OREGON STATE UNIVERSITY

college of pharmacy

New gonorrhea treatment targets enzyme needed for respiration

CORVALLIS, Ore. – Researchers have identified a possible new treatment for gonorrhea, using a peptide that thwarts the infection-causing bacterium by interfering with an enzyme the microbe needs to respirate.

The findings are especially important since Neisseria gonorrhoeae is considered a “superbug” due to its resistance to all classes of antibiotics available for treating infections.

Gonorrhea, a sexually transmitted disease whose numbers grow by 78 million new cases worldwide each year, is highly damaging to reproductive and neonatal health if untreated or improperly treated.

It can lead to endometritis, pelvic inflammatory disease, ectopic pregnancy, epididymitis and infertility. And babies born to infected mothers are at increased risk of blindness.

“The infections very often are silent,” said Oregon State University researcher Aleksandra Sikora. “Up to 50 percent of infected women don’t have symptoms, but those asymptomatic cases can still lead to some very severe consequences for the patient’s reproductive health, miscarriage or premature delivery.”

The need for better antibiotic therapy, and a vaccine, is pressing. N. gonorrhoeae strains resistant to the last effective treatment options have emerged, and failures in treatment are occurring.

Researchers led by Sikora, an associate professor in the OSU College of Pharmacy, have identified a new therapy target, an enzyme known as AniA. The bacteria need the surface-exposed enzyme to respirate without oxygen, or anaerobically, which is their preferred method of respiration in the biofilms of the genitourinary tract.

A biofilm is a group of one or more types of microorganisms that grow on a wet surface, such as dental plaque on teeth.

Sikora and her team identified a peptide – multiple amino acids linked in a chain – that inhibits the AniA enzyme’s nitrite reductase activity. That in turn damages the bacteria’s ability to grow in the oxygen-poor biofilm environment.

“Bacteria in biofilms display increased resistance to antimicrobials,” Sikora said. “The enzyme is only necessary for cell viability when these bacteria grow under anaerobic conditions, including when they grow in the biofilm. Most antibiotics target essential cell functions; this one doesn’t. It’s only at a certain stage of growth that the bacteria are affected, which means the development of resistance won’t be as fast.”

Through a technique known as biopanning, OSU scientists and collaborators at the University of Kentucky found 29 unique peptides that bound with the targeted enzyme. One of them, C7-3, was identified as most promising for inhibiting the protein’s interaction with nitrite, necessary for anaerobic respiration.

“Imagine this research approach as having a pond with a lot of fish, and you’re using the protein as the bait,” Sikora said. “The peptides bind with the protein, and you go through multiple rounds to identify the peptides that have the strongest binding ability. You start with a billion peptides and end up with one that strongly inhibits the enzyme and ultimately kills the bacteria.”

Findings were recently published in Antimicrobial Agents and Chemotherapy, and Sikora has applied for a provisional patent. The National Institutes of Health and the Medical Research Foundation of Oregon partially supported this research.

The research team included five undergraduate students, four of whom were from Oregon State University.

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Neisseria gonorrhoeae cells

Neisseria gonorrhoeae cells

Patients nearing end of life receptive to having cholesterol medicine ‘deprescribed’

PORTLAND, Ore. – New research suggests patients nearing the end of their lives because of a “life-limiting illness” such as cancer or heart disease may not feel medically abandoned if their doctor wants to take them off the statins that control their cholesterol.

The findings are important because little is known about the best way to manage chronic medications for patients with a life-limiting condition, including data regarding patient attitudes toward “deprescribing.”

Deprescribing medications has the potential to improve outcomes in some cases, but patient concerns over being taken off statin drugs have not been reported.

Statins are a class of drugs that work by blocking the liver enzyme responsible for cholesterol production, thus reducing the buildup of plaque on artery walls that can lead to a stroke or heart attack. The drugs are highly effective but not without side effects for some patients, the most common being muscle pain that ranges from mild to severe.

Jon Furuno, an associate professor in of the Oregon State University/Oregon Health & Science University College of Pharmacy, joined collaborators from around the United States in a study that included nearly 300 patients whose average age was 72 and whose life expectancy was one to 12 months. The patients were participants in a clinical trial to determine the safety and benefit of discontinuing statin therapy.

Fifty-eight percent were cancer patients, 8 percent had cardiovascular disease, and 30 percent had some other life-limiting diagnosis. The patients gave responses to a nine-item questionnaire designed to quantify potential benefits and concerns associated with discontinuing statins.

