college of pharmacy

Vitamin D, xanthohumol may offer new approach to obesity epidemic

CORVALLIS, Ore. – A growing body of evidence suggests that two natural compounds, vitamin D and xanthohumol, have the ability to address imbalances in gut microbiota that may set the stage for obesity and metabolic syndrome - problems that affect about one out of every three adults in the United States.

To explore and identify the specific mechanisms by which these compounds have beneficial effects, researchers in the Linus Pauling Institute at Oregon State University have received a new five-year, $2.64 million grant from the National Institutes of Health.

The possible payoff of this research, they say, may be an entirely new way to reduce or prevent some of the major diseases that are killing millions of people every year, such as heart disease and type-2 diabetes.

The new approach would attempt, using high dose supplementation, to prevent disease from developing, instead of treating it after the fact.

“The benefits of xanthohumol and vitamin D have been clearly shown in laboratory studies to reduce weight gain and improve gut barrier defenses,” said Adrian Gombart, an associate professor of biochemistry and biophysics in the OSU College of Science, and a principal investigator with the Linus Pauling Institute. “These compounds appear to activate nuclear receptors and pathways that may affect microbe composition, and in the process reduce the damage from metabolic syndrome.”

One study published by OSU researchers two years ago in the Journal of Biological Chemistry found that rats given xanthohumol supplements, which are made from hops, had a 14 percent reduction in weight gain, a 25 percent reduction in plasma fasting glucose, and improved lipid metabolism, compared to a control group of rats that ate the same amount of food. They had a higher rate of fatty acid oxidation and energy metabolism. In simple terms, they burned more fat.

In other studies, higher levels of vitamin D status in humans have been associated with reduced risk of obesity, metabolic syndrome, cancer, infectious diseases, autoimmune diseases, and other health problems.

Other lead investigators on this research include Claudia Maier, an OSU professor of chemistry; Fred Stevens, a professor in the OSU College of Pharmacy and also a principal investigator with the Linus Pauling Institute; and Balz Frei, a distinguished professor of biochemistry and biophysics, and director of the Linus Pauling Institute.

The OSU researchers believe some of the benefits of vitamin D and/or xanthohumol may be a strong increase in the expression of the cathelicidin antimicrobial peptide, or CAMP gene. The hypothesis to be tested in this research, using animal models, is that higher CAMP levels improve gut epithelial barrier function, reduce inflammation, modify gut microbiota and in the process reduce problems with obesity and metabolic syndrome.

“Some of the benefits we’re seeing are fairly clear and dramatic, and we need to better understand the mechanisms that cause them,” Stevens said.

The compounds may also affect liver function, shutting down metabolic pathways that produce fat and glucose, he said.

Vitamin D can be obtained through either the diet or produced by the skin, with adequate exposure to sunshine. Millions of people who live in temperate zones around the world, however, have been found to have inadequate levels of this vitamin, but this can be corrected by taking a supplement.

Xanthohumol, a flavonoid, is also a natural compound and is found in the hops used to make beer. Researchers point out, however, that the levels of xanthohumol being used in this research greatly exceed any amount that could be obtained by drinking beer.

Direct health care costs arising from obesity and related disorders accounts for almost 10 percent of U.S. health care expenditures each year, the researchers said. The health care costs of diabetes alone were estimated in the U.S. at $176 billion in 2012, and it’s one of the leading causes of death in the nation.

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Adrian Gombart, 541-737-8018

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Xanthohumol in hops

Vitamin D
Vitamin D in milk

System may offer new hope for personalized treatment of eczema

CORVALLIS, Ore. – Pharmaceutical researchers at Oregon State University have developed a new approach to treat eczema and other inflammatory skin disorders that would use individual tests and advanced science to create personalized treatments based on each person’s lipid deficiencies.

A patent has been applied for on this system, which could revolutionize the treatment of eczema if it works as scientists believe it will.

By identifying the specific problems each person has, moisturizers, skin protectants or other products or therapies could be created to address those specific problems.

Aside from powerful steroid treatments that have a wide range of unwanted side effects, the primary existing treatments for eczema are “one size fits all” moisturizing or protective products, with little basis for understanding whether or not that’s what an individual needs. Sometimes such products help, and often they are inadequate.

In 2012 in the United States, about 15 million Americans struggled with eczema, or atopic dermatitis, accounting for about $1 billion in health care costs and 10-20 percent of all visits to a dermatologist.

Eczema and some other skin disorders can be caused by a deficiency in lipids, which are various types of fat in the skin such as ceramides, cholesterol and free fatty acids, according to Arup Indra, an associate professor in the OSU College of Pharmacy and an expert on inflammatory skin disease.

