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New research scrutinizes off-label drug use

New research scrutinizes off-label drug use

row of pills - smallIn the U.S., more than one in five drug prescriptions are for off-label indications. Better tracking of these unapproved uses could help medical researchers identify potentially dangerous uses and prioritize promising ones for further study and eventual approval.

Prescription records don’t usually indicate the condition a drug is intended to treat, but physicians’ clinical notes are likely to include this information. Researchers at Stanford developed a new method to extract off-label uses from 9.5 million de-identified clinical records collected at Stanford since 1994. Their study was published online today in PLOS ONE.

In a news release, Nigam Shah, MBBS, PhD, assistant professor of medicine and senior author of the study, describes his team’s approach to sorting the 400 off-label uses they discovered:

To prioritize these uses for further study, the researchers took into account the cost of each drug and its risk of causing adverse reactions. They used these two parameters to rank each drug use. “Then we placed them into good and bad buckets,” Shah said. The “bad bucket” of high-cost, high-risk uses should raise red flags that prompt re-evaluation by physicians and regulators.

Lead author Kenneth Jung, a graduate student in biomedical informatics, was surprised by how many of the novel uses were predictable based on prior knowledge.

“A lot of it actually made sense,” he said. “We should have known about some of these uses already. This gives us confidence that the method we developed works.”

Among the low-risk prescriptions, folic acid was used to treat a wide range of conditions, while several immunosuppressants and anti-tumor agents were classified as especially high-risk. To test the robustness of their findings, the researchers plan to apply the same method to electronic medical records from other hospitals and compare their results.

Previously: Clinical informatics gains recognition as new medical sub-specialty, Stanford researchers use data mining to show safety of peripheral artery disease treatment and Studies document risky use of powerful clotting drug
Photo by Erin DeMay

Health and Fitness, Research, Sports, Stanford News

Study reveals initial findings on health of most extreme runners

Study reveals initial findings on health of most extreme runners

Running_guyThose of us who feel accomplished after jogging a 5K may wonder what drives more serious runners – marathoners, and even ultramarathoners, who run races longer than 26.2 miles. A pair of physicians believes that learning more about these extreme athletes could benefit the rest of us.

Eswar Krishnan, MD, an assistant professor of medicine at Stanford, and Martin Hoffman, MD, of UC Davis, plan to collect data on 1,200 ultrarunners for the next 20 years. They launched the Ultrarunners Longitudinal Tracking Study with a web-based questionnaire in November 2011, and baseline findings of the study were published online today in PLOS ONE.

In a news release, Krishnan explains the value of studying extreme exercise:

“It will help us to understand how much exercise is optimal, how much recreational activity is appropriate and beneficial, and if there is a reason not to push your body beyond a certain point,” he said.

Initial results show, not unexpectedly, that ultrarunners are healthier than the overall U.S. population. Most of their visits to health-care professionals were for exercise-related injuries, which were more common in younger, less-experienced runners. Injuries were mainly to the knees and lower extremities. Notably, ultrarunners reported a lower incidence of stress fractures than other runners, but stress fractures were more common in the foot, perhaps due to running on uneven terrain. These runners also had higher-than-average rates of asthma and allergies, possibly because they spend so much time outdoors.

Identifying what inspires ultrarunners may have broader applications:

The psychological profiles of ultrarunners are of particular interest to the researchers and will be a focus of the upcoming questionnaire. Krishnan and Hoffman are collaborating with several sports psychologists to study what drives these runners to such an extreme level of competition. “Understanding what motivates ultrarunners could be useful for encouraging others to meet minimum levels of exercise to enhance health,” Hoffman said.

Previously: Is extreme distance running healthy or harmful?, A closer look at ‘runner’s high’ and Untrained marathoners may risk temporary heart damage
Photo by Robeter

Immunology, Research, Stanford News

The latest buzz on the evolution of allergies

The latest buzz on the evolution of allergies

BEELike a vestigial sting from our evolutionary past, an allergic reaction is a jab to the system. Its most extreme form, anaphylaxis, causes a rapid drop in blood pressure, itchy hives and breathing problems, and can result in death.

But the same immune response to bee stings that can lead to anaphylaxis may have originated as a defense mechanism, according to research led by Stanford pathologist Stephen Galli, MD. In a study published today in the journal Immunity, Galli and his team showed that mice injected with a small dose of honeybee venom were later protected from a higher dose of the same venom. This protection depended on “allergic-type” immune reactions. The findings provide the first experimental evidence in support of the toxin hypothesis of allergy.