“We know these patients are on a lot of medications,” Furuno said. “There’s a lot of concern that patients will feel like doctors are giving up on them if they start to discontinue some of their medications, that there’s something comforting about continuing to take their medications, and this gives us some indication of what patients feel about the risks and benefits of deprescribing.”

Less than 5 percent of study participants expressed concern that deprescribing statins indicated being abandoned by their doctor, and many could see benefits of going off their statin, including spending less on medications (63 percent); the potential for being able to stop taking other meds also (34 percent); and having a better overall quality of life (25 percent).

Cardiovascular patients were particularly likely to envision quality-of-life benefits arising from statin discontinuation.

“Hopefully this will help inform prescribers who might be tentative to address this topic with their patients,” Furuno said. “As a patient’s prognosis changes and we think they have a relatively short lifespan left, it really requires risk/benefit re-examination of everything we’re doing for them, medications and everything else. There may still be benefits, but have the benefits changed or has the risk/benefit ratio changed?

“A lot of our work is trying to better inform the evidence base for medication use at the end of life, and patient perceptions are really important in trying to honor what the patient wants and what the family wants.”

Furuno notes that the primary limitation of this study is that all of the questionnaire respondents had also agreed to participate in a trial that involved possibly being chosen at random to go off statins – thus, they were all at least somewhat open to the idea of deprescribing.

“So this group is likely not completely representative of all people, because they might be foreseeing some benefits to stopping that other people hadn’t considered,” he said. “But while we don’t want to overlook that limitation, given the lack of information about patient perceptions regarding deprescribing, these data are important and useful as a stepping stone.”

The Palliative Care Research Cooperative Group, funded by the National Institute of Nursing Research, supported this study. Collaborators included researchers from the University of Massachusetts, the University of Colorado, Case Western Reserve University, Duke University, the University of Maryland, the University of California-San Francisco, Mayo Clinic, and Flatiron Health, a health care technology company.

Findings were recently published in the Journal of Palliative Medicine.

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Blocking TB germs’ metabolic ‘escape pathways’ may be key to better, shorter treatment

CORVALLIS, Ore. – New research suggests the bacteria that cause tuberculosis alter their metabolism to combat exposure to antimicrobials, and that these metabolic “escape pathways” might be neutralized by new drugs to shorten the troublesome duration of therapy.

The findings are important because the respiratory disease kills nearly 2 million people a year worldwide, and its long treatment regimen leads to poor compliance and, in turn, drug-resistant germs.

Oregon State University scientist Luiz Bermudez estimated that decreasing the time of treatment from six months to three weeks would likely eliminate many of the compliance problems.

His research may be a key step toward that shorter therapy.

About one-third of the global population is infected with the bacteria that cause TB – Mycobacterium tuberculosis, or Mtb – though only a small percentage will develop the actual disease. For those who do, treatment is basically the same now as it was a half-century ago: taking a combination of drugs for six months because the germs do not die easily or quickly.

As Bermudez notes, anyone who’s ever had trouble sticking with a 10-day antibiotic regimen for an ear infection can understand the hurdles in taking multiple medicines for a couple of dozen weeks – especially given the numerous side effects of the TB drugs.

Another compliance issue is that tuberculosis is particularly prevalent in impoverished countries in which patients often live great distances from pharmacies and other medical facilities.

“Because of problems with compliance, you have resistance becoming more and more of an issue,” said Bermudez, a physician and a faculty member in OSU’s College of Veterinary Medicine. “And the second line of drugs is much more toxic than the first line of drugs.”

Bermudez and collaborators at the veterinary college, as well as researchers at Oregon State’s colleges of science and pharmacy and Oregon Health & Science University, took a biology-driven approach to learn how Mtb prolongs survival following exposure to bactericidal concentrations of antimicrobials.

Researchers investigated how the bacteria reacted to each class of anti-TB drug with the goal of making headway toward developing a more-reasoned combination therapy.

They studied the proteomic responses of the bacteria to five compounds – isoniazid, rifampicin, moxifloxacin, mefloquine and bedaquiline – and discovered escape pathways and enzymes associated with changes in metabolic state.

