It’s not unusual for the standard dose of a drug to work well for one person but be less effective for another. One reason for such differences is that individuals can break down drugs at different rates, leading to different concentrations of drugs and of their breakdown products (metabolites) in the bloodstream. A promising new process called slug-flow microextraction could make it faster, easier and more affordable to regularly monitor drug metabolites so that medication dosages could be tailored to each patient’s needs, an approach known as personalized medicine. This technique could also allow researchers to better monitor people’s responses to new drug treatments during clinical trials. Continue reading “New Streamlined Technique for Processing Biological Samples”
As a kid, Alfred Atanda loved science, sports and tinkering. He dreamed of being a construction worker or an engineer. Today, he works on one of the most complex construction projects of all: the human body.
As a pediatric orthopedic surgeon, Atanda focuses on sports medicine and injuries to children. He has a special passion for young baseball pitchers who have torn the ulnar collateral ligament (UCL) in the elbow of their throwing arm.
This sort of injury is most often caused by overuse. Many small tears accumulate over a long period, resulting in pain and slower, less accurate pitches. Decades ago, this sort of damage occurred almost exclusively in elite athletes. Now, Atanda sees it in children as young as 12 years old. He aims not only to study and treat these injuries, but also to find ways to prevent them.
Atanda was first introduced to research on UCL injuries while working alongside team physicians for the Phillies, the professional baseball team in Philadelphia. The physicians wanted to determine whether ultrasound imaging could detect early warning signs—slight anatomical changes in the ligament—before the damage became severe enough to warrant an operation known as Tommy John surgery.
The research focused on Phillies pitchers who had no pain or other symptoms of injury. The multi-year project showed that the UCL in the throwing elbows of these players got progressively thicker and weaker compared to the same ligament in the players’ nonthrowing elbows. The scientists concluded that these physical changes are caused by prolonged exposure to professional-level pitching.
Atanda wondered whether ultrasound imaging could also detect early signs of UCL damage in young pitchers—those in Little League through high school. There has been a dramatic rise in the number of young pitchers who are experiencing the same injuries and undergoing the same surgery as the pros.
Atanda secured funding for this project from an Institutional Development Award (IDeA). The IDeA program builds research capacities in states like Delaware, where Atanda works, that historically have received low levels of funding from the National Institutes of Health.
Atanda’s project began about a year ago, and has examined 55 young athletes so far.
“We found similar results to what we found with the Phillies,” Atanda says, indicating that the UCL in the throwing elbows of young athletes was noticeably thicker than the UCL in the nonthrowing elbows. And the damage seems progressive, he says: “We saw that these ligaments got thicker as the pitchers got older and had more pitching experience.”
The immediate goal of this project, which he hopes to continue for another 3 years, is prophylaxis. “We’re trying to prevent any kind of overuse elbow injuries and the need for Tommy John surgeries later on,” Atanda says. He also hopes to establish quantitative correlations between pitching behavior and anatomical changes.
Atanda also has longer-term aspirations. “My goal is to change the culture in sports for young athletes in general,” he says. “I want to show there are downsides to pitching so much.”
In addition to championing pitch count limits recommended by the American Sports Medicine Institute, Atanda advises a focus away from excess competition and toward getting exercise, enjoying social interaction, building self-confidence and having fun.
Atanda’s research is funded by the National Institutes of Health through grant P20GM103464
Content adapted from the NIGMS Findings magazine article Game Changer
Antibiotics save countless lives and are among the most commonly prescribed drugs. But the bacteria and other microbes they’re designed to eradicate can evolve ways to evade the drugs. This antibiotic resistance, which is on the rise due to an array of factors, can make certain infections difficult—and sometimes impossible—to treat.
Read the Inside Life Science article to learn how scientists are working to combat antibiotic resistance, from efforts to discover potential new antibiotics to studies seeking more effective ways of using existing ones.
The effects some medicines have on our salivary glands can at times extend beyond the fleeting flavor we experience upon ingesting them. Sometimes drugs cause a prolonged bad taste or dryness in the mouth, both of which can discourage people from taking medicines they need. Now, a research team led by Joanne Wang of the University of Washington has discovered a possible mechanism behind this phenomenon. Working primarily with mice and using a commonly prescribed antidiabetic drug known to impair taste, the scientists identified a protein in salivary gland cells that takes up the drug from the bloodstream and secretes it in saliva. Wang and her colleagues were also able to pinpoint a specific gene that, when removed, hindered this process. They hope their new insights will aid efforts to develop medicines that do not cause salivary issues.
This work also was funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.
University of Washington News Release
Ever wonder how aspirin knocks out aches? Scientists have known that medicine prevents an enzyme called cyclooxygenase from producing compounds linked to pain and inflammation, but they recently made another discovery about how aspirin works.
