AstraZeneca says data support new Seroquel use
Anglo-Swedish drugmaker AstraZeneca Plc said on Friday new clinical trial data underlined the potential of its schizophrenia drug Seroquel as a treatment for bipolar disorder, a form of manic depression.
Europe's third-biggest drugmaker said it planned to file for a U.S. license extension for Seroquel to treat depressive episodes associated with bipolar disorder around the year-end.
Results of an 8-week study called BOLDER II showed patients taking Seroquel achieved a statistically significant reduction in levels of bipolar depression compared with placebo, AstraZeneca said in a statement.
The firm said bipolar disorder affects about 3-4 percent of the adult population and is the sixth leading cause of disability in the world.
Seroquel made around $1.3 billion of sales in the first half of this year.
AstraZeneca shares closed at 25.81 pounds on Thursday, valuing the business at about 41 billion pounds.
Diuretics Can Help Control Blood Pressure
Two low-cost alternative drugs -- amiloride and spironolactone -- may help patients who still have high blood pressure despite taking standard hypertension drugs, an Indiana University School of Medicine study has found.
Amiloride and spironolactone are diuretics (water pills) that have been available for many years but are often overlooked by doctors, the researchers noted. The drugs work by limiting the amount of sodium the kidneys reabsorb or take back into the body during the process of producing urine.
This study included 98 black Americans with high blood pressure. Some were given either amiloride or spironolactone, some were given both drugs, and some were given a placebo. All of the patients continued to take their standard medications to treat high blood pressure, also known as hypertension.
On average, patients taking the drugs separately or together showed significant blood pressure declines. The findings were published in the September issue of the journal Hypertension.
"The kidneys do an incredible job of holding on to sodium, which was important to the survival of our early ancestors who lived in a salt-poor world, but today there's so much salt in the food we eat that the kidneys end up holding onto too much sodium," and that can lead to high blood pressure, researcher Dr. Howard Pratt said in a prepared statement.
By limiting the amount of sodium that's retained in the kidneys, amiloride and spironolactone help lower blood pressure, Pratt said.
He noted that doctors treating patients who don't respond to standard therapy for high blood pressure often prescribe higher doses of the medicine already being used or add a new blood pressure drug that could be expensive and often is also ineffective.
The findings of this and other studies may convince doctors to try amiloride or spironolactone alternatives instead, Pratt said.
New Diabetes Drug Poses Danger to Patients, Cardiologists Say
A diabetes drug about to be approved by the U.S. Food and Drug Administration doubles the risk of death, heart attack and stroke, and it should not be approved until its safety is further explored, a team of prominent cardiologists reports.
"I wanted our actions to put a roadblock in a rapid approval that I thought would present a danger to patients. I'm trying to avoid another Vioxx," said study author Dr. Steven Nissen, medical director of the Cleveland Clinic Cardiovascular Coordinating Center. "In the manuscript, I have clearly requested that a large outcomes trial be done before approval, and I believe that the FDA will see that that's a wise thing to do."
Ironically, Nissen and study co-author Dr. Eric Topol were the ones who first raised safety issues about Vioxx back in 2001. "Nobody listened then because it was already on the market being advertised," Nissen said. "I saw this as a potential to stop a potentially risky drug before it got out of the gate."
His study and an accompanying editorial were released Thursday by the Journal of the American Medical Association because of the public health implications.
The medication, muraglitazar, is one of a class of drugs called dual peroxisome proliferator-activated receptors (PPARs), which affect both cholesterol levels and blood sugar levels in diabetic patients. Many people with diabetes suffer from both problems, and this drug was earlier hailed as a way to kill two big birds with one stone or one pill, as it were.
Two other drugs in the class, pioglitazone and rosiglitazone, are already on the market. A third, troglitazone, was withdrawn due to liver toxicity problems.
Muraglitazar was developed by Bristol-Meyers Squibb, which has signed a marketing agreement with Merck.
Briefing documents on muraglitazar were made available to the public on Sept. 8, and were reviewed by an FDA advisory committee a day later. The committee voted 8-to-1 in favor of approving the drug to control blood sugar in patients with type 2 diabetes.
On Oct. 18, the FDA issued an "approvable letter" for the drug, meaning that muraglitazar could be approved once the agency received and reviewed additional information.
Nissen said he accessed the briefing documents as soon as they became available on Sept. 8, and saw "what appeared to be a very strong signal for excess cardiovascular events." He immediately set about doing an analysis, writing a manuscript and submitting it for publication. A process that usually takes months or even years was completed in only slightly more than a month.
"I treated this as a public health emergency," Nissen said. "A drug that had an 8-to-1 vote in favor of approval and that could any day be approved by the FDA to be used by any of 18 million Americans with type 2 diabetes was, by my analysis, doubling of risk of serious irrevocable cardiovascular events like death, heart attacks and stroke. I dropped everything."