“When we looked at the enzymes carefully, we realized the enzymes being synthesized by the bacteria were enzymes connecting several different metabolic pathways,” Bermudez said. “Then we came up with the idea that maybe what the bacteria were trying to do, in the presence of a bactericidal compound that was threatening their way of living, was use other ways to survive. One of the things we saw, for example, was a shift to an anaerobic metabolism, which makes a lot of drugs inactive and incapable of killing bacteria. 

“The gene inactivation of some of these enzymes results in improved drug efficacy against Mtb,” he said. “The identified proteins may provide powerful targets for development of synergistic drugs aimed to accelerate bacterial killing.”

Bermudez said that using a combination of drugs to treat tuberculosis arose as an attempt to prevent antibiotic resistance.

“But the antibiotics used were never a rational combination of drugs and in some cases they could antagonize each other,” he said. “If we can use another compound that inhibits bacteria from shifting metabolic pathways, then we get a more reliable and desirable synergy of therapy. That might have a significant impact on reducing the time needed for therapy and improving compliance and, consequently, reducing the emergence of resistance.”

Findings were published recently in Antimicrobial Agents and Chemotherapy. The National Institutes of Health supported this research.

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By Steve Lundeberg, 541-737-4039

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Luiz Bermudez

Luiz Bermudez

New drug delivery system shows promise for fighting solid tumors

PORTLAND, Ore. – A new cancer-drug delivery system shows the ability to exploit the oxygen-poor areas of solid tumors that make the growths resistant to standard chemotherapy and radiation treatment.

Carcinomas that affect the breast, lung, prostate and colon are among the solid-tumor cancers, as are malignancies in the lymphatic system, known as lymphomas, and the much less common sarcomas that arise in connective tissue.

These solid masses often contain hypoxic regions, where the concentration of oxygen in the tissue is low. Hypoxic cancer cells grow slowly, and that makes them less susceptible to the drugs prescribed to kill or damage them.

Researchers at Oregon State University have found a way to turn the tables on those cells using a “prodrug” loaded into nanostructured platforms.

A prodrug is a pharmacologically inactive compound that the body metabolizes into an active drug, in this case the cancer drug vinblastine.

Provided with the prodrug vinblastine-N-oxide by research partners at Cascade Prodrug Inc. of Eugene, Ore., OSU scientists developed two different lipid-based platform formulations known as liposomes to carry the prodrug to the tumor’s hypoxic regions. There, the lack of oxygen triggers its metabolic conversion to vinblastine.

In both formulations – one with polyethylene glycol on its surface, one without – the prodrug proved both safe and much more effective against non-small cell lung cancer than when it was delivered without a liposome.

“One of the hallmarks of these solid tumors is their hypoxic regions,” said the study’s lead author, Adam Alani of the OSU College of Pharmacy. “One reason these cancers become very aggressive is the development of this hypoxia. Since the late 1990s, researchers have been trying to take advantage of the hypoxia. The tumor model we chose, lung cancer, is one of the very well established tumors and there’s a very strong hypoxia associated with that – as well as, lung cancer is one of these cancers that in its advanced stages, it’s a terminal disease, and there’s a need for new treatments.”

By itself, vinblastine-N-oxide had shown less than optimal efficacy in testing by Cascade Prodrug because of how fast the body clears it from the system – it has a half-life of less than half an hour.

“When it was tested in mice and dogs, it did not have a chance to assimilate in the cancer tissue to produce the desired pharmacological effect,” Alani said.

But the liposomes – both the “pegylated” one containing polyethylene glycol, and the non-pegylated one – increased the half-life dramatically: to 9.5 and 5.5 hours, respectively.

“The nano carriers performed much better than the prodrug itself,” Alani said. “We were able to literally cure the tumor.”

Alani’s research began with laboratory cultures and progressed to safety and efficacy testing in animals.

“We made sure the nanostructure platform worked properly against lung cancer in vitro, then looked at the safety of the formulation in healthy mice and looked at the maximum tolerated dose – the biggest dose you can use without producing side effects,” Alani said. “Then we determined how long the nano carriers could keep the drug in the blood compared to the drug without the nanostructures.”

When those data were “very encouraging,” Alani’s team assessed the efficacy of the formulations in mice that had tumors grafted into them.

Without any liposome, the drug showed some tumor suppression, but the mice that had received the drug alone had to be euthanized after 70 days because of tumors that were no longer being controlled.

Mice that had received the drug with one of the liposomes were healthy and tumor-free for the nearly 100-day run of the experiment.

