomes,” Karkowsky wrote in his review.

Because of the negative results seen in earlier trials, Karkowsky recommended the drug be contraindicated in patients with severe heart failure.

On Wednesday, the FDA’s panelists will weigh in that recommendation and others on who should receive the drug. The agency is not required to follow the group’s advice, though it normally does.

If approved by the FDA, Multaq would be the first new medication in more than 25 years to treat atrial fibrillation. Currently doctors frequently prescribe the drug amiodarone, a heart rhythm medication marketed as Cordarone or Pacerone. But that drug can have significant side effects, including breathing problems.

The most frequent side effects reported with Multaq were diarrhea and other intestinal problems.

Paris-based Sanofi has touted the drug as a significant new franchise, with a potential market of more than 6 million patients in the U.S. and Europe, where the drug is also under review.

“Whereas other drugs may treat the symptoms of rate and rhythm, Multaq actually addresses the more important outcomes of hospitalization and death,” said Dr. Paul Chew, president of Sanofi’s U.S. research and development division.

Atrial fibrillation accounts for about 15 percent of strokes, according to the American Heart Association. And with the number of patients affected by the condition expected to double by 2050, several drug makers are working on treatments.

Cardiome Pharma Corp. and partner Astellas Pharma currently have their own atrial fibrillation drug under review at the FDA. And earlier this month Bristol-Myers Squibb Co. licensed the rights to a comparable drug from two Japanese firms.

Shares of Sanofi-Aventis rose 37 cents, or 1.4 percent, to close at $26.67 Monday.

U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH NIH News
National Institute on Drug Abuse (NIDA)

For Release: Tuesday, March 17, 2009

NIDA research could lead to better treatment for pain and marijuana addiction

New research funded by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health, has identified a new mechanism for the processing of endocannabinoids, natural brain compounds similar to THC, the active ingredient in marijuana. The results of this study, led by researchers from Stony Brook University, were published March 16 in the Proceedings of the National Academy of Sciences.

Endocannabinoids are known to play a role in numerous physiological processes including appetite, memory, and pain. Researchers had long suspected that endocannabinoids needed a specific transporter that would ferry them to the location where they are broken down. This study successfully identified a couple of previously known fatty acid binding proteins (FABPs) as capable of carrying the endocannabinoid anandamide (also known as AEA) from the cell membrane, through the cell interior, to the location where it is destroyed.

“This finding is important because it significantly expands the range of potential targets for developing medications that could help fight pain, addiction, and other disorders,” said NIDA Director Dr. Nora D. Volkow. “For example, the manipulation of the endocannabinoid system has the potential to provide sorely needed therapeutics for the management of severe pain that are devoid of the side effects of opiate analgesics.”

The breakdown of AEA requires two factors. First, because AEA is a fatty compound and thus unable to move inside the watery cellular environment, there needs to be a mechanism for transporting AEA to the location where it is inactivated. Second, the cell must express an enzyme called FAAH, which is responsible for breaking down and inactivating AEA. In the laboratory, the researchers coaxed a non-neuronal cell type (Cos-7) to express FAAH. These FAAH-expressing Cos7 cells were able to break down AEA efficiently, indicating that the intracellular AEA transport mechanism was already present and operational in these cells. The researchers identified these carriers as two different, previously known fatty-acid binding proteins (FABPs). By specifically inhibiting FABPs, they were able to decrease the breakdown of AEA by about 50 percent.

“Inhibiting FABPs could potentially raise the levels of AEA in the brain’s synapses,” said Dr. Dale Deutsch, lead author of the study. “Naturally occurring AEA levels have been shown to curb pain without the negative side effects, such as motor coordination problems, of molecules like THC that can also bind the cannabinoid receptor. So it’s advantageous to try and target AEA for therapeutic purpose.”

“From a theoretical viewpoint, this approach could be used for treating marijuana addiction,” said Dr. Volkow. “Compounds that inhibit FABPs could produce an effect similar to nicotine patches for smokers or methadone for opiate replacement. This line of research may also be important for other types of addiction, such as chronic alcohol abuse, which also affects AEA levels,” she explained.