Nissen, Topol and biostatistician Kathy Wolski, all of the Cleveland Clinic, analyzed the information that had been made available by the FDA. In all, it included data from five clinical trials that involved 3,725 people randomized to receive either muraglitazar, pioglitazone or a placebo, either alone or in combination with other diabetes drugs. Participants took the drugs from 24 to 104 weeks, considered to be a relatively short period of time.
In the muraglitazar group, 1.47 percent of participants experienced death, heart attack or stroke, compared with 0.67 percent of those in the two other groups, meaning that those taking muraglitazar had a 2.23 times higher risk of one of these outcomes.
When congestive heart failure and mini-strokes were added to the analysis, the combined incidence of these events was 2.62 times higher in the muraglitazar group.
Because people with type 2 diabetes already have a high incidence of cardiovascular disease (it represents the cause of death in about 80 percent of these patients), drugs need to be carefully screened in terms of heart attack and stroke risk, the researchers noted.
The accompanying editorial also pointed out numerous methodological issues in the original studies that may have skewed the results. For one thing, those researchers included doses of 2.5 milligrams or less, doses that were significantly lower than the 5-milligram dose for which FDA approval is being sought. Overall, this made the drug look safer. The populations studied also appeared to be healthier than the general diabetic population. In addition, an increased incidence of cancer was seen and needs to be studied further. Last but not least, the editorial stated, the researchers limited peer-review publication of the results before going for FDA approval "so as to minimize scrutiny and debate."
Nissen acknowledged the studies yielded a relatively small number of actual adverse events, which does introduce "some uncertainty" into the equation.
When any drug is developed and brought to market, benefits need to be weighed carefully against risks. In this case, the researchers stated, the efficacy is not so dramatic that it overrules safety concerns.
"The drug's benefits are simply to lower blood sugar, something that is not a morbidity and mortality advantage, so my view is that safety has to be very clear before you're going to approve it, and we have 15 other drugs to lower blood sugar," Nissen said. "In my view, it didn't make any sense to approve the drug."
In response to the journal article, Merck & Co. issued a formal statement Thursday that said, "Following the receipt of an approvable letter for Pargluva (muraglitazar) earlier this week, Bristol-Myers Squibb and Merck said that we are eager to begin discussions with the FDA to address more fully the cardiovascular safety profile of the compound and to determine what additional information may be necessary. Pargluva was extensively studied and all available data were reported to the FDA."
The new findings points up now familiar problems with the U.S. drug approval and regulatory process.
"I felt that that committee that voted 8-to-1 was simply missing the boat," said Nissen, who has served on FDA advisory committees. "I didn't think they connected the dots."
Problems on the committee reflect problems at the FDA, Nissen added.
"There are some big problems," he acknowledged. "The FDA is under-funded. Given all the things that seem to get money in the United States, the FDA is not pork. It is protecting the public health, and it is under-funded and under-supported, and getting good advisory panels is hard."
The question now, the editorial points out, "is which safety message will the FDA buy?"
"We are fully aware of the results of the Pargluva clinical trials, both with regard to safety and efficacy, and likewise appreciate the need for careful assessment of risk vs. benefit for all drugs, particularly those indicated for long-term, preventive therapy," said FDA spokeswoman Crystal Rice. "The application is still pending before the agency and, as such, we can't comment further at this point."
"While we cannot specifically discuss this particular drug further, the FDA has made significant investments of resources and expertise in developing fundamentally better methods for identifying and monitoring cardiovascular safety issues with all drugs," she added.
Gene That Helps Control Heartbeat Found
Researchers have identified a gene that plays an important role in making sure the heart beats properly -- a discovery that could cast light on the abnormal heartbeats called arrhythmias that often lead to major cardiac problems.
It's a complicated business that centers on the tiny channels through which potassium pours into the heart, explained Benoit G. Bruneau, an assistant professor of molecular and medical genetics at the University of Toronto, and lead author of a paper about the finding in the Oct. 21 issue of Cell.
"The main role of potassium channels is to help the heart relax after each heartbeat," Bruneau said. "But potassium channels aren't expressed the same throughout the heart. There is a slope of density, with greater density of the channels on the outside of the heart. This gradient coordinates the relaxation of the heart," he explained.
"When this gene we discovered is not present, the gradient disappears. This causes a higher propensity for arrhythmias," he said.
The discovery was made in mice that were genetically engineered to lack the gene, which the researchers have named Irx5. "What we've shown is that taking out the gene flattens the gradient," Bruneau said.
Mice are admittedly very different from humans, but the same effect has been seen in dogs, "which are very similar to humans," he said. "When we looked at dogs' hearts for the gradient effect of Irx5, indeed it was present."
Other researchers now are looking for the same effect in humans, Bruneau added.
If the human work is successful, "right now the clinical applications as far as treatment is concerned are not obvious," Bruneau said. "But as far as understanding how arrhythmias happen, this defines an important pathway, so scientists and drug companies can use it. It is a very good starting point to develop therapy. We know it might be amenable to some kind of drug treatment."
