OREGON STATE UNIVERSITY

college of pharmacy

System to boost levels of resveratrol, quercetin could provide new options for cancer therapy

PORTLAND, Ore. – Resveratrol and quercetin, two polyphenols that have been widely studied for their health properties, may soon become the basis of an important new advance in cancer treatment, primarily by improving the efficacy and potential use of an existing chemotherapeutic cancer drug.

Resveratrol, a powerful antioxidant found in red wine and other foods, has already received much attention as a possible explanation for the “French paradox,” a low incidence of cardiovascular disease despite a diet often high in fats.

The new research suggests it may soon have value far beyond that.

In laboratory experiments, researchers at Oregon State University have developed a system to increase the bioavailability of these compounds in the body by using “copolymers” that make them water soluble and allow their injection into the blood stream, creating levels that are far higher than could ever be obtained by diet or oral intake.

The resveratrol and quercetin then appear to reduce the cardiac toxicity of a very widely used cancer drug, Adriamycin. Although highly effective in the treatment of lymphomas, breast, ovarian and other cancers, Adriamycin can only be used for a limited time in humans because of its cardiotoxicity.

The co-administration of these polyphenols might allow much more extensive use of this drug, while at the same time improving its efficacy and demonstrating the polyphenols’ own anti-cancer properties, scientists said.

Findings on this research have been published in the Journal of Controlled Release, by scientists from the College of Pharmacy at Oregon State University and the School of Pharmacy at Pacific University. Both institutions supported the research.

“This has great potential to improve chemotherapeutic cancer treatment,” said Adam Alani, an assistant professor in the Oregon State University/Oregon Health & Science University College of Pharmacy, and lead author on the research.

“The co-administration of high levels of resveratrol and quercetin, in both in vitro and in vivo studies, shows that it significantly reduces the cardiac toxicity of Adriamycin,” Alani said. “And these compounds have a synergistic effect that enhances the efficacy of the cancer drug, by sensitizing the cancer cells to the effects of the drug.”

It’s possible, Alani said, that after further research it could be demonstrated that use of these compounds can completely eliminate the cardiotoxicity of Adriamycin, as they scavenge the toxic free radicals produced by use of this drug. It’s also possible, he said, that administration of these natural polyphenols could have value in cancer therapy by themselves, or in combination with a wider range of other chemotherapeutic drugs.

Resveratrol is a natural compound found in foods such as grapes, red wine, green tea, some fruits, berries and dark chocolate, and has been the subject of dozens of scientific studies for its various health values. Quercetin, also a powerful antioxidant, reaches some of its highest natural levels in capers, some berries, fruits, vegetables and leafy greens.

Although they are still valuable nutrients, these polyphenol compounds when eaten as foods or taken as supplements reach only a tiny fraction of the level that’s possible with direct injection.

And such injection was not possible until the OSU and Pacific University researchers adapted the use of “polymeric micelles” to help make the polyphenols water soluble, so they could be directly inroduced into the body. Such systems have been used before with other compounds, but never these polyphenols.

“There are several advantages with this system,” Alani said. “We can finally reach clinical levels of these polyphenols in the body. We can load both the compounds at one time to help control the cardiotoxicity of the cancer drug, and we can help the polyphenols accumulate in cancer cells where they have their own anti-cancer properties.

“This is like hitting three birds with one stone,” Alani said. “It has great potential.”

Research has already shown that both resveratrol and quercetin appear to be safe at high concentrations in the body, Alani said, although continued research will study that issue, among others. And the fact that such delivery systems, as well as the cancer drugs, are already approved by the FDA should speed the clinical testing and possible medical use of this system, he said.

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Adam Alani, 503-346-4702

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Pactamycin analogs offer new, gentler approach to cancer treatment

 

The study this story is based on is available online: http://bit.ly/1PlJvdS

 

CORVALLIS, Ore. – Researchers at Oregon State University are pursuing a new concept in treatment of epithelial cancer, especially head and neck cancer, by using two promising “analogs” of an old compound that was once studied as a potent anti-tumor agent, but long ago abandoned because it was too toxic.