“The formulations clearly performed better than the unformulated drug as well as much better than Cisplatin, the standard-of-care drug for this research,” Alani said. “Now we’re collaborating with Cascade Prodrug and the College of Veterinary Medicine to assess safety and efficacy in dog models, and trying to look at other tumors, like bladder cancer, associated with dogs.”

One goal, Alani said, is to develop a new treatment for cancer in dogs, and another is to look at dogs as a model for drug development – “to get data Cascade can use to move the process forward for approval for use in dogs, as well as preliminary data for a new drug application with the FDA,” Alani said.

The Oregon Nanoscience and Microtechnologies Institute supported this research. Findings were recently published in the Journal of Controlled Release.

Co-authors on the paper were Alani’s colleagues in the Department of Pharmaceutical Sciences, Vidhi Shah, Duc Nguyen and Adel Alfatease, and Shay Bracha of the OSU veterinary college’s Department of Clinical Sciences.

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Altered lipids, skin infections may point to new personalized therapy for atopic dermatitis

CORVALLIS, Ore. – Researchers have discovered a new way to identify the lipids, or fats found in the skin of people who have atopic dermatitis, and compare them to people with healthy skin.

This is a fundamental advance in dermatology that could lead to new therapies for millions of people with this debilitating skin problem - atopic dermatitis is one of the most common forms of eczema.

The findings were just announced in the British Journal of Dermatology.

The new technology should open the door to the formulation of personalized treatments, scientists say. Patents have been applied for, and researchers are working with university officials to begin the process of licensing and commercialization.

As another part of this advance, the scientists also discovered a clear link between atopic dermatitis, altered lipid profiles and some types of bacterial infections such as staphylococcus aureus, or a staph infection. This had never before been reported.

They believe these staph infections may both lead to atopic dermatitis problems and make people more prone to further infections – a cycle of skin inflammation that can disrupt the skin microbiome and be one component of this disease that has been so resistant to long-term treatment.

“These findings about altered lipid profiles and the link to bacterial infections could be a breakthrough to ultimately help many people who struggle with atopic dermatitis and related skin problems,” said Arup Indra, an associate professor in the College of Pharmacy at Oregon State University, an expert on inflammatory skin disease and lead author of the study.

“For the first time we will be able to identify the individual lipids that may be needed to help someone’s skin return to health,” Indra said. “This may be of value not only to patients with atopic dermatitis or other skin diseases, but even for normal individuals who simply want their skin to be more healthy, well hydrated and resistant to aging.”

Lipids, or fats, are a vital part of healthy skin, serving almost as a “blanket” to help protect its integrity. They can also act as a natural barrier to infection; are part of the innate immune system; and when properly balanced and healthy can help prevent skin cancer. Skin lipids include ceramides, free fatty acids, cholesterol and triglycerides.

When these lipids are not available in the right type or amount, skin inflammation can occur. In atopic dermatitis patients this can range from mild, intermittent rashes to severe, almost continual skin problems over significant portions of a person’s body. Some amount of atopic dermatitis is common in infants, but in some people it’s a lifelong issue.

Steroid drugs, either topical or systemic, have been one of the few ways to treat atopic dermatitis, but they have a wide range of side effects that make long-term treatment a concern. Moisturizing creams, lotions, special diets and other approaches have shown limited success.

With the new technology, however, researchers can identify a person’s individual skin lipid profile with some simple tests. A type of tape has been developed that can pull some lipids off a person’s skin; allow testing of them with the use of a mass spectrometer; and have the results compared to the skin lipid profiles of generally healthy patients.

With this information, researchers in the future should be able to determine quite specifically what lipids are deficient, and develop topical compounds to replace them – either individually, or with compounds that could aid groups of people who share similar lipid profiles.

Researchers say they hope to interrupt the cycle of skin inflammation and staph infections through the use of personalized lipid-replacing compounds, and create a new, promising approach to therapy.

“This has the potential to remove any guess work that might have existed in the past regarding the correct combination of lipids required to improve skin health,’ Indra said, “and will help restore to people’s skin the right quantity and type of lipids they need.”

This research has been supported by the Atopic Dermatitis Research Network, funded by the National Institutes of Health and the Oregon Nanoscience and Microtechnologies Institute.

Collaborators on the research are from the Oregon Health & Science University, OSU’s Linus Pauling Institute, the University of Rochester Medical Center, National Jewish Health, and Rho, Inc.

