OREGON STATE UNIVERSITY

college of pharmacy

Communication among health care facilities key to preventing spread of drug-resistant bacteria

PORTLAND, Ore. – Communication breakdowns between care facilities can pave the way for outbreaks of infection, according to research on the spread of an extensively drug-resistant bacterium.

The OSU/OHSU College of Pharmacy teamed with the Oregon Health Authority and other collaborators on a two-year study of Acinetobacter baumannii, an opportunistic pathogen associated primarily with infections among patients who have compromised immune systems and are in health care facilities.

Looking at multiple sites in the Pacific Northwest, the scientists identified 21 cases, including 16 isolates of A. baumannii that contained a rare gene responsible for resistance to the carbapenem class of antibiotics.

The patients’ transfer history among the studied facilities and the isolates’ genetic profiles illustrated how the organism spread from place to place, aided by a lack of interfacility communication that patients who were infected or colonized by A. baummanii were being transferred.

Jon Furuno, co-author on the study and an associate professor in the College of Pharmacy, noted that the findings support a recent Oregon law requiring written notification from the discharging facility to the receiving facility anytime a patient carrying a multridrug-resistant organism, or other infection requiring transmission precautions, is transferred.

Extensively drug-resistant A. baumannii can contain many antibiotic resistance genes that can be transmitted to other organisms, he added.

“It just makes sense that you would want to alert a receiving facility if patients have a specific drug-resistant organism,” Furuno said. “The discharging facility needs to include that information with the discharge summary or somewhere on the chart, and the receiving facility needs to know where to look for it.”

The lead author is Genevieve Buser, a pediatric infectious disease specialist who worked as a Centers for Disease Control and Prevention Epidemic Intelligence Service officer based at the Oregon Health Authority when the study was done. Buser said communication can ensure appropriate contact precautions are taken.

“An entire chain of transmission can be prevented if staff at a receiving facility know about a patient’s multidrug-resistant organism status,” Buser said. “This outbreak might not have been identified if not for a new, limited, voluntary surveillance system in Oregon and an astute infection preventionist.”

Reporting of extensively drug-resistant A. baumannii infection is not required by most public health jurisdictions in the United States, and clinical laboratories generally do not test for an organism’s underlying genetic resistance mechanisms.

Other organizations collaborating on this research included the VA Portland Health Care System; the Division of Infectious Diseases at Oregon Health & Science University; the Oregon State Public Health Laboratory; the Louis Stokes Cleveland VA Medical Center; and Case Western Reserve University.

The CDC and the National Institutes of Health supported the study. Findings were recently published in Infection Control & Hospital Epidemiology.

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Steve Lundeberg, 541-737-4039

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Expensive drug driving up Medicare expenditures without evidence of greater efficacy

PORTLAND, Ore. – Medicare spent more than $1 billion over a five-year period on a high-priced drug that has not been proven more effective for a collection of inflammatory conditions than much less expensive corticosteroids, research by the OSU/OHSU College of Pharmacy shows.

The analysis also indicates that a comparatively small group of “frequent prescribers” combine to write prescriptions that lead to the bulk of Medicare’s expenditures on the drug, repository adrenocorticotropin, or ACTH.

In 2015 alone, Medicare spending topped $500 million on the drug, the cost of which has soared to $36,000 per course of therapy. 

Known by the trade name H.P. Acthar Gel, often shortened to just Acthar, the drug’s primary use is to treat rare epileptic spasms in children under age 2.

“The drug has an interesting back story,” said Dan Hartung, lead author on a research letter that was published today in JAMA Internal Medicine. “It’s a fairly old drug, first approved in 1952, prior to many of the FDA rules about clinical efficacy. The bar for what constitutes approved indications was much different then, much lower; it has many indications that came before the current rules were set in stone in the 1960s.”

The drug, classified as a “biologic,” was initially approved for a broad range of corticosteroid-responsive inflammatory conditions.

“It’s a hormone produced in the human body that signals the release of steroids,” Hartung said. “It does the same job as low-cost corticosteroids. And it really wasn’t much on anyone’s radar until 2007.”

Questcor Pharmaceuticals purchased the rights to the largely forgotten Acthar in 2001 for $100,000 and began steadily raising Acthar’s price. In 2007 Questcor increased the price of the drug, which once sold for $40 for a vial, or course of therapy, from $1,650 to $23,000 overnight.

Questcor, acquired by Mallinckrodt Pharmaceuticals in 2017, markets the drug aggressively for relatively common conditions such as rheumatoid arthritis, multiple sclerosis and nephrotic syndrome, Hartung said. The Food and Drug Administration approved Acthar for those types of conditions decades ago when requirements were less strict; no clinical trials were required.