One possible therapy would be development of drugs that open and close ion channels, he said. "Another would be to modify the genetic pathway," Bruneau added.
Another possibility is that mutations in the Irx5 genes in humans can cause arrhythmias. "That is something we are investigating as well," Bruneau said.
One specific syndrome, called "short QT," which causes very severe arrhythmias and is inherited, is a leading possibility. "It resembles what we have seen in the mice," Bruneau said.
Protein 'Pump' May Aid in Alzheimer's Prevention
A protein well known to scientists appears to clear the brain of amyloid beta, the main component of the plaques that are found in Alzheimer's patients, according to a new study with mice.
The protein, P-glycoprotein (Pgp), has long been known to obstruct chemotherapy drugs and other drugs used in treating brain disorders. But, by creating drugs that alter the natural levels of Pgp, it may be possible to prevent and treat Alzheimer's disease, the researchers suggest.
"We found a new way of getting amyloid out of the brain," said lead author John Cirrito, a postdoctorate research fellow at Washington University School of Medicine in St. Louis. "Now there are avenues we can explore to try to find a treatment. Anything you can do to prevent amyloid beta from being produced or helping get it cleared is good."
The study findings appear Oct. 20 in the online edition of the Journal of Clinical Investigation.
Pgp is one of several molecular transporters that form the blood-brain barrier, a layer of cells that limits the ability of many types of molecules -- including many drugs -- to enter the brain through the circulatory system, Cirrito said. "In the blood-brain barrier, it normally acts to keep molecules out of the brain," he explained, adding the protein actually pumps molecules out of brain cells.
Earlier research had hinted that Pgp could also transport amyloid beta molecules out of the brain, Cirrito said. "We basically show that if we inject amyloid beta into the brains of mice, Pgp can pump amyloid beta out of the brain," he said.
The researchers also found that when specially bred mice were given a Pgp inhibitor, amyloid beta levels significantly increased in just a few hours. Also, mice bred not to produce Pgp had higher levels of amyloid beta, compared with mice that were able to make the protein, the researchers said.
Cirrito believes these findings might be used one day to both treat and prevent Alzheimer's disease. "If you could enhance Pgp activity, perhaps you could get amyloid beta out of the brain and not let it build up," he said.
"There are drugs that are used to inhibit Pgp in cancer therapy to help chemotherapy drugs get into tumor cells," Cirrito said. "These inhibitors could make Alzheimer's worse," he noted. There are also common drugs such as statins that inhibit Pgp activity, Cirrito said. And there are compounds, such as St. John's wort, that enhance Pgp activity, he noted.
One expert thinks these findings add to the understanding of how amyloid beta plaque could be removed from the brain.
"This is an exciting paper, and it dovetails well with existing knowledge about the biology of Pgp," said Dr. Sam Gandy, chairman of the Medical and Scientific Advisory Council of the Alzheimer's Association, and director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia.
There have been fewer studies about how amyloid beta can be removed from the brain than studies examining how it is generated, Grandy said. "But now we can add Pgp to the growing list of molecules that control amyloid beta catabolism," he said.
Grandy thinks this discovery might lead to new treatments for Alzheimer's. Some dietary substances or medications may block Pgp and increase the risk for Alzheimer's disease, while others may enhance the protein, he said.
"It might be possible to develop Pgp modulators that accelerate clearance of amyloid beta in a beneficial way," Gandy said.
Why drink water?
Your body is 60% water -- and not drinking enough can wreak havoc from head to toe. Up to half of all Americans suffer chronic mild dehydration that can cause fatigue, headache, loss of appetite, dry eyes and mouth. As we age, thirst becomes a less sensitive indicator of dehydration, so don't wait until you're thirsty to grab a glass. If you work out, drink more during intense physical activity, when dehydration is a real threat -- your body rapidly loses water through sweat and vapor in exhaled air. A rapid water loss of 5% of body weight can reduce muscular work by 20 - 30%.
Fitness Tip of the day:
Be a road scholar.
It's easy to find out where you can work out on a business trip, if you know where to look online. Before you leave, go to a travel or city guide Web site for your destination and research the parks, community centers, tracks and fitness centers where you can get a little exercise. Nothing boosts your energy, creativity and effectiveness on the road like a workout. Bonus: Explore the local jogging paths, and you'll get a taste of city life you'll never find in a hotel or pitch meeting.
FAQ of the day:
What is "good" and "bad" cholesterol?
There are two kinds of cholesterol carriers in the blood: HDLs (high-density lipoproteins) and LDLs (low-density lipoproteins). They are also commonly referred to as "good" and "bad" cholesterol -- to remember which is which, think "H" for Healthy and "L" for Lousy. Another tip: Keep the bad LDLs "Low," because their cholesterol ends up in arterial plaques, while you want the good HDLs "High," because they carry cholesterol away from arteries. A desirable level for LDL cholesterol is less than 130 mg/dL. For HDL, a level below 40 mg/dL increases risk, while 60 mg/dL or higher protects against heart disease.