From our news release:

The study builds on earlier work by the researchers, characterizing the innate immune response to snake venom and honeybee venom. Innate immune responses occur in subjects exposed to a foreign substance, such as a pathogen or a toxic material like venom, for the first time. Immune cells called mast cells, which reside in most of the body’s tissues, are poised to unleash signals that turn on defense responses when a pathogen or toxin intrudes. In a previous study, the researchers found that mast cells produce enzymes that can detoxify components of snake venom, and that mast cells can also enhance innate resistance to honeybee venom.

Such innate immune responses do not require prior immunization or the development of specific antibodies. By contrast, during an adaptive immune response, the immune system generates antibodies that recognize the invading pathogen or toxin; this process makes it possible to vaccinate against infectious diseases. Adaptive immunity is usually a faster, more specific and more effective form of defense than innate immunity.

In allergic reactions, a type of antibody called IgE binds to the surface of mast cells and prompts them to initiate an adaptive immune response when exposed to the antigen recognized by that IgE. “The functions of IgE and mast cells are mostly known in the context of allergies,” said Thomas Marichal, DVM, PhD, a postdoctoral scholar and co-lead author of the study.

To find out whether IgE antibodies were also involved in adaptive defense responses to venom, Marichal, along with Philipp Starkl, PhD, the other lead author, compared responses of mice pre-immunized with bee venom to those of control mice injected with a salt solution. The immunized mice had more venom-activated immune cells and more venom-specific IgE antibodies. They were also three times more likely to survive a potentially lethal dose of venom. Three types of mutant mice – mice without IgE antibodies, without IgE receptors on their mast cells, or without mast cells – were not protected from the lethal dose of venom by pre-immunization. This showed the defense response was dependent on IgE antibodies and mast cells. Similar experiments using snake venom from the Russell’s viper demonstrated that the response could be generalized to different types of toxic venom.

Galli explains the implications of the research for understanding the origins of allergies:

Our findings support the hypothesis that this kind of venom-specific, IgE-associated, adaptive immune response developed, at least in evolutionary terms, to protect the host against potentially toxic amounts of venom, such as would happen if the animal encountered a whole nest of bees, or in the event of a snakebite. Anaphylaxis probably represents the extreme end of a spectrum of IgE-associated reactivity, which in some unfortunate individuals is either poorly regulated or excessively robust, so the reaction itself can become dangerous to them.

Future work will examine why IgE responses reach such a harmful level in some individuals.

Previously: Mast cells not required for wound healing, according to Stanford study, Researchers find mechanism for destruction of key allergy-inducing complexes, and Synthetic antibodies may be able to mimic the real thing
Photo by ndboy

Research, Stanford News, Transplants

Extracting signal from noise to combat organ rejection

Extracting signal from noise to combat organ rejection

Last year, 28,000 patients in the United States received organ transplants. Because the body’s immune system is programmed to recognize a transplanted organ as foreign and attack it, the organ is often rejected.

Although immunosuppressant drugs such as cyclosporine act to prevent organ rejection, and better knowledge of molecular mechanisms of rejection has improved donor-recipient matching, organ rejection is still a frequent problem. For instance, 15 to 20 percent of adults who received kidney transplants between 2005 and 2009 experienced acute organ rejection within five years, according to statistics from the Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients.

To improve both prediction and treatment methods, Purvesh Khatri, PhD, harnessed the power of multiple data sets to find the common links among thousands of organ rejection cases. Khatri is an acting assistant professor of medicine at the Stanford Center for Biomedical Informatics Research; among his collaborators were co-senior authors Minnie Sarwal, MD, PhD, of the California Pacific Medical Center, and Atul Butte, MD, PhD, associate professor of pediatrics at Stanford and director of the Center for Pediatric Bioinformatics at Lucile Packard Children’s Hospital. In a paper published today in the Journal of Experimental Medicine, Khatri and his colleagues found that the same 11 genes were highly expressed in four types of rejected organs – heart, lung, liver, and kidney.

By examining this 11-gene signature in patient biopsies taken six months after transplants, the researchers could predict the risk of organ rejection after two years. This finding could have implications for more targeted treatment of patients at risk for organ rejection.

In addition, Khatri and his team searched the medical literature for existing drugs that might target any of the 11 genes involved in rejection. They came up with two drugs, atorvastatin and dasatinib, which are currently used for the treatment of high cholesterol and cancer, respectively. To find out whether these drugs could effectively prevent organ rejection, they teamed up with colleagues at the Stanford Cardiovascular Institute to test the drugs on a mouse heart-transplant model. They found that both atorvastatin and dasatinib increased survival rates for mice after heart transplants.

