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Unwanted impact of antibiotics broader, more complex than previously known

CORVALLIS, Ore. – Researchers at Oregon State University have discovered that antibiotics have an impact on the microorganisms that live in an animal’s gut that’s more broad and complex than previously known.

The findings help to better explain some of the damage these medications can do, and set the stage for new ways to study and offset those impacts.

The work was published online in the journal Gut, in research supported by Oregon State University, the Medical Research Foundation of Oregon and the National Institutes of Health.

Researchers have known for some time that antibiotics can have unwanted side effects, especially in disrupting the natural and beneficial microbiota of the gastrointestinal system. But the new study helps explain in much more detail why that is happening, and also suggests that powerful, long-term antibiotic use can have even more far-reaching effects.

Scientists now suspect that antibiotic use, and especially overuse, can have unwanted effects on everything from the immune system to glucose metabolism, food absorption, obesity, stress and behavior.

The issues are rising in importance, since 40 percent of all adults and 70 percent of all children take one or more antibiotics every year, not to mention their use in billions of food animals. Although when used properly antibiotics can help treat life-threatening bacterial infections, more than 10 percent of people who receive the medications can suffer from adverse side effects.

“Just in the past decade a whole new universe has opened up about the far-reaching effects of antibiotic use, and now we’re exploring it,” said Andrey Morgun, an assistant professor in the OSU College of Pharmacy. “The study of microbiota is just exploding. Nothing we find would surprise me at this point.”

This research used a “cocktail” of four antibiotics frequently given to laboratory animals, and studied the impacts.

“Prior to this most people thought antibiotics only depleted microbiota and diminished several important immune functions that take place in the gut,” Morgun said. “Actually that’s only about one-third of the picture. They also kill intestinal epithelium. Destruction of the intestinal epithelium is important because this is the site of nutrient absorption, part of our immune system and it has other biological functions that play a role in human health.”

The research also found that antibiotics and antibiotic-resistant microbes caused significant changes in mitochondrial function, which in turn can lead to more epithelial cell death. That antibiotics have special impacts on the mitochondria of cells is both important and interesting, said Morgun, who was a co-leader of this study with Dr. Natalia Shulzhenko, a researcher in the OSU College of Veterinary Medicine who has an M.D. from Kharkiv Medical University.

Mitochondria plays a major role in cell signaling, growth and energy production, and for good health they need to function properly.

But the relationship of antibiotics to mitochondria may go back a long way. In evolution, mitochondria descended from bacteria, which were some of the earliest life forms, and different bacteria competed with each other for survival. That an antibiotic would still selectively attack the portion of a cell that most closely resembles bacteria may be a throwback to that ingrained sense of competition and the very evolution of life.

Morgun and Schulzhenko’s research group also found that one of the genes affected by antibiotic treatment is critical to the communication between the host and microbe.

“When the host microbe communication system gets out of balance it can lead to a chain of seemingly unrelated problems,” Morgun said.

Digestive dysfunction is near the top of the list, with antibiotic use linked to such issues as diarrhea and ulcerative colitis. But new research is also finding links to obesity, food absorption, depression, immune function, sepsis, allergies and asthma.

This research also developed a new bioinformatics approach named “transkingdom network interrogation” to studying microbiota, which could help further speed the study of any alterations of host microbiota interactions and antibiotic impact. This could aid the search for new probiotics to help offset antibiotic effects, and conceivably lead to systems that would diagnose a person’s microbiome, identify deficiencies and then address them in a precise and individual way. 

Healthy microbiota may also be another way to address growing problems with antibiotic resistance, Morgun said. Instead of trying to kill the “bad” bacteria causing an illness, a healthy and functioning microbiota may be able to outcompete the unwanted microbes and improve immune function.

Collaborators on this research were from the OSU College of Pharmacy; OSU College of Veterinary Medicine; OSU College of Science; the National Cancer Institute; University of British Columbia; University of Maryland School of Medicine; and the National Institutes of Health.