The analogs are more highly selective than the parent compound, pactamycin, which originally was found to kill all cells, from bacteria to mammals, by inhibiting their protein synthesis.

The pactamycin analogs, which were developed with biosynthetic engineering, also offer a different approach toward cancer therapy – an effort to essentially put cancer cells to sleep, instead of killing them. If successful, this trend may herald a new future in “kinder and gentler” cancer treatments.

Findings on this promising approach to cancer were just published in PLOS One, in work supported by the National Institute of Health and other agencies.

The effects of the pactamycin analogs, called TM-025 and TM-026, were characterized in head and neck cancer cell lines, which cause the eighth most common cancer in the world. But they may have applications to a wider range of cancers, the researchers said, particularly melanoma.

“A traditional view of chemotherapy is that you try to completely kill cancer cells and destroy tumors,” said Arup Indra, an associate professor in the OSU College of Pharmacy and one of the lead authors on the study. “Sometimes this is effective, sometimes not as much. An alternative approach is to cause rapid cell aging and induce premature senescence, which we believe could become a new frontier in cancer drug development.”

A senescent cancer cell, Indra said, doesn’t usually die, but the growth of it and the larger tumor is slowed or stops, and it continues to live in a vegetative state, almost like being asleep. Such an approach can be an alternative way to control cancer without completely killing it, which may help reduce problems with resistance that can quickly develop to chemotherapeutic drugs. And it also avoids some of the most toxic and debilitating side effects of cancer chemotherapies, which are often caused by cell death.

The new findings showed that these analogs of pactamycin largely stopped cancer cell proliferation and growth, causing cells to age and lose their ability to divide and grow. These effects are partly mediated by tumor suppressor p53, which is frequently mutated in human cancers. They do not yet form the basis for a therapy, researchers said, because methods must still be perfected to get them more selectively into the cancer cells.

“With further research we hope to create a nontoxic nanocarrier that could provide targeted delivery of the TM-025 and TM-026 analogs specifically to cancer cells,” said Gitali Indra, an OSU assistant professor and also a lead and corresponding author on the study. “In some cases, such as oral cancer, it may also be possible to use topical treatments. But this approach should have significant promise if we can develop techniques to adequately target the cancer cells.”

The OSU researchers are continuing work to more fully understand the mode of action of these pactamycin analogs. Collaborators on this study include Taifo Mahmud, an OSU professor in the College of Pharmacy, and researchers from the Oregon Health & Science University.

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Arup Indra, 541-737-5775

No lotions needed: Many animal species produce their own sunscreen

CORVALLIS, Ore. – Researchers have discovered why many animal species can spend their whole lives outdoors with no apparent concern about high levels of solar exposure: they make their own sunscreen.

The findings, published today in the journal eLife by scientists from Oregon State University, found that many fish, amphibians, reptiles, and birds can naturally produce a compound called gadusol, which among other biologic activities provides protection from the ultraviolet, or sun-burning component of sunlight.

The researchers also believe that this ability may have been obtained through some prehistoric, natural genetic engineering.

The gene that provides the capability to produce gadusol is remarkably similar to one found in algae, which may have transferred it to vertebrate animals – and because it’s so valuable, it’s been retained and passed along for hundreds of millions of years of animal evolution.

“Humans and mammals don’t have the ability to make this compound, but we’ve found that many other animal species do,” said Taifo Mahmud, a professor in the OSU College of Pharmacy, and lead author on the research.

The genetic pathway that allows gadusol production is found in animals ranging from rainbow trout to the American alligator, green sea turtle and a farmyard chicken.

“The ability to make gadusol, which was first discovered in fish eggs, clearly has some evolutionary value to be found in so many species,” Mahmud said. “We know it provides UV-B protection, it makes a pretty good sunscreen. But there may also be roles it plays as an antioxidant, in stress response, embryonic development and other functions.”

In their study, the OSU researchers also found a way to naturally produce gadusol in high volumes using yeast. With continued research, it may be possible to develop gadusol as an ingredient for different types of sunscreen products, cosmetics or pharmaceutical products for humans.

