OREGON STATE UNIVERSITY

college of pharmacy

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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Cancer therapy

Lack of pharmacy access sends some patients back to the hospital

PORTLAND, Ore. – Hospital readmissions, a $17 billion annual problem, are higher in rural, remote or smaller communities that sometimes have significantly less access to pharmacies, according to a study published today that was one of the first to examine this issue.

Researchers at Oregon State University and Oregon Health & Science University found that the average number of readmissions from rural areas was 15.3 percent, compared to 14.7 percent for their urban counterparts where the days and hours a person could find an open pharmacy were much higher.

Unplanned hospital readmissions are such a serious national problem that recent changes in federal law are penalizing hospitals that have high readmission rates. It can be a problem with various groups: older adults; people who have several medical conditions; those taking multiple medications; and people who have difficulty adhering to their medication regimen.

The study was done in Oregon with census data of patients over 65, studying 507 pharmacies and 58 hospitals. It was supported by the OHSU Layton Alzheimer Disease Center, which is funded by the National Institutes of Health.

“It’s a huge burden both on a patient and our medical system when they have to be readmitted to a hospital,” said David Lee, an assistant professor in the OSU/OHSU College of Pharmacy, and senior author on a new study in the Journal of the American Pharmacists Association.

“The modern pharmaceutical profession is increasingly being recognized as an important partner in health care, and as its services continue to expand it will help even more. This research shows that pharmacy access can help people from going back to the hospital. For older populations who often find hospital experiences quite exhausting, that’s extremely important to their overall health.

“The sooner a person gets out and stays out of a hospital, the better off they usually will be.”

In some rural areas of Oregon, Lee noted, a person might have to drive 100 miles or more to find a pharmacy. In one of Oregon’s rural communities there is a single pharmacy that’s open 54 hours a week; by comparison, in some major urban areas a person might be able to find multiple pharmacies that collectively are open more than 3,800 hours a week.

These challenges of availability, distance and convenience to professional pharmaceutical products, service and counsel are a problem, researchers said. Another interesting corollary to the issue, they said, is identification of what have been called “pharmacy deserts” even within major urban areas, such as Chicago.

“Large, urban, predominantly white communities usually have a lot of pharmacies and access,” said Sarah Bissonnette, lead author on this study and an OSU postdoctoral fellow. “But in some lower socioeconomic areas even within cities, it’s much more difficult to find an open pharmacy.”

If more conventional pharmacies are not economically viable, the researchers said, a possible remedy to the problem is growth and improvement of what’s called “telepharmacy,” or mail-order services that are carefully backed up by personal advice, monitoring and counsel from professional pharmacists.

Improved hospital discharge medication counseling has been shown to increase adherence to use of new or changed medications, the study indicated. And some hospitals around the country have also taken it upon themselves to open community and 24-hour pharmacies in an attempt to reduce readmission rates.

Nonadherence to medication usage ranges from 25-50 percent in the United States, depending on the disease state, and is associated with increased illness and death, the study noted.  Causes can include adverse side effects, insurance coverage, costs, education levels, cognition and pharmacy access.

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David Lee, 503-494-2258

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Pharmacist consult

Xanthohumol in lab tests lowers cholesterol, blood sugar and weight gain

CORVALLIS, Ore. – A recent study at Oregon State University has identified specific intake levels of xanthohumol, a natural flavonoid found in hops, that significantly improved some of the underlying markers of metabolic syndrome in laboratory animals and also reduced weight gain.

The findings were published in a special issue of Archives of Biochemistry and Biophysics that was focused on “Polyphenols and Health,” and they suggest a possible new approach to issues such as human obesity, high cholesterol and elevated glucose.

Combinations of these problems, collectively known as metabolic syndrome, are linked to some of the major health issues and causes of death in the developed world today - especially cardiovascular disease and type-2 diabetes.

In this research, laboratory mice were fed a high-fat diet, and given varying levels of xanthohumol. Compared to animals given none of this supplement, the highest dosage of xanthohumol given to laboratory rats cut their LDL, or “bad” cholesterol 80 percent; their insulin level 42 percent; and their level of IL-6, a biomarker of inflammation, 78 percent.