Edward Dennis and colleagues at the University of California, San Diego School of Medicine researched aspirin’s effect on macrophages–white blood cells that play a role in the body’s immune response to injury. They found that in addition to killing cyclooxygenase, aspirin causes the enzyme to make a product called 15-HETE. During infection and inflammation, 15-HETE can get converted by another enzyme into lipoxin, a compound that terminates and reverses inflammation.
Researchers will likely use lipoxin and similar compounds to develop new anti-inflammatory drugs.
University of California, San Diego News Release
Dennis Lab (no longer available)
LovD9, a mutated version of an enzyme extracted from mold growing in soil, produces the cholesterol-reducing drug simvastatin 1,000 times faster than its natural predecessor. But scientists didn’t understand why because the enzyme’s mutations are far from the active site, where the drug is actually made. Now they do.
Yi Tang of the University of California, Los Angeles (UCLA), in partnership with the pharmaceutical company Codexis, generated LovD9 by repeatedly inducing random mutations, each time selecting the mutated versions of the enzyme with the most promise for industrial simvastatin production.
Then, the team collaborated with UCLA colleagues Kendall Houk and Todd Yeates to unlock the secret of the enzyme’s speed. Using ANTON, a special-purpose supercomputer at the Pittsburgh Supercomputing Center, they simulated how different parts of the enzyme rotate and twist when synthesizing the drug. The scientists discovered that as LovD9 moves, it forms shapes that facilitate simvastatin production more often than the natural enzyme does.
With their better understanding of how mutations far from an active site may affect an enzyme’s motion, the researchers hope to one day directly engineer enzymes with precise mutations that enhance drug production.
University of California, Los Angeles News Release
Houk , Tang and Yeates Labs
Drugs that target a single essential protein in a microbial invader can be effective treatments. But the genomes of pathogens—including bacteria, fungi and parasites—mutate rapidly, and resistance can develop if a mutation changes a target protein’s structure. Molecules that interfere with multiple microbial proteins at once have the potential to overcome the growing problem of antimicrobial drug resistance.
Researchers led by Eric Oldfield of the University of Illinois recently explored whether an experimental drug called SQ109, developed to treat tuberculosis (TB), could be tweaked to attack multiple enzymes, as well as to kill different types of microbes. The scientists succeeded in creating several multitarget analogs of SQ109 that were more effective than the original drug at killing their target pathogens in laboratory experiments. These analogs included one compound that was five times more potent against the bacterium that causes TB while also being less toxic to a human cell line tested.
This work was also funded by the National Cancer Institute; the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases and the NIH Office of the Director.
Pharmacology is the scientific field that studies how the body reacts to medicines and how medicines affect the body. Scientists funded by the National Institutes of Health are interested in many aspects of pharmacology, including one called pharmacokinetics, which deals with understanding the entire cycle of a medicine’s life inside the body.
Knowing more about each of the four main stages of pharmacokinetics—absorption, distribution, metabolism and excretion—aids the design of medicines that are more effective and that produce fewer side effects.
Read more about a medicine’s life inside the body in this Inside Life Science article.
Many compounds that show promise as new antibiotics for treating bacterial infections never make it to the clinic because they turn out to be toxic to humans as well as to bacteria. A research team led by Kodi Ravichandran of the University of Virginia recently gained insights into why one such antibiotic, trovafloxacin, harms human cells. They found that the compound cuts off a channel for communication between cells, which in turn interferes with how dying cells are broken down and recycled by the body. Roughly 200 billion cells in the human body die and are replaced every day as part of a routine cleanup process, and interference in this process by trovafloxacin may have contributed to the serious liver damage seen in some patients in clinical trials of the drug. Understanding how trovafloxacin causes toxicity in people may help researchers re-engineer this and related compounds to make them safe and effective for use in fighting bacterial infections.
Heart disease is the leading cause of death for both men and women in the United States, according to the Centers for Disease Control and Prevention. One treatment challenge is developing non-invasive ways to direct medication to damaged or clogged arteries, which can block blood flow and increase the risk for heart attack and stroke. A team led by Naren Vyavahare at Clemson University has engineered extremely tiny particles—nanoparticles—that offer a promising step forward.
Healthy arteries have elastic fibers that make the arteries flexible. But, in most cardiovascular diseases, the fibers get damaged. The new nanoparticles, which can deliver drugs, attach only to damaged fibers and could enable site-specific drug delivery to minimize off-target side effects. The nanoparticles also allow drugs to be released over longer periods of time, potentially increasing the drugs’ effectiveness. The new biomaterial was tested in rodent models for studying vascular disease, so it is still in the early stages of development.
This work also was funded by NIH’s National Heart, Lung, and Blood Institute.
Clemson University News Release