A conceptual possibility, Mahmud said, is that ingestion of gadusol could provide humans a systemic sunscreen, as opposed to a cream or compound that has to be rubbed onto the skin.

The existence of gadusol had been known of in some bacteria, algae and other life forms, but it was believed that vertebrate animals could only obtain it from their diet. The ability to directly synthesize what is essentially a sunscreen may play an important role in animal evolution, and more work is needed to understand the importance of this compound in animal physiology and ecology, the researchers said.

Collaborators on this research were Robert Tanguay and Alan Bakalinsky from the OSU College of Agricultural Sciences and Andrew Karplus from the OSU College of Science. The study was supported by the OSU College of Pharmacy and the National Institutes of Health.

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Taifo Mahmud, 541-737-9679

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Drug prices to treat multiple sclerosis soar, point to larger problem

PORTLAND, Ore. – A new study released today found that drugs used to treat multiple sclerosis have soared in price in the past two decades, in some cases more than 700 percent, even though newer drugs have come to the market - a process that normally should have stabilized or reduced the cost of at least the older medications.

There are no multiple sclerosis drugs now available in the United States with a list price below $50,000 a year, which is two to three times more than the price in Canada, Australia or the United Kingdom. The group of drugs available to treat this disease is rising in price at five to seven times the normal rate of drug inflation in the U.S.

The findings of this research also point to a systemic problem in the U.S. pharmaceutical industry, with relevance to more than just drugs for multiple sclerosis, according to the authors of the study, which was supported by the Oregon State University College of Pharmacy.

Enormous, uncontrolled and rapidly increasing prices for some types of drugs, they say, may be linked to non-transparent drug pricing policies, a dysfunctional market and the lack of a national healthcare system to negotiate prices more aggressively and directly with pharmaceutical companies.

The end result, they say in the report, may be another industry “too big to fail.”

This research was published today in Neurology, the medical journal of the American Academy of Neurology, by scientists at the Oregon State University/Oregon Health & Science University College of Pharmacy, the Oregon Health & Science University, and the Veterans Affairs Medical Center in Portland, Oregon.

“The issue of astronomical drug costs, especially for newer drugs or rare conditions, is more and more common,” said Daniel Hartung, lead author of the study and an associate professor in the Oregon State University/Oregon Health & Science University College of Pharmacy.

“There are often several drugs in a class available to treat a disease or condition, and ‘economics 101’ would suggest that competition should lower prices,” Hartung said. “In the pharmaceutical industry we often don’t see that. Many professionals now believe that it’s time to push back, to say enough is enough.”

Escalating costs for specialty pharmaceuticals, for conditions such as multiple sclerosis, cancer, and hepatitis C, have been a growing concern among many in the health care industry, the authors wrote in their study, raising questions about the ethics of our current approach, exorbitant pricing and increased burdens on “our already stressed healthcare system.”

“Pricing in the pharmaceutical industry increasingly is a case of whatever the market will bear,” Hartung said. “We used to think that any drug with $1 billion in sales was a blockbuster, but last year a drug for hepatitis C had 10 times that, or $10 billion in sales. This does not necessarily mean that drug research and innovation will be 10 times better.”

In the specific case of multiple sclerosis, the research looked at first-generation drugs which became available in the 1990s at prices ranging from $8,000 to $10,000 a year. More competition from other drugs then entered the field. But instead of the price of the original drugs staying about the same or going down, as classic economic theory might dictate, their price soared. One drug that originally cost $8,700 now costs $62,400 a year.

The cause for escalation in the cost of these older drugs is unexplained and “alarming,” the researchers said. It most likely was not attributable to a rise in manufacturing costs, and general and prescription drug inflation was only about 3-5 percent a year over the same period.

“The simplest explanation is that pharmaceutical companies raise prices of new and old MS disease modifying therapies in the United States to increase profits, and our healthcare system puts no limits on these increases,” the researchers wrote in their report. “The U.S. Medicare program, the largest single-payer healthcare system in the U.S., is legally prohibited from negotiating drug prices directly with the pharmaceutical industry.”