Media Contact: 

Andrey Morgun, 541-737-8047

“Glowing” new nanotechnology guides cancer surgery, also kills remaining malignant cells

CORVALLIS, Ore. – Researchers at Oregon State University have developed a new way to selectively  insert compounds into cancer cells - a system that will help surgeons identify malignant tissues and then, in combination with phototherapy, kill any remaining cancer cells after a tumor is removed.

It’s about as simple as, “If it glows, cut it out.” And if a few malignant cells remain, they’ll soon die.

The findings, published in the journal Nanoscale, have shown remarkable success in laboratory animals. The concept should allow more accurate surgical removal of solid tumors at the same time it eradicates any remaining cancer cells. In laboratory tests, it completely prevented cancer recurrence after phototherapy.

Technology such as this, scientists said, may have a promising future in the identification and surgical removal of malignant tumors, as well as using near-infrared light therapies that can kill remaining cancer cells, both by mild heating of them and generating reactive oxygen species that can also kill them.

“This is kind of a double attack that could significantly improve the success of cancer surgeries,” said Oleh Taratula, an assistant professor in the OSU College of Pharmacy.

“With this approach, cancerous cells and tumors will literally glow and fluoresce when exposed to near-infrared light, giving the surgeon a precise guide about what to remove,” Taratula said. “That same light will activate compounds in the cancer cells that will kill any malignant cells that remain. It’s an exciting new approach to help surgery succeed.”

The work is based on the use of a known compound called naphthalocyanine, which has some unusual properties when exposed to near-infrared light. It can make a cell glow as a guide to surgeons; heat the cell to kill it; and produce reactive oxygen species that can also kill it. And by adjusting the intensity of the light, the action of the compound can be controlled and optimized to kill just the tumor and cancer cells. This research was done with ovarian cancer cells.

However, naphthalocyanine isn’t water soluble and also tends to clump up, or aggregate, inside the body, in the process losing its ability to makes cells glow and generate reactive oxygen species. This also makes it difficult or impossible to find its way through the circulatory system and take up residence only in cancer cells.

OSU experts overcame these problems by use of a special water-soluble polymer, called a dendrimer, which allows the napthalocyanine to hide within a molecule that will attach specifically to cancer cells, and not healthy tissue. The dendrimer, an extremely tiny nanoparticle, takes advantage of certain physical characteristics that blood vessels leading to cancer cells have, but healthy ones do not. It will slip easily into a tumor but largely spare any healthy tissue.

Once in place, and exposed to the type of light needed, the cancer cells then will glow – creating a biological road map for a surgeon to follow in identifying what tissues to remove and what to leave. At the same time, a few minutes of this light exposure activate the naphthalocyanine to kill any remaining cells.

This one-two punch of surgery and a nontoxic, combinatorial phototherapy holds significant promise, Taratula said. It’s quite different from existing chemotherapies and radiotherapies.

“For many cancers, surgery is a first choice of treatment,” Taratula said. “In coming years we may have a tool to make that surgery more precise, effective and thorough than it’s been before.”

Before attempting human clinical tests, OSU researchers hope to perfect the process and then collaborate with Shay Bracha, an assistant professor in the OSU College of Veterinary Medicine, to test it on live dogs that have malignant tumors. The technique has already been shown successful in laboratory mice. Worth noting, the researchers said, is that even as phototherapy was destroying their malignant tumors, the mice showed no apparent side effects and the animals lost no weight.  

Systems with technology similar to this are also being tested by other researchers, but some of them require several imaging and therapeutic agents, repeated irradiation and two lasers. This increases cost, may lessen effectiveness and increase risk of side effects, OSU researchers said in their report.

This research was supported by the OSU College of Pharmacy, the Medical Research Foundation of Oregon and the PhRMA Foundation.