 

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Arup Indra, 541-737-5775

arup.indra@oregonstate.edu

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Atopic dermatitis
Atopic dermatitis

Research outlines how low-dose aspirin can help prevent cancer

PORTLAND, Ore. – Researchers have outlined for the first time a key mechanism by which low-dose aspirin may inhibit cancer cell proliferation and metastasis.

Aspirin reduces the ability of blood platelets to raise the levels of a particular protein that can support malignant cells and allow them to survive and spread, scientists say.

It has long been known that low-dose, or “baby” aspirin can have some benefits in protection against cardiovascular disease, and there’s increasing evidence it may be useful in cancer prevention as well – especially colon cancer. The new study reveals at least one of the ways the cancer inhibition may take place.

The research was published by scientists from Oregon Health & Science University and Oregon State University in AJP-Cell Physiology, with support from the National Institutes of Health, the American Heart Association and Altarum Institute.

Low-dose aspirin does not appear to directly affect cancer cells, the researchers said. Instead, it inhibits the normal function of blood platelets and reduces their ability to upregulate an “oncoprotein” called c-MYC, which plays an important role in cancer cell proliferation and survival.

“The benefit of aspirin may be due to its effect on blood cells called platelets, rather than acting directly on tumor cells,” said senior author Owen McCarty, a professor in the Department of Biomedical Engineering at Oregon Health & Science University.

“Our work suggests that the anti-cancer action of aspirin might be in part as follows: during their transit in the blood, circulating tumor cells interact with platelets, which spur tumor cell survival by activating oncoproteins such as c-MYC. The inhibition of platelets with aspirin therapy reduces this signaling between platelets and tumor cells, thus indirectly reducing tumor cell growth.”

C-MYC in its normal biological role orchestrates the expression of more than 15 percent of all genes, including those involved in cell cycles, survival, protein synthesis and cell metabolism. But it also appears to be overexpressed, the researchers said, in a large number of human cancers, including colon, pancreas, breast, lung and prostate cancers.

“Early cancer cells live in what’s actually a pretty hostile environment, where the immune system regularly attacks and attempts to eliminate them,” said Craig Williams, a professor in the OSU/OHSU College of Pharmacy, and co-author on the study. “Blood platelets can play a protective role for those early cancer cells and aid metastasis. Inhibition with aspirin appears to interfere with that process and c-MYC may explain part of that mechanism.”

Also of interest, the researchers said, is that this effect of aspirin on platelet function is as great at low doses as it is at the higher doses which are sometimes used to treat inflammation, headaches or pain. This is consistent with epidemiological studies which show that the anti-cancer benefit of aspirin occurs at these very low doses.

This is significant, because using low doses of aspirin allows clinicians to minimize the risk of bleeding, which is a serious concern with any antiplatelet medication.

Blood platelets in healthy biological systems play an important role in blood clotting after injuries, and also in the repair of the walls of blood vessels. Unfortunately, they have also been found to play a role in tumor survival, growth, proliferation and metastasis.

This study shows for the first time the ability of platelets to regulate the expression of the oncoprotein c-MYC in cancer cells. Elevated expression of c-MYC has been found in almost one-third of colon cancers and 42 percent of advanced pancreatic cancer, the researchers noted in the study.

Anyone considering use of low-dose aspirin should do so only in consultation with their physician, researchers said, in order to balance the potential benefits against known risks.

“Because the interaction between platelets and cancer cells is believed to occur early… the use of anti-platelet doses of aspirin might serve as a safe and efficacious preventive measure for patients at risk for cancer,” the researchers wrote in their conclusion.

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Craig Williams, 503-494-1598

williacr@ohsu.edu

Immune system uses gut bacteria to control glucose metabolism

CORVALLIS, Ore. – Researchers at Oregon State University and other institutions have discovered an important link between the immune system, gut bacteria and glucose metabolism – a “cross-talk” and interaction that can lead to type 2 diabetes and metabolic syndrome when not functioning correctly.

The findings, published today in Nature Communications, are one example of how different mammalian systems can affect each other in ways not previously understood.

A better understanding of these systems, researchers say, may lead to new probiotic approaches to diabetes and other diseases.

The research also shows the general importance of proper bacterial functions in the gut and the role of one bacteria in particular – Akkermansia muciniphila -  in helping to regulate glucose metabolism.