“Lipids in our skin help retain moisture, they act like a blanket that protects against irritation and infection,” Indra said. “You could think of skin cells as the bricks of a wall, but lipids are the mortar that prevent things from getting through the cracks. When they are deficient, problems can develop.”

Part of what makes eczema so difficult to treat, however, is that there are hundreds of lipids, serving various functions as a skin protector, barrier or antimicrobial agent – and every individual has a slightly different lipid composition. Most of the moisturizers now available are just random compositions of lipids that may or may not help address what is missing in a given individual.

The new system created at OSU starts with surprising simplicity. A piece of tape is stuck to the skin and then pulled off, removing with it some skin cells. The painless procedure is totally noninvasive and could be used on anyone from infants to the elderly.

Those skin and lipid samples are then analyzed with sophisticated mass spectrometry in a process created at OSU that literally produces a “lipid fingerprint” – a measurement of that person’s skin and lipid profile. This profile can then be compared against those of healthy individuals, to help identify missing or deficient lipids that may be an underlying cause of the skin disorder.

From that, various products or other therapies can be developed that would help replace or increase the lipids that are deficient in a person. They could be used topically like conventional moisturizers.

OSU’s research, the first of its type, has already shown that the lipid profiles of people with healthy skin often differ markedly from those with eczema or other inflammatory skin disorders. This offers further evidence that altered lipid composition in the skin of eczema patients may be a determinant of disease onset, progression and severity, the researchers said.

“We believe it’s likely that supplementation with the lipids a person specifically needs will help address their skin problems and improve epidermal barrier function, and we plan to test that in continued research,” Indra said.

Findings in this area could also be used in veterinary medicine, the researchers said, since many pets such as cats and dogs also have skin disorders.

Further collaboration and support from private industry is being sought by OSU to help bring these systems more rapidly to availability, through its Office for Commercialization and Corporate Development.

This research has been supported by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

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Arup Indra, 541-737-5775

Hospice patients, practitioners face quandary about antibiotic use

PORTLAND, Ore. – A survey of hospice programs in Oregon found that only 31 percent had policies for initiating the use of antibiotics, and only 17 percent a policy for when to discontinue them – pointing to a continued uncertainty about the use of such medications in this select group of terminal patients.

The findings, published in the American Journal of Hospice and Palliative Medicine, are among the first to quantify policies for antibiotic use in hospice, where the primary goal is to promote patient comfort and quality of remaining life, but not to prolong it.

A concern highlighted in the research is that antibiotics may have unwanted side effects that can decrease a patient’s comfort, such as nausea, vomiting, diarrhea or yeast infection. It found that such symptoms were observed “sometimes or often” by about half or more of responding hospice programs.

Respondents to the survey did say that they rarely or never use antibiotics to prolong patient’s lives – but 14 percent of programs also reported that this sometimes occurs.

“The lack of specific policies and guidelines about antibiotic use in hospice care reflects the difficulty and uncertainty that still exists in how to manage end-of-life care, even among this group of people who have chosen not to prolong their life,” said Jon Furuno, an associate professor in the Oregon State University/Oregon Health & Science University College of Pharmacy, and lead author on the study.

“There may be situations where antibiotic use does improve symptoms and patient comfort,” Furuno said. “On the other hand, antibiotic use is not always benign. They can have adverse events associated with their use, such as gastrointestinal problems. These are difficult decisions in a situation where we’re trying to reduce the number of medications taken at the end of life.”

The development of policies is also complicated by medical uncertainty over exactly how a patient may respond to antibiotic use, Furuno said, and by a paucity of scientific evidence over how well they may work to reduce symptoms in patients who are already terminally ill and often have compromised immune systems.

“The goals of hospice, in general, are fairly well understood by the parties involved, but the application in the field is much more variable,” Furuno said. “There will always be, and should be, flexibility in decisions that vary from patient to patient, and even if we did develop policies they could not be too rigid. But it would help if we could develop some better guidelines to help inform these decisions.”

According to Barbara Hansen, CEO of the Oregon Hospice Association, this study is an important first step toward quantifying the issues related to antibiotic use in hospice patients, and understanding current practices.

“This issue is challenging and problematic, but we all face it, and this research has now laid the groundwork to know what is happening in the field,” Hansen said. “We do need to be more systematic in our approaches, and give hospice practitioners more support in how to talk with patients and their families about antibiotic use.”

A step toward policies, Hansen said, might be guidance about determining whether an infection is actually causing a patient significant discomfort – if not, some may be better left untreated, rather than risk the additional complications that could ensue from treatment. And there may be communication that could be developed earlier to help family members understand the wishes of the patient being care for, she said.

Complicating the problem, the researchers said, is that antibiotic use is so ingrained in contemporary medicine. Previous studies at OSU have shown that 27 percent of hospice patients are still taking antibiotics in the final week of their life. This is a special concern for people who have specifically chosen an end-of-life approach that is focused on protecting the remaining quality of life without aggressively continuing medical treatment.