Media Contact: 

Oleh Taratula, 541-737-5785

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Phototherapy system
Phototherapy system

“Antibiogram” use in nursing facilities could help improve antibiotic use, effectiveness

PORTLAND, Ore. – Use of “antibiograms” in skilled nursing facilities could improve antibiotic effectiveness and help address problems with antibiotic resistance that are becoming a national crisis, researchers conclude in a new study.

Antibiograms are tools that aid health care practitioners in prescribing antibiotics in local populations, such as a hospital, nursing home or the community. They are based on information from microbiology laboratory tests and provide information on how likely a certain antibiotic is to effectively treat a particular infection.

The recent research, published by researchers from Oregon State University in Infection Control and Hospital Epidemiology, pointed out that 85 percent of antibiotic prescriptions in the skilled nursing facility residents who were studied were made “empirically,” or without culture data to help determine what drug, if any, would be effective.

Of those prescriptions, 65 percent were found to be inappropriate, in that they were unlikely to effectively treat the target infection.

By contrast, use of antibiograms in one facility improved appropriate prescribing by 40 percent, although due to small sample sizes the improvement was not statistically significant.

“When we’re only prescribing an appropriate antibiotic 35 percent of the time, that’s clearly a problem,” said Jon Furuno, lead author on the study and an associate professor in the Oregon State University/Oregon Health & Science University College of Pharmacy.

“Wider use of antibiograms won’t solve this problem, but in combination with other approaches, such as better dose and therapy monitoring, and limiting use of certain drugs, we should be able to be more effective,” Furuno said.

“And it’s essential we do more to address the issues of antibiotic resistance,” he said. “We’re not keeping up with this problem. Pretty soon, there won’t be anything left in the medical cabinet that works for certain infections.”

In September, President Obama called antibiotic resistant infections “a serious threat to public health and the economy,” and outlined a new national initiative to address the issue. The Centers for Disease Control and Prevention has concluded that the problem is associated with an additional 23,000 deaths and 2 million illnesses each year in the U.S., as well as up to $55 billion in direct health care costs and lost productivity.

Antibiograms may literally be pocket-sized documents that outline which antibiotics in a local setting are most likely to be effective. They are often used in hospitals but less so in other health care settings, researchers say. There are opportunities to increase their use in nursing homes but also in large medical clinics and other local health care facilities for outpatient treatment. The recent study was based on analysis of 839 resident and patient records from skilled nursing and acute care facilities.

“Antibiograms help support appropriate and prudent antibiotic use,” said Jessina McGregor, also an associate  professor in the OSU/OHSU College of Pharmacy, and lead author on another recent publication on evaluating antimicrobial programs.

“Improved antimicrobial prescriptions can help save lives, but they also benefit more than just an individual patient,” McGregor said. “The judicious use of antibiotics helps everyone in a community by slowing the spread of drug-resistant genes. It’s an issue that each person should be aware of and consider.”

Multi-drug resistant organisms, such as methicillin-resistant Staphylococcus aureus, or MRSA, and other bacterial attacks that are being called “superinfections” have become a major issue.

Improved antibiotic treatment using a range of tactics, researchers say, could ultimately reduce morbidity, save money and lives, and improve patients’ quality of life.

The research led by Furuno was supported by the U.S. Department of Health and Human Services. Collaborators include researchers from the University of Maryland School of Medicine, Denver Health and Hospital Authority, University of Colorado Health Sciences Center, and Agency for Healthcare Research and Quality in Maryland.

Media Contact: 

Jon Furuno, 503-418-9361

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Antibiotic resistant bacteria
MRSA bacteria

“Mild” control of systolic blood pressure in older adults is adequate: 150 is good enough

CORVALLIS, Ore. – A broad review of the use of medications to reduce blood pressure has confirmed that “mild” control of systolic pressure is adequate for adults age 65 or older - in the elderly, there’s no clear benefit to more aggressive use of medications to achieve a lower pressure.

Historically, most medical practitioners tried to achieve control of systolic pressure – the higher of the two blood pressure readings – to 140 or less. Recently changed guidelines now suggest that for adults over 60, keeping the systolic pressure at 150 or less is adequate, and this extensive analysis confirms that.