“There are a variety of FDA-approved indications that lack a lot of evidence that Acthar is even effective, let alone better than inexpensive corticosteroids,” Hartung said. “And what allows for this kind of pricing is that it’s a fairly complex molecule and no competitors can exactly duplicate it; they have a monopoly on this particular molecule.”

In 2015, Acthar generated gross revenue of about $1 billion – more than half of which came from Medicare, and much of the rest coming from Medicaid, Hartung said, meaning public expenditures likely accounted for almost all of the sales.

Hartung and the other collaborators found Medicare spending on the drug increased tenfold and totaled $1.3 billion from 2011 to 2015.

In 2014, a total of 1,621 prescribers were responsible for $391.2 million in Acthar spending; among those, 203 frequent prescribers – 94 rheumatologists, 55 neurologists and 54 nephrologists, each with more than 10 prescriptions – accounted for $165 million of the total.

“And in general these physicians are prescribing about the same number of other drugs compared to their peer specialty groups, so we suspect they are not treating more severely ill patients,” Hartung said. “Mallinckrodt is really aggressively marketing in ways that possibly subject prescribers to conflicts of interest. From the payer side, there’s really little that little justifies this drug and its exorbitant cost over much cheaper alternatives. If Medicare were to take a firm stand on reimbursements, this wouldn’t be happening.”

Joining Hartrung on the study were Kirbee Johnston, Shelby Van Leuven, Atul Deodhar, David Cohen and Dennis Bourdette.

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Steve Lundeberg, 541-737-4039

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Dan Hartung, 503-494-4720

Conference at OSU explores intravenous vitamin C as treatment for cancer, sepsis

CORVALLIS, Ore. – The Linus Pauling Institute will host its biennial “Diet and Optimum Health” conference Sept. 13-16 at Oregon State University, attracting an international audience of experts in nutrition, preventive medicine and oncology.

The conference will also honor recently retired Linus Pauling Institute director Balz Frei and welcome new director Richard van Breemen.

The ninth edition of the event takes place 100 years after Linus Pauling began his OSU studies as an undergraduate. It also coincides with the ramp-up of the university’s 150th anniversary celebration and the 20th anniversary of the Linus Pauling Institute’s move to Oregon State from Palo Alto, Calif.

The conference will include a day-long symposium on vitamin C with a focus on the micronutrient’s capabilities in treating cancer and sepsis, as well as sessions on dietary components and the microbiome; lipid metabolism; vitamin E; bioactives; and diet, neuropathy and dementia.

“Linus Pauling wanted to cure the common cold with vitamin C, and there’s some indication that by taking vitamin C you can shorten the duration of a cold – this is a natural progression of that idea to preventing bacteria from killing you,” said conference chair Maret Traber, principal investigator and Ava Helen Pauling Professor at the Linus Pauling Institute. “We really are changing people’s lives.”

In addition to the professional conference, the Linus Pauling Institute will host a free public session from 9 to 11 a.m. Saturday, Sept. 16, at the CH2M Hill Alumni Center on the OSU campus. It will feature Emily Ho of the Linus Pauling Institute, who will talk about diet and cancer prevention, and Jeanne Drisko of the University of Kansas Medical Center, who will discuss treating cancer with intravenous vitamin C.

“Linus Pauling and his colleagues tried to show people in the 1970s that intravenous vitamin C was beneficial in treating cancer, and they forced the National Institutes of Health to do several clinical trials,” said Drisko, director of KU Integrative Medicine and the Riordan Endowed Professor of Orthomolecular Medicine.

“The Mayo Clinic ran the trials and said vitamin C showed no benefit in double-blind, placebo-controlled testing. It wasn’t until years later that it was found out that Linus Pauling and his colleagues had been giving it intravenously and the Mayo Clinic used only oral vitamin C, and that’s a huge difference. When it’s given in a vein, it makes hydrogen peroxide around the cancer cells, and the hydrogen peroxide kills them.”

Anitra Carr of New Zealand’s University of Otago, chair of the professional sessions on the mechanisms of vitamin C in cancer, said “vitamin C administration appears to have a clear impact on patient quality of life, particularly in those receiving chemotherapy.”

It’s not yet clear, though, which types of cancer respond best to intravenous vitamin C.