Hospice is covered by Medicare for people with a life expectancy of less than six months. It often allows people to die in their own homes, helps to reduce medical costs and hospital stays, and its services are now used by more than one third of dying Americans.

Collaborators on this study were from the OSU/OHSU College of Pharmacy and the Oregon Health & Science University. It was supported by the National Institutes of Health.

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Jon Furuno, 503-418-9361

Advance in photodynamic therapy offers new approach to ovarian cancer

PORTLAND, Ore. – Researchers at Oregon State University have made a significant advance in the use of photodynamic therapy to combat ovarian cancer in laboratory animals, using a combination of techniques that achieved complete cancer cell elimination with no regrowth of tumors.

The findings were just published in the journal Nanomedicine: Nanotechnology, Biology and Medicine, and after further research may offer a novel mechanism to address this aggressive and often fatal cancer that kills 14,000 women in the United States each year.

Ovarian cancer has a high mortality rate because it often has metastasized into the abdominal cavity before it’s discovered. Toxicity and cancer-cell resistance can also compromise the effectiveness of radiation and chemotherapy that’s often used as a follow-up to surgery.

The new approach being developed by researchers from the OSU College of Pharmacy and the University of Nebraska takes existing approaches to photodynamic therapy and makes them significantly more effective by adding compounds that make cancer cells vulnerable to reactive oxygen species, and also reducing the natural defenses of those cells.

“Surgery and chemotherapy are the traditional approaches to ovarian cancer, but it’s very difficult to identify all of the places where a tumor has spread, and in some cases almost impossible to remove all of them,” said Oleh Taratula, an assistant professor in the Oregon State University/Oregon Health & Science University College of Pharmacy.

“Photodynamic therapy is a different approach that can be used as an adjunct to surgery right during the operation, and appears to be very safe and nontoxic,” Taratula said. “In the past its effectiveness has been limited, but our new findings may make this technology far more effective than it’s ever been before.”

Using the new approach, a patient is first given a photosensitizing compound called phthalocyanine, which produces reactive oxygen species that can kill cells when they are exposed to near-infrared light. In addition, a gene therapy is administered that lowers the cellular defense against reactive oxygen species.

Both the phthalocyanine and genetic therapy, composed of “small, interfering RNA,” are attached to what researchers call “dendrimer-based nanoplatforms,” a nanotechnology approach developed by OSU researchers. It delivers the compounds selectively into cancer cells, but not healthy cells.

Compared to existing photodynamic therapies, this approach allows the near-infrared light to penetrate much deeper into abdominal tissues, and dramatically increases the effectiveness of the procedure in killing cancer cells.

Using photodynamic therapy alone, some tumors in laboratory animals began to regrow after two weeks. But with the addition of the combinatorial genetic therapy to weaken the cancer cell defenses, there was no evidence of cancer recurrence. During the procedures, mice receiving the gene therapy also continued to grow and gain weight, indicating a lack of side effects.

“Cancer cells are very smart,” Taratula said. “They overexpress certain proteins, including one called DJ1, that help them survive attack by reactive oxygen species that otherwise might kill them. We believe a key to the success of this therapy is that it takes away those defensive mechanisms.”

The overexpression of DJ1, researchers said in their study, is associated with invasion, metastasis, resistance to cancer therapies, and overall cancer cell survival. That excess of DJ1 is silenced by the genetic therapy composed of siRNA.

The findings of this research, Taratula said, could also build upon some other recent advances in photodynamic therapy, in which a different compound called naphthalocyanine could be administered prior to surgery, causing the cancer cells to “glow” and fluoresce when exposed to near-infrared light. This provides a literal road map for surgeons to follow, showing which tissue is cancerous and which is not.

There’s no reason that approach couldn’t be combined with the newest advance, Taratula said, providing multiple mechanisms to improve surgical success and, with minimal side effects, help eradicate any remaining cancer cells that were not completely removed.

“Our study established a prospective therapeutic approach against ovarian cancer,” the researchers wrote in their conclusion. “The tumors exposed to a single dose of a combinatorial therapy were completely eradicated from the mice.”

The studies were supported by the Medical Research Foundation of Oregon and the College of Pharmacy at OSU. Continued research will take place with treatment of malignant tumors on live dogs in the OSU College of Veterinary Medicine, prior to any human clinical tests.

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Oleh Taratula, 503-346-4704

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Cancer therapy
New cancer therapy

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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Cancer therapy
Improved cancer therapy

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.


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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New approach to sunscreen
Animals produce sunscreen

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.

Story By: 

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.”

Story By: 

Craig Williams, 503-494-1598