However, researchers also say in the report that more work needs to be done studying blood pressure in older populations, since most of the research, and the medical guidelines based on them, were done using predominately younger adults.

The review was just published in Drugs & Aging, a professional journal, by scientists from the College of Pharmacy at Oregon State University and Oregon Health & Science University.

“The goal of a systolic pressure at or below 140 has been around a long time, and there’s still skepticism among some practitioners about accepting a higher blood pressure,” said Leah Goeres, an OSU postdoctoral fellow and lead author on the publication.

“Keeping systolic blood pressure in older adults below 150 is important, it’s what we consider a mild level of control,” Goeres said. “But for older people that level is also good enough. After an extensive review, there was no significant evidence that more intensive management is necessary.”

The issue about how low is low enough, researchers say, is important because blood pressure medications can have unwanted side effects that increase as higher dosages of medications are used. The problem is common – in the United States, about 70 percent of adults age 65 or older have hypertension, and millions of people take medication to control it.

One of the more significant side effects is what’s called “orthostatic hypotension,” a condition in which a person’s blood pressure can suddenly fall when they rise or stand, making them feel light-headed or dizzy, and sometimes leading to dangerous falls. More than 30 percent of people over the age of 80 have this problem.

High blood pressure is a serious health concern, but also one of the most treatable with medication, if such things as diet, exercise, weight management or lifestyle change prove inadequate.  Hypertension is often called the “silent killer” because it causes few obvious symptoms, but it weakens blood vessels and has been linked to higher levels of heart attacks, kidney disease and especially stroke.

“There’s clearly a value to controlling blood pressure, enough to keep it at 150 or less,” said David Lee, an OSU assistant professor of pharmacy practice. “Keeping blood pressure within acceptable levels will lower death rates. But as people get older, there’s less clear evidence that stringent control of systolic blood pressure is as important.”

The researchers said a goal for the future should be to do more studies specifically with older adult populations and try to identify health situations and conditions that might benefit from different types of management. Such “individualized” treatments, they said, would consider a person’s entire health situation instead of treating them based on findings made with large groups.

In this study, the researchers did not find that one approach or another to lowering blood pressure stood out and was clearly better than other alternatives. A variety of medications can be used to treat the condition.

Media Contact: 

David Lee, 503-494-2258

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Blood pressure test

Oral contraception may become renewed option for HIV-positive women

CORVALLIS, Ore. – Contrary to guidelines issued by the World Health Organization, new research has found that HIV-positive women receiving one of the most common forms of drug therapy should be able to use at least some forms of oral contraceptives for birth control.

The findings, just published in the journal Contraception, may lead to new options of birth control for women with HIV. Further research should be done to confirm that clinical outcomes are consistent with conclusions that have been based on pharmacokinetic analysis, scientists said.

Worldwide, the leading cause of death among women ages 18-45 is HIV/AIDS, and prevention of mother-to-child transmission of HIV by reducing unintended pregnancy is a United Nations millennium goal for 2010-15. This research, and broad access to oral contraception, could help reach that goal.

The research was done by scientists from the Oregon State University/Oregon Health & Science University College of Pharmacy, the Albert Einstein College of Medicine and the University of Southern California.

Although millions of women around the world routinely use oral contraception, it has been largely avoided by those with HIV infections because some of the drugs commonly used to control HIV are believed to reduce the effectiveness of birth control pills.

Because of that, both the World Health Organization and Centers for Disease Control have suggested that oral contraceptives should not be used by HIV-positive women if other methods of birth control are available – such as barrier devices, IUDs or other approaches.

The new study, however, raises doubts about such a broad guideline against oral contraception. It found that while some types of oral contraceptives may be subject to this concern, others that are highly efficacious should be even more effective when particular HIV drugs are used.