This bacteria’s function is so important, scientists say, that it has been conserved through millions of years of evolution to perform a similar function in both mice and humans.

“We’re discovering that in biology there are multiple connections and communications, what we call cross-talk, that are very important in ways we’re just beginning to understand,” said Dr. Natalia Shulzhenko, an assistant professor in the OSU College of Veterinary Medicine, and one of the corresponding authors on this study.

“It’s being made clear by a number of studies that our immune system, in particular, is closely linked to other metabolic functions in ways we never realized. This is still unconventional thinking, and it’s being described as a new field called immunometabolism. Through the process of evolution, mammals, including humans, have developed functional systems that communicate with each other, and microbes are an essential part of that process.”

It had been previously observed that an immune mediator - one type of interferon, or signaling protein called IFN-y – can affect the proper function of glucose metabolism. IFN-y helps fight several pathogens and infections, but a decrease in its levels can lead to improvement in glucose metabolism. However, this actual process has not been understood.

“Before this, no one had a clue exactly how IFN-y affected glucose tolerance,” said Andrey Morgun, an assistant professor in the OSU College of Pharmacy and also a corresponding author on the study. “The involvement of microbes had not really been considered. But with the help of a statistical model and an approach we call a transkingdom network, we were able to pinpoint some likely bacterial candidates.”

The bacteria A. muciniphila, was found to play a critical role in this communication process – in their study, the scientists called it a “missing link.” Research showed that mice specially bred with reduced levels of IFN-y had higher levels of A. muciniphila, and significantly improved glucose tolerance. When IFN-y levels increased, A. muciniphila levels declined, and glucose tolerance was reduced.

Similar observations were also made in humans. It’s been observed, for instance, that athletes who are extremely fit have high levels of the gut bacteria A. muciniphila, which is a mucus-degrading bacteria. The research makes clear that two systems once believed to be functionally separate – immunity and glucose metabolism – are, in fact, closely linked, and the bridge can be provided by gut bacteria.

There’s probably more than one bacteria involved in this process of communication and metabolic control, researchers said. The gut harbors literally thousands of microbes that appear to function almost as a metabolically active organ, emphasizing the critical importance of gut bacterial health.

Bacteria-mediated communication, of course, is just one part of complex human systems – issues such as proper diet, exercise, and appropriate weight control are all still important, the researchers said.

This research was supported by the National Institutes of Health. Other collaborating researchers were from the University of Sao Paulo in Brazil, University of North Carolina, National Institute of Allergy and Infectious Diseases, and Duke University Medical Center. Co-first authors were Renee Greer of the OSU College of Veterinary Medicine and Xiaoxi Dong of the OSU College of Pharmacy.

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Dr. Natalia Shulzhenko, 541-737-1051

natalia.shulzhenko@oregonstate.edu

Simple test may help address $150 billion problem of post-operative delirium

PORTLAND, Ore. – Researchers at VA Portland Health Care System (VAPORHCS), in collaboration with Oregon State University and Oregon Health & Science University, have identified a simple test that takes about 2-3 minutes and can predict which surgical candidates are most at risk of delirium, a common complication following surgery in older patients.

Delirium, or acute confusion and disorientation, has become a $150 billion national problem.

After surgery, delirium can lead to slower recovery, a long-term worsening of memory and thinking, and even death - while significantly increasing health care costs. Identification of those most at risk could help guide decisions about whether or not to have surgery, and allow prompt, low-cost interventions after surgery to help prevent this problem.

The findings were just published in the Journal of the American Geriatric Society by doctors from the Veterans Affairs Research Department in Portland, who led and funded the study, and worked with partnering investigators from OSU and OHSU.

“Before this study, identifying people at risk for delirium following surgery required complicated or time-consuming evaluations,” said Dr. Sarah Goodlin, the lead VAPORHCS investigator for the study.

“We try to avoid delirium whenever possible, but our tools have been limited. Now we believe we can identify people at high risk and help physicians make informed decisions with their patients about the hazards and benefits of pursuing elective surgery.”

Further research will be needed to confirm the findings and broaden them to other groups, Goodlin said. This research, for instance, was done with 76 veterans age 65 or older who were almost exclusively male.

Several tests have been available for some time to test memory and mental function. One test, a brief screening tool called the “Mini-Cog,” was developed by Dr. Soo Borson at the University of Washington to detect dementia.