There’s some evidence that generic drug growth might slow the rising drug costs in the U.S., the researchers said, but so far most multiple sclerosis drugs are not exposed to price competition from generics.

For the patient, the soaring costs of these drugs threaten access to them, the study indicated. Initial denials of insurance coverage for multiple sclerosis drugs, for both new and established patients, occur much more often now than in the past, the study reported, often requiring multiple approval steps for patients and their neurologists.

“As a doctor, I’m deeply concerned about making sure these life-changing drugs are within reach for patients,” said Dr. Ruth H. Whitham, co-author of the study, a professor of neurology in the OHSU School of Medicine, and co-founder of the Multiple Sclerosis Center at OHSU. “The driving force behind this study was our experience that the high cost of MS drugs interferes with our ability to take good care of our patients.

“We decided to shine a light on this growing problem so that those of us who care for patients with chronic illness can work together and advocate for changes to drug pricing mechanisms,” she said.

Hartung suggested that, lacking other major changes in the health care system, public awareness and involvement may be an important first step.

“The court of public opinion is pretty powerful,” he said. “We need to shed some light on this issue and do something about it.”

Authors of the study concluded that “it is time for neurologists to begin a national conversation about unsustainable and suffocating drug costs for people with MS – otherwise we are failing our patients and society.”

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Dan Hartung, 503-494-4720

Survey shows half of older adults in U.S. now taking aspirin

CORVALLIS, Ore. – A national survey suggests that slightly more than half of the older adults in the United States are now taking a daily dose of aspirin, even though its use is not recommended by the Food and Drug Administration for most people who have not yet had a heart attack or stroke.

The analysis was published today in the American Journal of Preventive Medicine. It observed that aspirin use is continuing to surge, especially among adults who are using it for “primary prevention,” meaning in order to prevent an initial cardiovascular event, and in some cases to prevent cancer.

In this survey of more than 2,500 respondents aged 45-75, 52 percent reported current aspirin use, and another 21 percent had used it at some point in the past. The average age of respondents in the survey was 60. A different report found that aspirin use increased 57 percent between 2005 and 2010.

Aspirin is a blood thinner and can cause bleeding events, which is a primary reason some medical experts recommend caution in its use, even at the “baby aspirin” dose of 81 milligrams often used for disease prevention. The FDA has determined that in primary use to prevent a first heart attack or stroke, for every such event that’s prevented, there’s approximately one major bleeding event that’s caused, such as gastrointestinal bleeding.

Largely on that basis, they have concluded physicians should routinely recommend its use only to patients that have already had a heart attack or stroke. But this study found that 81 percent of older adults who are now using aspirin have not had a heart attack or stroke, and are taking it for primary prevention.

“The use of aspirin is still a very contentious issue among medical experts,” said Craig Williams, a pharmacotherapy specialist with the College of Pharmacy at Oregon State University, and lead author of the new report.

“There’s no doubt that aspirin use can have value for people who have experienced a first heart attack, stroke or angina,” said Williams, a professor in the Oregon State University/Oregon Health & Science University College of Pharmacy. “The data to support that is very strong. The support of its use in primary prevention is more of a mixed bag.

“But this survey clearly shows that more and more people who have not experienced those events and are not technically considered at high risk by the FDA are also deciding to use aspirin, usually in consultation with their doctors.”

Aside from cardiovascular events, some studies have suggested a role for aspirin in preventing cancer, Williams said, especially colon cancer. That has further increased interest in its use, he said.

While the FDA takes a more cautious stance, Williams said, some other professional organizations, such as the U.S. Preventative Services Task Force, says aspirin use may be appropriate for primary prevention in people with serious risk factors for cardiovascular disease, such as high blood pressure, high cholesterol, smoking or diabetes. Objective criteria for aspirin use in those patients are based on the number of the risk factors, the age and gender of the patient.

Surveys such as this are needed to help determine how people are managing their own health, Williams said, since aspirin is an over-the-counter medication and its use cannot be determined solely by medical records. And the findings suggest that tens of millions of Americans have reviewed the issues involved, often discussed it with their doctors, say they know what they are doing - and decided to use aspirin.