“Oral contraception is used by millions of women and is among the most popular forms of birth control,” said Ganesh Cherala, an OSU assistant professor of pharmacy practice, a corresponding author on the study. Cherala is an expert in pharmacokinetics, or how drugs behave, interact and are transformed in the body.

“It’s important for women to have access to – and the ability to choose from – as wide a range of birth control options as possible,” Cherala said. “We believe this research shows the WHO guidelines are too generic and unnecessarily cautious. There clearly appear to be oral contraceptives that should be safe and effective in women being treated with HIV medications.”

In general, there are two types of oral contraceptives: “combination” drugs that include both estrogen and progestin, and drugs that are based solely on progestin for their efficacy. The concerns raised about reduced efficacy were based primarily on studies of the combination oral contraceptives, and may be valid for that group of drugs, Cherala said.

However, the new study found that progestin-only contraceptives based on at least one progestin, norethindrone, should actually have a slightly higher level of birth control efficacy, not a reduced one, when a women is taking one of the primary therapies for HIV, called a ritonavir-boosted atazanavir antiretroviral therapy.

Other progestin-only birth control drugs may also have the same properties as the ones based on norethindrone, but that has not yet been conclusively demonstrated, Cherala said. 

The research was done with both treatment and control groups of women who were HIV-positive, ages 18-44, with no other recent use of hormonal contraception.

“These findings are interesting and exciting,” Cherala said. “They should ultimately give women more options to consider for birth control.”

Historically, some of the progestin-only oral contraceptives had unwanted side effects more than the combination contraceptives, Cherala said. However, those differences are now very small as improved forms of progestin-only contraceptives have come to market.

This research was supported by the National Institutes of Health.

Media Contact: 

Ganesh Cherala, 503-418-0447

Report urges individualized, cholesterol-targeted approach to heart disease and stroke

PORTLAND, Ore. – A recent guideline for using statins to reduce atherosclerotic cardiovascular disease has wavered too far from the simple cholesterol goals that have saved thousands of lives in the past decade, and doesn’t adequately treat patients as individuals, experts said today in a national report.

An expert panel coordinated by the National Lipid Association has created its own outline for how to best treat people at risk for cardiovascular disease, which they say focuses on reducing cholesterol to an appropriate level, and puts less emphasis on whether or not a patient fits into a certain type of group.

“We continue to believe in cholesterol targets that are easy for patients to understand and work toward, first using changes in lifestyle and then medication if necessary,” said Matt Ito, one of two lead authors on the report, an expert in cardiovascular drug treatments and a professor in the Oregon State University/Oregon Health & Science University College of Pharmacy.

“We’re also concerned about treating people just because they fall into a group that’s supposedly at risk,” Ito said. “There are ways to more accurately treat patients as individuals and understand their complete health profile. And we have a better understanding now of what conditions pose the most risk for causing a heart attack or stroke, and how to address that in a comprehensive manner.”

A report issued last year by the American College of Cardiology and American Heart Association identified four general groups that would primarily benefit from statins, and its recommendations if followed will dramatically increase the number of people using these drugs.

By contrast, the new report from the National Lipid Association has outlined what their experts believe to be a more individualized set of recommendations that practitioners could use to treat people at risk of cardiovascular disease; more information is available online at www.lipid.org/recommendations. They are intended to complement the guidelines issued by the American College of Cardiology and the American Heart Association, Ito said.

Among the conclusions in the report:

  • A root cause of atherosclerotic cardiovascular disease is cholesterol-containing particles attaching to the walls of arteries.
  • A healthy lifestyle that incorporates diet, weight management and exercise should be the first approach to lowering cholesterol levels that are too high.
  • Control and reduction of LDL, or “bad” cholesterol is important, but an even better overall marker of risk is “non-HDL cholesterol,” which is total cholesterol minus its HDL component.
  • Patients at very high risk, such as those who have already had a cardiac event, should try to achieve non-HDL cholesterol levels below 100, while those at lower risk levels should try to achieve levels below 130.
  • Drug therapies specifically aimed at lowering triglyceride levels may not be necessary unless they are very high, over 500; and efforts to specifically raise HDL levels have been shown to be both less important and less achievable.
  • Use of more potent statin drugs, at moderate to high doses if necessary, should be the first approach to reach cholesterol goals if lifestyle changes have not been adequate.
  • Use of other medications or therapies, such as fibrates, cholesterol absorption inhibitors, niacin or omega-3 fatty acids can be considered if cholesterol and triglyceride goals are not reached with statins alone.
  • Non-lipid risk factors should also be managed, such as high blood pressure, cigarette smoking and diabetes.