“There is also considerable debate around the potential anti-cancer mechanisms by which vitamin C works,” she said. “Future preclinical and clinical studies will help to elucidate these questions through clarifying the mechanisms by which vitamin C works and also if these vary depending on the type of cancer. This will facilitate personalized medicine, whereby the right treatment can be targeted to the right patient.”

Carr is also one of the presenters during the session on intravenous vitamin C therapy for sepsis, as is Berry Fowler of Virginia Commonwealth University.

“Over the past 30 years, over $2 billion has been spent by the National Institutes of Health and the pharmaceutical industry on over 15,000 patients with sepsis. No treatment has proven effective that doesn’t have side effects,” said Fowler, professor of medicine in the Pulmonary Disease and Critical Care Medicine Division and director of the VCU Johnson Center for Critical Care and Pulmonary Research.

“Trials have been predominantly performed with proteins like antibodies and inflammatory protein inhibitors. These protein treatments don’t get transported into the cell where they are needed. Vitamin C is a micronutrient – it’s effectively transported into every cell in the body.”

When vitamin C is infused intravenously, Fowler said, it’s actively moved from the bloodstream into the cells where the injury and damage are happening.

“When it’s there it acts as an antioxidant and, importantly, it decreases the inflammatory process that leads to injury,” he said. “This micronutrient theory may be the secret as to how vitamin C works so effectively. There’s finally a therapy that can be transported into places where it needs to be to be effective as opposed to remaining free in the plasma. That’s what differentiates vitamin C – it’s effectiveness is because the body moves it across tissue planes.”

Carr said critically ill patients with sepsis and septic shock have very low levels of vitamin C and that several recent clinical studies have shown that administration of vitamin C to these patients can significantly decrease organ failure and also decrease death rates by up to 80 percent.

“Sepsis and septic shock are the leading causes of death in critically ill patients and the incidence of severe sepsis continues to rise around the world,” she said. “If these results can be reproduced in other studies, this will be the biggest breakthrough in care for these patients since antibiotics.”

Media Contact: 

Steve Lundeberg, 541-737-4039

Richard van Breemen named director of Linus Pauling Institute at Oregon State University

CORVALLIS, Ore. – Oregon State University has named Richard van Breemen as the director of the university’s Linus Pauling Institute.

Van Breemen, professor of pharmacy at the University of Illinois at Chicago, will succeed Balz Frei as director and endowed chair of the institute, which studies the role of vitamins and other micronutrients in enhancing health and preventing disease.

Van Breemen characterized his new role as director of the Linus Pauling Institute as a “dream job.”

“Richard brings the prestige and accomplishments we were looking for in a new director,” said Cynthia Sagers, vice president for research at OSU. “He runs a National Institutes of Health-funded center for botanical dietary supplement research and is someone who makes things happen. He is very collaborative and people here already know his work. Richard feels a real passion for the work we do here at OSU and at the Linus Pauling Institute in particular.”

Van Breemen has a Ph.D. in pharmacology from Johns Hopkins University and was a post-doctoral scholar at Johns Hopkins in mass spectrometry. His undergraduate degree in chemistry is from Oberlin College.

His research includes clinical trials regarding prostate cancer prevention, and the safety and efficacy of botanical dietary supplements used by women.

At the University of Illinois at Chicago, where he has worked since 1994, van Breemen is the founding academic director of the Mass Spectrometry, Metabolomics and Proteomics Facility for the university’s Research Resources Center. He is also the director of the Botanical Center for Dietary Supplements Research, which has NIH funding through 2020 and has been continually funded since 1999.

From 1986 to 1993, van Breemen was a faculty member at North Carolina State, where he founded and directed the Mass Spectrometry Laboratory for Biotechnology Research.

Linus Pauling, who died in 1994 at age 93, was an Oregon State alumnus and is the only person to win two unshared Nobel Prizes – for chemistry in 1954 and for peace in 1962. A chemistry professor at California Institute of Technology, he founded what would become the Linus Pauling Institute in 1973.

Pauling bequeathed his vast scientific archives to OSU, and in 1996 the institute moved from Palo Alto, Calif., to Oregon State. The following year, Frei became director and endowed chair, a position he held until his retirement in June 2016.

Van Breemen met Pauling shortly before his death when the Nobel laureate spoke at a symposium at North Carolina State.

“Of course I had followed his work with dietary supplements for years, and I also got to know Balz upon visits to Oregon State,” van Breemen said. “I have visited several times and gotten to know the investigators and other faculty and have always known it to be a wonderful place to live and work. OSU and the Linus Pauling Institute offer a wealth of infrastructure and support that is unparalleled. The institute can help the work I have been doing be even more productive and make a bigger imprint and footprint on society.”