Among the findings of the report:

  • Several markers of healthy lifestyle choices were also associated with aspirin use.
  • The strongest predictor of regular aspirin use was a patient having discussed aspirin therapy with a health care provider.
  • About 35 percent of people who don’t objectively have risk factors that might merit aspirin therapy still use it.
  • About 20 percent of people who have already had a heart attack or stroke, and should be on aspirin therapy, do not use it.
  • A majority of both current and previous aspirin users rated themselves as being somewhat or very knowledgeable about it.
  • Among aspirin users, the reasons cited for its use by respondents was for heart attack prevention, 84 percent; stroke prevention, 66 percent; cancer prevention, 18 percent; and prevention of Alzheimer’s disease, 11 percent.
  • Significant predictors of aspirin use included people who were physically active, ate healthy foods, had achieved a healthy weight, managed their stress, tried to quit smoking, and/or had undergone health screenings.

 

This study was sponsored by the Partnership for Prevention and the Council on Aspirin for Health and Prevention. This council receives financial support from Bayer HealthCare, which has no influence over its programs or activities, and played no role in the decision to conduct this research or publish the results.

Collaborators with Oregon State University on the research were from Harvard/Brigham and Women’s Hospital; the Partnership for Prevention; The Ohio State University; the University of North Carolina; and Stanford University.

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Craig Williams, 503-494-1598

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Publication bias and ‘spin’ raise questions about drugs for anxiety disorders

CORVALLIS, Ore. – A new analysis reported in JAMA Psychiatry raises serious questions about the increasingly common use of second-generation antidepressant drugs to treat anxiety disorders.

It concludes that studies supporting the value of these medications for that purpose have been distorted by publication bias, outcome reporting bias and “spin.” Even though they may still play a role in treating these disorders, the effectiveness of the drugs has been overestimated.

In some cases the medications, which are among the most widely prescribed drugs in the world, are not significantly more useful than a placebo.

The findings were made by researchers from Oregon State University, Oregon Health & Science University, and the University of Groningen in The Netherlands. The work was supported by a grant from the Dutch Brain Foundation.

Publication bias was one of the most serious problems, the researchers concluded, as it related to double-blind, placebo-controlled clinical trials that had been reviewed by the U.S. Food and Drug Administration. If the FDA determined the study was positive, it was five times more likely to be published than if it was not determined to be positive.

Bias in “outcome reporting” was also observed, in which the positive outcomes from drug use were emphasized over those found to be negative. And simple spin was also reported. Some investigators concluded that treatments were beneficial, when their own published results for primary outcomes were actually insignificant.

“These findings mirror what we found previously with the same drugs when used to treat major depression, and with antipsychotics,” said Erick Turner, M.D., associate professor of psychiatry in the OHSU School of Medicine, and the study’s senior author. “When their studies don’t turn out well, you usually won’t know it from the peer-reviewed literature.”

This points to a flaw in the way doctors learn about the drugs they prescribe, the researchers said.

“The peer review process of publication allows, perhaps even encourages, this kind of thing to happen,” Turner said. “And this isn’t restricted to psychiatry – reporting bias has been found throughout the medical and scientific literature.”

Craig Williams, a professor in the Oregon State University/Oregon Health & Science University College of Pharmacy, and co-author of the study, said that “most of these drugs are fairly safe and well-tolerated, but if a medication is less effective than believed, this still raises serious questions about its use.

“The level of bias we found did not change the fact that some antidepressants can have value in treating anxiety disorders,” Williams said. “However, there is less evidence for value of these drugs than published studies would have you believe. And these concerns are increased when such medications are frequently prescribed by general practitioners with less training in psychiatry.”

In this study, the researchers examined a broad body of the evidence and scientific research that had been presented to the Food and Drug Administration, including studies that had been done but were not published in open scientific literature. They found that negative data on drug efficacy tended not to get published, or was de-emphasized when it was published.