“Cholesterol is still a primary factor in atherosclerotic cardiovascular disease,” Ito said. “If it’s too high, the levels should be brought down by changes in lifestyle and medication if necessary. And in general, the lower the cholesterol, the better.”

Statins have proven themselves as one of the most effective way to reduce cholesterol, Ito said, and are now comparatively inexpensive with limited side effects. Proper medication management and reducing the potential for drug interactions can address some types of side effects, and any problems should be weighed against the risk of heart attack or stroke, he said.

Factors known to raise the risk of atherosclerotic cardiovascular disease include age, family history, smoking, high blood pressure, overweight, diabetes, and high cholesterol levels, especially those caused by genetics.

Media Contact: 

Matthew Ito, 503-494-3657

Strategies identified to improve oral contraceptive success with obese women

PORTLAND, Ore. – The findings of a new study suggest two ways to effectively address the problem that birth control pills may not work as well in obese women, compared to women of a normal body mass index.

Birth control pills are a one-size-fits-all method, researchers say, but as the population has increased in weight, concern has grown about how well the pill works for obese women. Studies have consistently found that obesity has a negative impact on drug levels in the body, which may in turn affect how well the pill prevents pregnancy. 

“Birth control pills have been shown in a large population study to fail at a higher rate in women who are obese,” said Ganesh Cherala, an assistant professor in the Oregon State University/Oregon Health & Science University College of Pharmacy.

“Our original studies were focused on why this might occur,” Cherala said, “and we found that obesity changes how a woman’s body clears contraceptive hormones.”

It takes longer for the pill to reach a steady state level in obese women, with possible impacts on efficacy of the birth control, and putting them at greater risk for a pill failure if they forget to take a pill or take it later.

In order to offset these changes, Cherala and Dr. Alison Edelman, an associate professor of obstetrics and gynecology at Oregon Health & Science University, studied two alternative strategies. They found that either a slight increase in the pill dose, from a very low dose to a low dose pill; or using the pill continuously without a “period week” off, appeared to counteract the changes that obesity causes.

This, in turn, may provide improved pregnancy prevention for women of differing weights who use the pill, the researchers said. Their work is published in Contraception, a professional journal, and was supported by the National Institutes of Health.

“Since oral contraception remains one of the most popular forms of birth control in the United States and the majority of our population is obese or overweight, it’s important to find methods of contraception that work for all women, no matter what their weight,” Edelman said.

“The strategies that we studied can be, and are currently being used by women, but now we know that they help to counteract the adverse effects of weight on contraceptive hormones,” she said.

For obese women, simply shifting to an alternative form of birth control is an option, the researchers said. But they also pointed out that oral contraceptives are the most preferred form of birth control and that a woman’s individual preference influences her adherence and continuation with any method.

Media Contact: 

Ganesh Cherala, 503-418-0447

Antibiotic use prevalent in hospice patients despite limited evidence of its value

CORVALLIS, Ore. – New research suggests that use of antibiotics is still prevalent among terminal patients who have chosen hospice care as an end-of-life option, despite little evidence that the medications improve symptoms or quality of life, and sometimes may cause unwanted side effects.

The use of antibiotics is so engrained in contemporary medicine that 21 percent of patients being discharged from hospitals directly to a hospice program leave with a prescription for antibiotics, even though more than one fourth of them don’t have a documented infection during their hospital admission.