In addition to pain control, researchers are also examining manipulation of the endocannabinoid system for treating anxiety, obsessive-compulsive disorder, traumatic brain injury, and other substance abuse disorders.

The National Institute on Drug Abuse is a component of the National Institutes of Health, U.S. Department of Health and Human Services. NIDA supports most of the world’s research on the health aspects of drug abuse and addiction. The Institute carries out a large variety of programs to inform policy and improve practice. Fact sheets on the health effects of drugs of abuse and information on NIDA research and other activities can be found on the NIDA home page at www.drugabuse.gov>. To order publications in English or Spanish, call NIDA’s new DrugPubs research dissemination center at 1-877-NIDA-NIH or 240-645-0228 (TDD) or fax or email requests to 240-645-0227 or . Online ordering is available at .

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit .

TimesOnline.co.uk, by Mark Henderson — A “gene doping” technique that makes the muscles of mice grow up to 30 per cent stronger will be the next frontier of cheating in professional sport, scientists gave warning today.

The new form of gene therapy, which is being developed to treat patients with muscular dystrophy and other wasting diseases, will inevitably be abused by athletes seeking the ultimate illegal edge, according to the researchers behind it and anti-doping experts.

Experiments at the University of Pennsylvania have revealed that when normal mice are injected with a modified virus that adds a vital growth gene to their cells, they develop into heavily muscled, super-strong animals that the scientists have nicknamed “mighty mice”.

The effects are almost doubled when the gene therapy is coupled with a weight-training regime.

Such genetic enhancements would deliver vast improvements in speed, power and strength if given to an athlete, said Lee Sweeney, who led the Pennsylvania research.

Gene doping has the potential to boost an unscrupulous sportsman’s performance more steeply even than existing drugs such as anabolic steroids and erythropoeitin (EPO).

It would also be extremely difficult to detect, as it mimics the quirks of inheritance that give some athletes a natural genetic advantage.

Dr Sweeney told the American Association for the Advancement of Science that while the technology was designed for bona fide medical purposes, it was “inevitable” that it would eventually be abused “off label” in sport.

He has already been approached by coaches and athletes, mainly bodybuilders, seeking to try gene therapy, even though the technique is barely ready for patient trials.

“This is but one example of a number of potential gene therapies that are being developed with disease treatment as the goal, but if given to a healthy individual would provide genetic enhancement of some trait,” Dr Sweeney said.

“As these developments go forward, they inevitably will find their way into the healthy population.

“The prospects are especially high that muscle-directed gene transfer will be used by the athletic community for performance enhancement, just as many drugs are used and abused today.

“It is unclear what the risks are that are associated with such use. In many cases, policing such abuse in the sports community will be much more difficult that in the case of drugs, since detection will be difficult.”

In the experiments, Dr Sweeney’s team genetically engineered a harmless virus to carry a gene known as insulin-like growth factor I (IGF-I), which is critical to muscle growth and repair.

The gene is often missing or faulty in patients with wasting diseases such as muscular dystrophy, and the goal of the work is to design a means of fixing this genetic mistake and curing these conditions.

When the virus was injected into normal, healthy mice, their muscles grew in size and strength by between 15 and 30 per cent. The genetically-enhanced muscles were more durable, and repaired themselves much more quickly when damaged.

The added IGF-I gene also stopped the ageing process in its tracks: when middle-aged mice were injected with it, and then grew old, they suffered none of the muscle wastage typical of old age.

The benefits of gene doping were greater still when combined with a training regime. The team injected IGF-I into the muscle of one leg of a rat, which was then kept in a cage in which it had to climb ladders regularly to reach food.

At the end of this training, the gene-doped leg was nearly twice as powerful as the untreated one, and retained its strength for longer when training was stopped.

The findings, which will be published next month in the Journal of Applied Physiology, indicate that gene doping in human athletes would provide benefits even greater than those of anabolic steroids.