The current research found that one way of using and scoring the Mini-Cog offered high predictive accuracy of delirium following elective surgery with major anesthesia. Other tests and patient factors did not really improve the predictive risk of delirium.

“We wanted to identify a tool that was simple and accurate, and the Mini-Cog does that,” said Amber An DO, who designed the study with Goodlin during her geriatric medicine fellowship.

The Mini-Cog may help to prevent this problem, said David Lee, an assistant professor in the OSU/OHSU College of Pharmacy, and co-author on the study.

“This is such a serious issue,” Lee said. “Delirium can cause serious health and cognitive problems, begin a process of decline that can lead to dementia, and can almost double the cost of a hospital stay.”

However, the researchers pointed out in their study that medical care is more effective at preventing delirium, especially in people at moderate risk, than in treating it once it develops. That makes a predictive tool all the more helpful. More research is needed to understand steps that can be taken during or following surgery to decrease post-operative delirium rates.

The Mini-Cog test itself is quick and simple, can be done in any language and has no ethnic, educational or cultural barriers. A person is told three ordinary words and asked to repeat them, such as “apple,” “watch” and “penny.” They are then asked to draw a simple clock face, including the numbers and hands set to a specific time. Finally, they are asked to repeat the three words they were told. That’s all there is to the test.

The authors of the current study scored the Mini-Cog from 0-5. A person gets 2 points for correctly drawing a clock and time; and 1 point each for recalling the three words.

According to this research, a person with a score of 0-1 had a 50 percent or greater probability of post-operative delirium. Those with a score of 3 had a 20 percent probability; a score of 4 a 13 percent probability; and a score of 5 less than 5 percent probability of delirium after surgery.

The incidence of delirium ranges from 7-10 percent in older adults after simple elective surgery, rising to at least half of older adults undergoing emergency, cardiac or orthopedic surgery. Individuals who develop delirium are more likely to be debilitated, require skilled nursing care, and die in the year after surgery.

Factors that have been significantly associated with delirium risk include existing dementia, depression, use of multiple medications, sensory impairment, and the use of alcohol or psychoactive drugs.

 

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Daniel Herrigstad, 503-402-2975

daniel.herrigstad@va.gov

System may help treat rare genetic disorder, reduce severe side effects

PORTLAND, Ore. – Researchers at Oregon State University and other institutions have discovered a type of drug delivery system that may offer new hope for patients with a rare, ultimately fatal genetic disorder – and make what might become a terrible choice a little easier.

No treatment currently exists for this disease, known as Niemann Pick Type C1 disease, or NPC1, that affects about one in every 120,000 children globally, and results in abnormal cholesterol accumulation, progressive neurodegeneration and eventual death.

However, a compound that shows promise is now undergoing clinical trials, but it has major drawbacks – the high doses necessary also cause significant hearing loss, requires direct brain injection and causes lung damage.

New findings, published today in Scientific Reports, outline the potential for a nanotech-based delivery system to carry the new drug into cells far more effectively, improve its efficacy by about five times, and allow use of much lower doses that may still help treat this condition without causing such severe hearing loss.

The same system, they say, may ultimately show similar benefits for 50 or more other genetic disorders, especially those that require “brain targeting” of treatments.

“Right now there’s nothing that can be done for patients with this disease, and the median survival time is 20 years,” said Gaurav Sahay, an assistant professor in the Oregon State University/Oregon Health & Science University College of Pharmacy, and corresponding author on the new study.

“The new cholesterol-scavenging drug proposed to treat this disorder, called cyclodextrin or HPβCD, may for the first time offer a real treatment. But it can cause significant hearing loss and requires multiple injections directly into the brain, which can be very traumatic. I’m very excited about the potential of our new drug delivery system to address these problems.”

In this approach, the HPβCD drug is attached to an extraordinarily small, nanotech-sized lipid particle that can carry it into cells, where it helps to flush out cholesterol. Researchers were surprised to discover, however, that the carrier itself also helped address the problem, while working in synergy with the drug it carries to greatly increase its effectiveness.

This should allow use of much lower dosages, Sahay said, and possibly an easier delivery through intravenous injection, instead of brain injection. In the form currently used, only 0.2 percent of the drug is able to cross the blood brain barrier.

In previous research with the HPβCD drug in animal models, the treatment did slow the progression of this disease, but did not reverse it. The disease focuses its damage on liver and brain cells.