Because they were still growing, eating a rich diet, gaining weight and becoming obese, the weight of the lab animals increased, but by 22 percent less in those receiving xanthohumol, even though all animals ate the same amount of food. Intake of xanthohumol appears to increase their oxygen consumption and metabolic rate, with implications for weight control.

“This is the first time we’ve seen one compound with the potential to address so many health problems,” said Cristobal Miranda, a research assistant professor with OSU’s Linus Pauling Institute and lead author on this study. “These were very dramatic improvements.”

More research will be required to show safety and efficacy in humans, the researchers said.

“Work is still needed to further demonstrate the safety of high doses of xanthohumol, but dosages 15-30 times higher than we used have already been given to animals with no apparent problems,” said Fred Stevens, a professor in the OSU College of Pharmacy, principal investigator with the Linus Pauling Institute, and corresponding author on the research.

“After further study, this might provide an effective treatment for metabolic syndrome at a very low cost.”

This study for the first time also identified one of the mechanisms of action of xanthohumol – it appears to decrease plasma levels of PCSK9, a protein that plays a role in cholesterol levels. Lowering levels of PCSK9 should increase the clearance of LDL cholesterol from the blood.

Metabolic syndrome is defined by clinical diagnosis of three or more of several conditions, including abdominal obesity, elevated lipids, high blood pressure, pro-inflammatory state, a pro-thrombotic state, and insulin resistance or impaired glucose tolerance. About 25-34 percent of the adults in the United States meet these criteria, putting them at significantly increased risk for cardiovascular disease and type-2 diabetes.

Direct health care costs arising from obesity or related disorders account for up to 10 percent of U.S. health care expenditures, the researchers noted in their study.

Xanthohumol has been the subject of considerable research for its potential health benefits, as have other flavonoids such as those found in tea, garlic, chocolate, apples and blueberries.

Xanthohumol is found naturally in hops and beer, but the highest level used in this research was 60 milligrams per kilogram of body weight per day. This corresponds to a human equivalent dose of 350 milligrams per day for a 70-kilogram person, which far exceeds any amount that could be obtained by ordinary dietary intake. A level that high would equate to a beer intake of 3,500 pints per day for a human adult.

However, that amount of xanthohumol could readily be obtained in a dietary supplement that could be taken once a day.

This work was supported by the Linus Pauling Institute; OSU College of Pharmacy; Hop Steiner, Inc.; the Buhler-Wang Research Fund; and the National Institutes of Health.

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Cristobal Miranda, 541-737-5512

cristobal.miranda@oregonstate.edu

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New policies, educational programs help - but don't solve - problems with opioid abuse

PORTLAND, Ore. – A recent study showed that medical provider training, new clinic policies and efforts to “taper” opioid use for pain treatment could significantly reduce the level of opioid medication that patients used – a limited but positive step for a nation enmeshed in opioid use, abuse and overdose deaths.

The findings were made by researchers from the Oregon Health & Science University and Oregon State University, and published in the journal Substance Abuse. They offer some of the first evidence to show that systematic efforts actually do help constrain opioid prescriptions, while raising both doctor and patient awareness of the dangers involved.

Such help, experts say, is desperately needed, given that prescriptions of opioid medications in the U.S. have risen about 600 percent in the past two decades, and the number of people dying from either prescription or illegal drug overdoses now exceeds those killed in motor vehicle accidents. In Washington state, deaths from opioid-related overdose increased by 17 times from 1995 to 2008.

This research was done with 514 patients who had been prescribed long-term, chronic opioid therapy. In one group of patients prescribed high-dose opioids, it showed that proactive steps and opioid dosing policies helped 37 percent of the patients to taper their doses to what’s considered a safer level, 120 milligrams per day of “morphine equivalent.” In many cases dosages were reduced by almost half – but the research also found that women had less success with the tapering approach.

“The approach used in this study showed progress, but not enough,” said Dr. Melissa Weimer, an assistant professor of medicine at Oregon Health & Science University. “We’d rather have a higher success rate. But in some cases we’re dealing with a generation of patients who have been prescribed high-dose opioids for many years.”