Van Breemen will start Jan. 1, 2018. Fred Stevens, professor of medicinal chemistry in the Oregon State College of Pharmacy, will continue as the interim director until then.

Van Breemen’s appointment at OSU will also be in the College of Pharmacy. 

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Steve Lundeberg, 541-737-4039

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Oregon State University agricultural sciences, pharmacy deans transition

CORVALLIS, Ore. – Oregon State University Provost and Executive Vice President Ed Feser announced today that Dan Arp, dean of the College of Agricultural Sciences, and Mark Zabriskie, dean of the College of Pharmacy, will step down from these university leadership roles effective June 30, 2018.

Arp, who has been dean since May 2012 and also serves as director of the Oregon Agricultural Experiment Station, will retire. Zabriskie, dean since September 2010, will return to his faculty position.

“Both Dan and Mark have had many outstanding accomplishments in these important leadership roles—not just at OSU but in the agriculture and healthcare industries respectively,” Feser said. “Their contributions to the university and the state of Oregon are significant, and they personify OSU’s commitment to excellence and service to the state.”

Arp joined OSU’s colleges of agricultural sciences and science in 1990 in a joint botany and plant pathology position that was split between the two units. He eventually headed the Department of Botany and Plant Pathology where he earned the honor of “distinguished professor.” In 2008, Arp was named dean of the University Honors College, where he worked closely with students to enhance their learning experience. Four years later, he was appointed as the Reub Long Dean of Agricultural Sciences and director of the Oregon Agricultural Experiment Station at OSU.

While serving as dean, Arp oversaw record-high student enrollment and the addition of 25 new faculty members in 2015 as the result of increased funding from the state Legislature for statewide public services. He also was instrumental in obtaining more than $40 million in private gifts and industry support for the college. A strong collaborator, Arp developed and enhanced key partnerships with agricultural commodity groups, companies, government agencies and non-governmental organizations. In 2014, he served as a co-chair of the Governor’s Task Force on Genetically Engineered Seeds and Agricultural Products.

“I have tremendously enjoyed my five years of service as dean of the College of Agricultural Sciences, and I look forward to doing all I can during my sixth and final year as dean,” Arp said. ”I am extremely proud of the progress the college has made over the past several years and our recognition as one of the world’s top agriculture programs.”

Oregon State has been recognized as a world-class center in agriculture and forestry, ranking 13th this year in an international survey. The listing appeared in the QS World University Rankings of approximately 200 top institutions for agriculture and forestry worldwide.

Zabriskie joined the faculty of the Department of Pharmaceutical Sciences at OSU in 1992. He directed the college’s infectious disease drug discovery program from 2005 to 2010 before being appointed dean. During his tenure as dean, Zabriskie oversaw a strong period of growth and expansion for the college and helped further extensive partnerships, including key collaborations with Oregon Health & Science University. He led initiatives to strengthen OSU’s presence in Portland and further the College of Pharmacy’s collaboration with OHSU. He represented OSU on the construction and management of the Collaborative Life Sciences Building that opened in 2014 on OHSU’s South Waterfront campus in Portland. This facility is a partnership among OHSU, OSU and Portland State University. Zabriskie also oversaw OSU’s role in the new partnership with the OHSU Knight Cancer Institute focused on cancer prevention and control.

In the past seven years, the college experienced a 35 percent increase in faculty and staff; a 40 percent increase in external grant support and research expenditures; and doubled the number of graduate research and teaching assistantships. Over the same period, scholarship support for OSU PharmD students (those pursuing professional doctorates to practice pharmacy) increased by 30 percent.

“The opportunity seven years ago to serve at the helm of the college turned into one of the most rewarding times of my career,” Zabriskie said. “Nothing has made the job more fulfilling to me than the support of the outstanding faculty and staff I had the good fortune to serve, and I’m extremely proud of the accomplishments we’ve made together.”

Zabriskie has maintained an active research program while serving as dean and will return to the faculty as a professor of pharmaceutical sciences next July. His research involves the discovery, biosynthesis and development of natural product antimicrobial agents.

Feser will launch national searches for both dean positions immediately.  

Media Contact: 

Annie Athon Heck, 541-737-0790

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Dan Arp, 541-737-2331
Dan.J.Arp@oregonstate.edu;
Mark Zabriskie, 541-737-5781
mark.zabriskie@oregonstate.edu

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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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Steve Lundeberg, 541-737-4039

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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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Steve Lundeberg, 541-737-4039

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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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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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Steve Lundeberg, 541-737-4039

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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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