In their report, researchers noted that this type of drug delivery system has several advantages, including prolonged circulation times, the ability to incorporate multiple drugs with different mechanisms of action, and a variety of “targeting ligands” that can help cross the blood brain barrier.

The researchers have also partnered with Dr. Edward Neuwelt at the OHSU Blood Brain Barrier Program, who has pioneered temporary opening of the blood brain barrier in humans to access drugs to the brain. They are also working leaders in the NPC disease field to translate these findings in-vivo.

“Taken together, nanocarriers can serve as a platform that can effectively deliver small molecules, genes and perhaps imaging agents for treatment and diagnosis of a wide variety of other rare lysosomal storage disorders,” the researchers wrote in their conclusion.

This research was supported by the OSU College of Pharmacy, OSU Venture Development Funds, AACP New Investigator Award, Birmingham Fellowship and Wellcome Trust Seed Award. Collaborating researchers were from the University of Birmingham, Oregon Health & Science University, and Newcastle University.

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Gaurav Sahay, 503-346-4698

sahay@ohsu.edu

Important advance made with new approach to “control” cancer, not eliminate it

PORTLAND, Ore. – Researchers have created a new drug delivery system that could improve the effectiveness of an emerging concept in cancer treatment – to dramatically slow and control tumors on a long-term, sustained basis, not necessarily aiming for their complete elimination.

The approach, called a “metronomic dosage regimen,” uses significantly lower doses of chemotherapeutic drugs but at more frequent time intervals. This would have multiple goals of killing cancer cells, creating a hostile biological environment for their growth, reducing toxicity from the drug regimen and avoiding the development of resistance to the cancer drugs being used.

A system just published in Chemistry of Materials by a group of researchers from Oregon and the United Kingdom offers an even more effective way to deliver such drugs and may be able to greatly improve this approach, scientists say. Further testing is needed in both animals and humans for safety and efficacy.

“This new system takes some existing cancer therapy drugs for ovarian cancer, delivers both of them at the same time and allows them to work synergistically,” said Adam Alani, an associate professor in the Oregon State University/Oregon Health & Science University College of Pharmacy, and lead author on the new study.

“Imagine if we could manage cancer on a long-term basis as a chronic condition, like we now do high blood pressure or diabetes. This could be a huge leap forward.”

This approach is still in trial stages, Alani said, but shows promise. In some prior work with related systems in animal tests, OSU and collaborating researchers have been able to completely eradicate tumors.

Total remission, Alani said, may be possible with metronomic dosage, but the initial goal is not only to kill cancer cells but to create an environment in which it’s very difficult for them to grow, largely by cutting off the large blood supply these types of cells often need.

Most conventional cancer chemotherapy is based on the use of “maximum tolerable doses” of a drug, in an attempt to completely eliminate cancer or tumors. In some cases such as ovarian cancer, however, drug-free intervals are needed to allow patient recovery from side effects, during which tumors can sometimes begin to grow again or develop resistance to the drugs being used.

The types of cancers this approach may best lend itself to are those that are quite complex and difficult to treat with conventional regimens based on “maximum tolerable dose.” This includes ovarian, sarcoma, breast, prostate, and lung cancers.

One example of the new metronomic regimen, in this instance, is use of two drugs already common in ovarian cancer treatment – paclitaxel and rapamycin – but at levels a tenth to a third of the maximum tolerable dose. One drug attacks cancer cells; the other inhibits cancer cell formation and the growth of blood vessels at tumor sites.

The new system developed in this research takes the process a step further. It attaches these drugs to polymer nanoparticles that migrate specifically into cancer cells and are designed to release the drugs at a particular level of acidity that is common to those cells. The low doses, careful targeting of the drugs and their ability to work in synergy at the same time appeared to greatly increase their effectiveness, while almost completely eliminating toxicity.
“Our goal is to significantly reduce tumors, slow or stop their regrowth, and allow a person’s body and immune system time to recover its health and natural abilities to fight cancer,” Alani said. “I’m very optimistic this is possible, and that it could provide an entirely new approach to cancer treatment.”

This research was supported by OSU, the Medical Research Foundation of Oregon, and the AACP New Pharmacy Faculty Research Award Program. It was done in collaboration with researchers from the Oregon Health & Science University, Pacific University, and Kingston University in the United Kingdom.

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Adam Alani, 503-346-4702

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