Conclusions might have been manipulated or exaggerated because positive results receive more scientific attention, are published sooner, and lead to higher sales of a drug, said Annelieke Roest, the lead author of the publication at the University of Groningen.

“Lots of research is funded eventually by the taxpayer, and that’s reason enough to say that scientists should publish all their results,” Roest said.

The study reiterated this point, and the need to more routinely publish nonsignificant results.

“There is strong evidence that significant results from randomized controlled trials are more likely to be published than nonsignificant results,” the researchers wrote in their study. “As a consequence, the published literature . . . may overestimate the benefits of treatment while underestimating their harms, thus misinforming clinicians, policy makers and patients.”

Antidepressants are now widely prescribed for conditions other than depression, the study noted. They are being used for generalized anxiety, panic disorder, social anxiety, post-traumatic stress disorder and other uses. In both the U.S. and Europe, use of antidepressant drugs has significantly increased in the past two decades, the researchers said, with much of that use driven by non-specialists in primary care settings.

The level of reporting bias in the scientific literature, the researchers wrote, “likely impacts clinicians’ perceptions of the efficacy of these drugs, which could reasonably be expected to affect prescription behavior.”

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Craig Williams, 503-494-1598

OSU pharmacy students to help address health emergency at the University of Oregon

CORVALLIS, Ore. – The students at the University of Oregon are facing a rare health emergency that’s led the Center for Disease Control to call for a meningitis vaccine for the entire student body – and the pharmacy students at Oregon State University are helping to answer the call.

Next week, on March 2-5, up to 40 pharmacy students at OSU will journey to the University of Oregon in Eugene to assist in a mass vaccination effort designed to help protect the health of their fellow Oregon college students.

The program will be organized and supervised by Safeway pharmacists, who have the contract to administer the vaccine, which may cost $7 million or more before 20,000 students are vaccinated in a three-dose regimen. The unusual and aggressive public health response was decided when the CDC declared a meningitis outbreak after four UO students acquired this disease since January, and one died.

“Meningitis is fairly rare and difficult to transmit, usually requiring hours of close contact,” said Lorinda Anderson, an OSU faculty member who manages the immunization initiatives for the College of Pharmacy. “But it’s a serious disease, it can be fatal, and the close confines of a school are one of the situations in which it has to be taken very seriously.”

Vaccines will be offered from 10 a.m. to 8 p.m. in the Matthew Knight Arena on the UO campus next Monday through Thursday, with OSU students assisting other pharmacists in the program. Vaccine will be made available to all UO undergraduate students. More information is available online at http://bit.ly/1LsEFnR

It’s unusual for such large numbers of people to need vaccinations in such a short time, Anderson said.

“This is a unique opportunity to help our friends at the University of Oregon, working with other members of the Eugene medical community,” Anderson said. “Giving vaccinations has become a common part of the training for pharmacists, and it’s rewarding that we’re able to assist in this situation. The need for mass vaccinations such as this is really quite rare, and we’re glad we can help.”

The meningitis vaccine being used is fairly new, Anderson said, and designed for people ranging in age from 10 to 25. Meningitis is most common in young adults such as those of college age. Efforts will be made to bill insurance programs for the vaccine when possible, she said.

The vaccine itself is generally safe, Anderson said, similar in terms of side effects to the influenza vaccine. The most common side effects are reactions at the injection site. This new vaccine is not available to the general public, and there have been no reported cases of meningitis recently in the Eugene area beyond the university campus.

People who are infected with meningitis have about a 10 percent chance of it causing inflammation in the brain and spinal cord, Anderson said, where it can cause the most serious problems. It’s treatable with antibiotics, especially if treatment is begun early enough.

Sequential doses of the vaccine will be necessary at two and six months, Anderson said, and plans for those vaccinations in Eugene have not yet been made.

There have been no recent cases of meningitis at OSU, and no mass vaccination programs are planned there. However, vaccines are available to OSU students through Student Health Services. More information is available online at http://studenthealth.oregonstate.edu/

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Lorinda Anderson, 541-737-313

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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.

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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.

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Oleh Taratula, 541-737-5785

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“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.

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Jon Furuno, 503-418-9361

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