The therapy would enhance lean muscle mass, allow athletes to train for longer and to recover more quickly from injury, and would prolong their careers by slowing down the muscle wastage that takes place with age.

Dick Pound, chairman of the World Anti-Doping Agency, said he was concerned that gene doping would become a major problem for sport.

At the 2012 Olympics it is certainly realistic to see the potential of gene doping.

“The thought that we might be able to cure muscular dystrophy is wonderful, but what’s not so good is the idea you’d have an 8ft shot-putter who could throw the shot 100 meters into the crowd.”

Many existing performance-enhancing drugs used in sport were originally developed for medical use. Synthetic EPO, for instance, is used for treating anemia, and human growth hormone for treating growth deficiencies and wasting diseases.

Thomas Murphy, president of the Hastings Centre, a US bioethics group, said athletes were certain to start using gene enhancement, even before it is available for therapeutic use. “Knowing what I know about athletes, long before it’s perfected people will be peddling gene enhancement technologies,” he said.

“I’m sure somebody out there is formulating a business plan about how they’re going to do this.”

He said gene therapy would pose great challenges for testing regimes, as it would be extremely difficult to detect. One possibility would be to test athletes for an immune response to the viral vector involved. “I’m not completely pessimistic about the prospects of detection, but neither am I optimistic,” he said.

Dr Pound said another answer would be to insist on the development of a test to show whether gene therapy has been used before potential techniques are allowed to begin clinical trials.

Any test would have to be sensitive enough to discriminate between artificial and natural performance-enhancing genetic oddities. “If God did it to you, your competitors have to live with it,” Dr Pound said.

“If your genetic consultant did it, that’s different.”

WebMD.com, March 17, 2009, by Marlene Busko — (Toronto, Ontario) — Evidence for health benefits from eating more servings of oily fish is not conclusive–especially for primary prevention of coronary events–and must be balanced against projections that worldwide fish stocks will be depleted in 40 years if current consumption continues, a review concludes [1].

Study researchers, led by Dr David Jenkins (University of Toronto, ON), suggest that until alternative sources of omega-3 fatty acids from plants, algae, or yeast become more available, “it would seem responsible to refrain from advocating to people in developed countries that they increase their intake of long-chain omega-3 fatty acids through fish consumption.”

On the other hand, the AHA still stands by its recommendation to consume two servings of fish–preferably fatty fish–per week to reduce risk of cardiovascular disease, Dr Penny M Kris-Etherton (University of Pennsylvania, University Park), a member of the AHA Nutrition Committee, told heartwire when asked to comment on the study.

The study is published in the March 17, 2009 issue of the Canadian Medical Association Journal.

According to Dr John L. Sievenpiper (Univ of Toronto), “If you are already leading a healthy lifestyle–if you are eating a heart-healthy diet, exercising, and you have a healthy body weight–there is certainly no evidence from randomized controlled trials to support a benefit” from fish oil for primary prevention of CVD. Meta-analyses and individual trials are divided about the value of fish oils for prevention of CAD, the authors write. The Prevenzione trial reported a 15% benefit in a four-way analysis for a combined outcome of all-cause mortality, nonfatal MI, or nonfatal stroke. However, the Diet and Angina Randomized Trial (DART-2) showed that men with angina who were advised to consume fish oil had an increased risk of cardiac death. Similarly, a meta-analysis of three major studies of implantable defibrillators documented that some individuals benefitted while others were adversely affected by taking fish oil.

Fish Stocks Threatened

In contrast to the uncertainty over the value of omega-3 fish oils in the scientific literature, there is scientific consensus about the rapid worldwide decline in fish stocks. Since 1950, the number of fish stocks that have collapsed–shrunk to 10% of their historic maximum yield–has grown exponentially, and there are now over 100 confirmed cases of marine-population extinctions. If this trend continues, all commercially exploited stocks of fish will likely be collapsed by 2048, said Sievenpiper.

“Yet the dire status of fisheries resources is largely unrecognized by the public, who are both encouraged to eat more fish and are misled into believing that we still sail in the sea of plenty,” the authors write.