About 27 percent of hospice patients are still taking antibiotics in the final week of their life.

This raises serious questions about whether such broad and continued antibiotic use is appropriate in so many hospice cases, experts say, where the underlying concept is to control pain and protect the remaining quality of life without aggressively continuing medical treatment.

Additional concerns with antibiotic use, the study concluded, include medication side effects and adverse events, increased risk of subsequent opportunistic infections, prolonging the dying process and increasing the risk of developing antibiotic resistant microorganisms.

The findings were just published in Antimicrobial Agents and Chemotherapy by researchers from Oregon State University and the Oregon Health & Science University. It was supported by the National Institutes of Health.

“Hospice care is very patient centered and in terminal patients it focuses on palliative care and symptom relief, not curative therapy,” said Jon Furuno, an associate professor in the Oregon State University/Oregon Health & Science University College of Pharmacy.

“It’s not for everyone, and it’s a serious decision people usually make in consultation with their family, nurses and doctors. These are tough conversations to have.

“Having decided to use hospice, however, the frequency and prevalence of antibiotic use in this patient population is a concern,” Furuno said. “Antibiotics themselves can have serious side effects that sometimes cause new problems, a factor that often isn’t adequately considered. And in terminally-ill people they may or may not work anyway.”

Issues such as this, Furuno said, continue to crop up in the evolving issue of hospice care, which is still growing in popularity as many people choose to naturally allow their life to end with limited medical treatment and often in their own homes. Hospice is covered by Medicare for people with a life expectancy of less than six months, helps to control medical costs and reduce hospital stays, and its services are now used by more than one third of dying Americans.

Unnecessary and inappropriate antibiotic use is already a concern across all segments of society, researchers said in the report, and more efforts are clearly needed to address the issue in hospice patients. The design of the study probably leads to it underestimating the significance of the problem, the researchers wrote in their conclusion.

Media Contact: 

Jon Furuno, 503-418-9361

Research may yield new ways to treat antibiotic-resistant TB

CORVALLIS, Ore. – Scientists in the United States and India have successfully modified the precursor to one of the drugs used to treat tuberculosis, an important first step toward new drugs that can transcend antibiotic resistance issues that experts consider a serious threat to global health.

The findings, reported in the Journal of Biological Chemistry, indicate that a new compound, 24-desmethylrifampicin, has much better antibacterial activity than rifampicin against multi-drug-resistant strains of the bacteria that cause tuberculosis.

Rifampicin and related drugs are important antibiotics, the key to an effective “drug cocktail” that already takes about six months of treatment to cure tuberculosis, even if everything goes well. But two forms of tuberculosis, referred to as “multi-drug-resistant,” or MDR, and “extensively drug-resistant,” or XDR, have become resistant to rifampicin.

In 1993, resurging levels of tuberculosis due to this antibiotic resistance led the World Health Organization to declare it a global health emergency. Today more than 1 million people around the world are dying each year from tuberculosis, and after AIDS it remains the second most common cause of death by infectious disease.

“We believe these findings are an important new avenue toward treatment of multi-drug-resistant TB,” said Taifo Mahmud, a professor in the College of Pharmacy at Oregon State University, and a corresponding author on the new publication.

“Rifampicin is the most effective drug against tuberculosis, and it’s very difficult to achieve a cure without it,” Mahmud said. “The approach we’re using should be able to create one or more analogs that could help take the place of rifampicin in TB therapy.”

A combination of genetic modification and synthetic drug development was used to create the new compound, which so far has only been developed in laboratory, not commercial quantities. Further development and testing will be necessary before it is ready for human use, researchers said.

Drug resistance in rifampicin and related antibiotics has occurred when their bacterial RNA polymerase enzymes mutate, Mahmud said, leaving them largely unaffected by antibiotics that work by inhibiting RNA synthesis. The new approach works by modifying the drug so it can effectively bind to this mutated enzyme and once again achieve its effectiveness.