In a testament to the power of publically available electronic medical records, the team obtained data on more than 2,500 kidney transplant patients from University Hospital in Leuven, Belgium. Sixty percent of these patients were receiving statin treatment for heart-related conditions, and these patients had a 30 percent lower risk of organ rejection. This suggests that statins may be effective as a routine anti-rejection treatment. “You’ve been giving this drug to these patients for other reasons and their grafts are surviving longer,” Khatri, lead author of the study, told me. “So you might as well start making it part of the standard protocol.”

Because atorvastatin and dasatinib are already approved for other uses by the Food and Drug Administration, the time between laboratory studies and approval for patients can be shortened. The innovative approach taken in this study – to use large data sets and computational methods to extrapolate common genes involved in medical conditions, and then to predict new treatments – is likely to become more common. As Khatri, a computer scientist, explained, “Despite all the heterogeneity in the data, we can find the signal that can be used for predicting drugs, and then we can use electronic medical records to see if the drug would actually work before we do the experiment.”

Molly Sharlach is a writing intern in the medical school’s Office of Communication & Public Affairs. She is a student in the Science Communication Program at the University of California-Santa Cruz.

Previously: Shushing T cells promotes acceptance of stem cell therapies, say Stanford researchers and Biomarker can predict graft-versus-host disease in men after transplants from women donors

Cardiovascular Medicine, Chronic Disease, Health and Fitness, Research, Stanford News

The exercise pill: A better prescription than drugs for patients with heart problems?

The exercise pill: A better prescription than drugs for patients with heart problems?

3358308022_f97cdfda6a_nLast week, my colleague wrote about a six-nation survey from the World Heart Organization showing that a majority of adults walk for less than half an hour each day. September 29 was World Heart Day, and this year’s theme was changing lifestyles to prevent and control cardiovascular disease, the number one cause of death in the United States and worldwide.

Both common sense and medical science increasingly point to regular physical activity as a simple and effective way to decrease the risk of cardiovascular disease and a host of other ailments. But what about patients who have already had a stroke or heart failure, or those with coronary heart disease or prediabetes? Can exercise help keep these patients alive? How do the outcomes of exercise interventions compare with those of drug treatments?

Stanford professor John Ioannidis, MD, DSc, addresses these questions in a meta-analysis published today in the British Medical Journal. In collaboration with Huseyin Naci, a researcher and fellow at the London School of Economics and Harvard Medical School, Ioannidis culled data from more than 300 clinical trials, representing more than 300,000 individual patients. Ioannidis and Naci compared the effectiveness of exercise with various drug interventions to prevent mortality for patients recovering from stroke or heart failure, as well as those with coronary heart disease or prediabetes.

For patients with coronary heart disease or prediabetes, exercise and drug interventions appeared to have similar effects on mortality. However, for those recovering from a stroke, exercise led to better outcomes than drugs, while for those with previous heart failure, diuretics in particular prevented deaths more effectively than exercise or other drugs.

Still, Ioannidis and Naci emphasize that not enough trials have been done on the mortality benefits of exercise – only 57 of the 305 trials they analyzed included exercise interventions – and that in future trials, exercise should be directly compared to drug treatments. They caution that “the lopsided nature of modern medical research may fail to detect the most effective treatment for a given condition if that treatment is not a prescription drug.”

While Centers for Disease Control and Prevention statistics show that about one-third of primary care physicians prescribe an “exercise pill” to their patients, these prescriptions may be more effective when supervised by a rehabilitation program. Further studies are needed to understand the types of exercise that are most effective for different conditions, as well as the potential harmful side effects of exercise interventions as compared with drug treatments.

“Exercise has been quite neglected to-date,” Ioannidis told me. “There is plenty of room to reap more benefits from something that is both effective and enjoyable. The pendulum may need to swing back [from drug treatments to lifestyle interventions] for many reasons, including the intolerable cost of many medications and their potential toxicities.”

Molly Sharlach is a writing intern in the medical school’s Office of Communication & Public Affairs. She is a student in the Science Communication Program at the University of California-Santa Cruz.

Previously: Global survey highlights the need for people to keep track of walking distanceStanford preventive-medicine expert: Lay off the meat, get out the sneaksMore evidence that boosting Americans’ physical activity alone won’t solve the obesity epidemic and Ask Stanford Med: Answers to your questions about heart health and cardiovascular research
Photo by Ed Yourdon

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