Developed countries are importing fish from the developing world, while in the developing world, where people depend on fish for protein, population growth is also increasing demand for fish, according to Dr Ussif Rashid Sumaila (University of British Columbia Fisheries Centre, Vancouver). Large demand–for example, for shrimp–is also a factor behind bycatch–when fish other than the targeted species are just discarded–which can be destructive to the marine habitat, he added.

Potential Solutions

Fish farming, as currently practiced in developed countries, is unlikely to resolve the problem, the authors write, since the fish are raised on fishmeal and fish oils from smaller fish. According to Sievenpiper, “the equation is quite unfavorable, because it requires an input of more fish than you get out.”

On the other hand, nonmarine-based sources of the two long-chain omega-3 fatty acids in fish oil–docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)–might be viable solutions. Martek Biosciences (Colombia, MD) produces DHA from algae, which is added to foods, and other companies are exploring using yeast to produce EPA, said Sievenpiper. In addition, the plant-derived shorter-chain fatty acid alpha-linolenic acid (ALA) might be an alternative in populations with low intake of omega-3 fatty acid.

“We should be increasing our efforts in exploring these alternatives,” he said.

Significant Health Benefits

Kris-Etherton concurs that alternate sources of omega-3 fatty acids need to be investigated. In the meantime, depletion of fish stocks is not a reason to stop recommending eating more fish, she said, since current fish consumption is low.

Despite negative research results, most evidence clearly shows benefits of fish oil in cardiac patients, she added. The negative DART-2 study has been criticized for study limitations. On the other hand, the Prevenzione trial documented benefits that included a 45% reduction in sudden death. The many reported heart and brain benefits from omega-3 fatty-acid consumption include a significant decrease in age-related memory loss and Alzheimer’s disease.

“Americans on average eat about one serving of fish per week. If the population–more than 300 million–were to increase this even a little bit, this would have very significant health benefits,” she said.

Sievenpiper and Sumaila disclosed having no conflicts of interest; disclosures of the other authors are listed in the paper. Kris-Etherton disclosed having no conflicts of interest.

1. Jenkins DJA, Sievenpiper JL, Pauly D, et al. Are dietary recommendations for the use of fish oils sustainable? CMAJ 2009; 180:633-637.

If you think preventing climate change is politically difficult, look at the political problems of adapting to it.

The Guardian, March 17, 2009, by George Monbiot — Quietly in public, loudly in private, climate scientists everywhere are saying the same thing: it’s over. The years in which more than two degrees of global warming could have been prevented have passed, the opportunities squandered by denial and delay. On current trajectories we’ll be lucky to get away with four degrees. Mitigation (limiting greenhouse gas pollution) has failed; now we must adapt to what nature sends our way. If we can.

This, at any rate, was the repeated whisper at the climate change conference in Copenhagen last week(1). It’s more or less what Bob Watson, the environment department’s chief scientific adviser, has been telling the British government(2). It is the obvious if unspoken conclusion of scores of scientific papers. Recent work by scientists at the Tyndall Centre for Climate Change Research, for example, suggests that even global cuts of 3% a year, starting in 2020, could leave us with four degrees of warming by the end of the century(3,4). At the moment emissions are heading in the opposite direction at roughly the same rate. If this continues, what does it mean? Six? Eight? Ten degrees? Who knows?

Faced with such figures, I can’t blame anyone for throwing up his hands. But before you succumb to this fatalism, let me talk you through the options.

Yes, it is true that mitigation has so far failed. Sabotaged by Clinton(5), abandoned by Bush, attended half-heartedly by the other rich nations, the global climate talks have so far been a total failure. The targets they have set bear no relationship to the science and are negated anyway by loopholes and false accounting. Nations like the UK which are meeting their obligations under the Kyoto protocol have succeeded only by outsourcing their pollution to other countries(6,7). Nations like Canada, which are flouting their obligations, face no meaningful sanctions.