“We found out how the antibiotic-producing bacteria make this compound, and then genetically modified that system to remove one part of the backbone of the molecule,” Mahmud said. “Understanding this whole process should allow us to create not just this one, but a range of different analogs that can be tested for their efficacy as new antibiotics.”

In human history and before the advent of antibiotics, tuberculosis was one of the great infectious disease killers in the world. At its peak in the 1800s in Europe, it was the cause of death of one in four people. It’s still a major concern in the developing world, where drugs are often not available to treat it, and it often causes death in tandem with HIV infection.

As the bacterial strains of this disease that are multi- or extensively-drug-resistant increase in number, so too does the difficulty of treating it. Instead of a six-month regimen, these drug-resistant strains can take 18 months to several years to treat, with antibiotics that are more toxic and less effective.

Collaborators on this research were from the University of Delhi and the Institute of Genomics and Integrative Biology in India. The research has been supported by the M.J. Murdock Charitable Trust and the Medical Research Foundation of Oregon.

The approach used in this research “holds great potential to generate more rifamycin analogs to combat the threat of MDR strains of M. tuberculosis, and/or other life-threatening pathogens,” the researchers wrote in their conclusion.

Media Contact: 

Taifo Mahmud, 541-737-9679

Statin use associated with less physical activity

CORVALLIS, Ore. – One of the longest studies of its type has found that use of statins in older men is associated with less physical activity, a significant issue for a population that’s already sedentary.

The findings, published today in JAMA Internal Medicine, raise concerns about a decline in much-needed physical activity among men who take some of the most widely prescribed medications in the world. Almost one-third of older Americans take statins, usually to reduce their cholesterol levels.

The research did not identify why men who took statins exercised less – it just confirmed that they did. Possible causes include the muscle pain that can be a side effect of statin use, and also disruption of the mitochondrial function in cells, which could contribute to fatigue and muscle weakness.

Physical activity in older adults helps to maintain a proper weight, prevent cardiovascular disease and helps to maintain physical strength and function,” said David Lee, an assistant professor in the Oregon State University/Oregon Health & Science University College of Pharmacy, and lead author of the study.

“We’re trying to find ways to get older adults to exercise more, not less,” Lee said. “It’s a fairly serious concern if use of statins is doing something that makes people less likely to exercise.”

Muscle pain is found in 5-30 percent of people who take statins, Lee said, and some people also report feeling less energetic, weak or tired.

In an analysis of 3,071 community-living men, age 65 or older, from six geographic regions in the United States, researchers found that men who took statins averaged about 40 minutes less of moderate physical activity over a one-week period, compared to those who weren’t taking the medication.

That would equate to the loss of 150 minutes a week of slow-paced walking, Lee said.

“For an older population that’s already pretty sedentary, that’s a significant amount less exercise,” he said. “Even moderate amounts of exercise can make a big difference.”

Of some significance, the study also found that new statin users had the largest drop in physical activity. An increase in sedentary behavior, which is associated with all-cause mortality and also death from cardiovascular disease, was also observed in statin users.

Some previous studies with older adults and statins had found similar results, but those analyses were short-term. This research followed men for almost seven years after initial baseline studies were done, and compared changes in physical activity among users and non-users of statins. In parts of the experiments, men wore accelerometers for a week to track by the minute their level of activity.

“Given these results, we should be aware of a possible decrease in physical activity among people taking a statin,” Lee said.

“This could decrease the benefit of the medication,” he said. “If someone is already weak, frail, or sedentary, they may want to consider this issue, and consult with their doctor to determine if statin use is still appropriate.”

This study was done with older men, and generalization of the findings to older women may not be appropriate, the researchers noted in their study.

The research was done by scientists from OSU; the Oregon Health & Science University; the Department of Veterans Affairs Medical Center in Portland, Ore.; the California Pacific Medical Center Research Institute in San Francisco; the Stanford Prevention Research Center; and the Department of Medicine at the University of California.

The study was supported by the National Institutes of Health and the Medical Research Foundation of Oregon.

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