Lord Stern made it too easy: he appears to have underestimated the costs of mitigation. As the professor of energy policy Dieter Helm has shown, Stern’s assumption that our consumption can continue to grow while our emissions fall is implausible(8). To have any hope of making substantial cuts we have both to reduce our consumption and transfer resources to countries like China to pay for the switch to low-carbon technologies. As Helm notes, “there is not much in the study of human nature—and indeed human biology—to give support to the optimist.”

But we cannot abandon mitigation unless we have a better option. We don’t. If you think our attempts to prevent emissions are futile, take a look at our efforts to adapt.

Where Stern appears to be correct is in proposing that the costs of stopping climate breakdown – great as they would be – are far lower than the costs of living with it. Germany is spending E600m just on a new sea wall for Hamburg(9) – and this money was committed before the news came through that sea level rises this century could be two or three times as great as the Intergovernmental Panel on Climate Change has predicted(10). The Netherlands will spend E2.2bn on dykes between now and 2015; again they are likely to be inadequate. The UN suggests that the rich countries should be transferring $50-75bn a year to the poor ones now to help them cope with climate change, with a massive increase later on(11). But nothing like this is happening.

A Guardian investigation reveals that the rich nations have promised $18bn to help the poor nations adapt to climate change over the past seven years, but they have disbursed only 5% of that money(12). Much of it has been transferred from foreign aid budgets anyway: a net gain for the poor of nothing(13). Oxfam has made a compelling case for how adaptation should be funded: nations should pay according to the amount of carbon they produce per capita, coupled with their position on the human development index(14). On this basis, the US should supply over 40% of the money and the European Union over 30%, with Japan, Canada, Australia and Korea making up the balance. But what are the chances of getting them to cough up?

There’s a limit to what this money could buy anyway. The Intergovernmental Panel on Climate Change says that “global mean temperature changes greater than 4°C above 1990-2000 levels” would “exceed … the adaptive capacity of many systems.”(15) At this point there’s nothing you can do, for example, to prevent the loss of ecosystems, the melting of glaciers and the disintegration of major ice sheets. Elsewhere it spells out the consequences more starkly: global food production, it says, is “very likely to decrease above about 3°C”(16). Buy your way out of that.

And it doesn’t stop there. The IPCC also finds that, above three degrees of warming, the world’s vegetation will become “a net source of carbon”(17). This is just one of the climate feedbacks triggered by a high level of warming. Four degrees might take us inexorably to five or six: the end – for humans – of just about everything.

Until recently, scientists spoke of carbon concentrations – and temperatures – peaking and then falling back. But a recent paper in the Proceedings of the National Academy of Sciences shows that “climate change … is largely irreversible for 1,000 years after emissions stop.”(18) Even if we were to cut carbon emissions to zero today, by the year 3000 our contribution to atmospheric concentrations would decline by just 40%. High temperatures would remain more or less constant until then. If we produce it we’re stuck with it.

In the rich nations we will muddle through, for a few generations, and spend nearly everything we have on coping. But where the money is needed most there will be nothing. The ecological debt the rich world owes to the poor will never be discharged, just as it has never accepted that it should offer reparations for the slave trade and for the pillage of gold, silver, rubber, sugar and all the other commodities taken without due payment from its colonies. Finding the political will for crash cuts in carbon production is improbable. But finding the political will – when the disasters have already begun – to spend adaptation money on poor nations rather than on ourselves will be impossible.

The world won’t adapt and can’t adapt: the only adaptive response to a global shortage of food is starvation. Of the two strategies it is mitigation, not adaptation, which turns out to be the most feasible option, even if this stretches the concept of feasibility to the limits. As Dieter Helm points out, the action required today is unlikely but “not impossible. It is a matter ultimately of human well being and ethics.”(19)

Yes, it might already be too late – even if we reduced emissions to zero tomorrow – to prevent more than two degrees of warming, but we cannot behave as if it is, for in doing so we make the prediction come true. Tough as this fight may be, improbable as success might seem, we cannot afford to surrender.