The problems, researchers said, began in the 1980s and 90s as one part of an effort to better manage pain, especially for chronic, non-cancer pain, from such health issues as neuropathy or lower back problems. At the time, some experts even advised that opioid medications were neither harmful nor addictive.

“This is now known to be an extremely serious problem,” Weimer said. “We have a prescription opioid abuse epidemic in the U.S.”

A primary goal of this research, which was some of the first of its type, was to find out if an aggressive program to educate doctors, patients, and promote safe tapering of opioid doses would work. The study was supported by the Society of General Internal Medicine.

The researchers found that tapering, backed by health system policies and educational programs, not only could reduce dosages, but that patients who took substantially lower doses did not report any higher levels of pain as a result. But the issue is not simple, the scientists said.

“Part of the problem with these issues is that the concern is not just opioids,” said Daniel Hartung, an associate professor in the Oregon State University/ Oregon Health & Science University College of Pharmacy, and co-author on this study.

“Many of the patients who are taking long-term medications for pain management often have other issues as well, such as anxiety, post-traumatic stress disorder or substance abuse,” Hartung said. “They may be taking medications for those conditions, and sometimes these combinations can be dangerous.”

A close collaboration and continued monitoring between doctors, pharmacists and patients would help to better address these concerns, Hartung said. Pharmacists who are often on the front line of patient drug use and management may need to play a stronger educational role and also be heavily involved in this issue, he said.

Among the other findings or observations made in the study:

  • Chronic non-cancer pain affects 20-50 percent of patients in primary care, and has been increasingly treated with opioid therapy despite little evidence to support its safety or efficacy.
  • Risk of opioid overdose and death increases when patients use more than 100 milligrams of morphine equivalents per day.
  • In this limited sample size, clinical outcomes of subjective pain and quality of life scores did not appear to be affected by the opioid dose limitation policy.
  • Female sex was the only significant predictor of less success with opioid tapering.
  • Patients with substance abuse disorders succeeded in tapering their opioid doses as well as other patients.
  • The length of time providers had been in practice was linked with greater prescribing of high-dose opioids.

While recognizing that the program helped, the researchers also noted that a year after policy adoption, only a minority of patients had successfully tapered their dosages below the policy threshold.

“Educational efforts and opioid dose-limitation policies may not be sufficient to decrease opioid misuse, addiction, or opioid-related mortality,” the researchers wrote in their conclusion, “but they appear to be one step in the right direction.”

 

 

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Daniel Hartung, 503-494-4720

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Nanotech drug delivery shows promise for improved melanoma treatment

PORTLAND, Ore. – Researchers have developed a new three-drug delivery system for cancer treatment, especially metastatic melanoma, the deadliest form of skin cancer - and shown that the system may have particular value with cancers like this that often spread through the lymphatic system.

The new technology takes advantage of nanoparticles that can migrate to, and increase the effectiveness of an attack on cancer cells in the body’s lymph nodes. This can also reduce the development of drug resistance and the broader toxicity often associated with this type of chemotherapy.

The findings were made with laboratory animals, and just published in the Journal of Controlled Release by researchers from the College of Pharmacy at Oregon State University. The work was supported by an  OSU startup fund, and a provisional patent has been granted for this technology.

“Melanoma can be a very difficult cancer to treat because it often metastasizes and travels through the lymphatic system,” said Adam Alani, an assistant professor in the Oregon State University/Oregon Health & Science University College of Pharmacy, and lead author on this research.

“Melanoma has a high mortality rate because the lymph nodes tend to act as a haven for cancer cells, and allow them to resist treatment through chemotherapy,” he said.

The new OSU research, however, was able to combine three anti-cancer drugs at the same time into a nanoparticle delivery system. After injection, these nanoparticles primarily migrated to lymph nodes, acted in a synergistic manner that was more powerful than any one drug could be separately, and were able to maximize their impact in those locations while minimizing the development of drug resistance and overall toxicity.

Laboratory mice treated with this approach all survived. The therapy caused no apparent negative effects, and at least one type of the nanoparticles migrated effectively to distant lymph nodes, where the drugs significantly reduced the number of melanoma cells.

More research with animals, experiments with more aggressive forms of cancer, and eventually human clinical trials will still be needed for any treatment is available for use.

This could become an important advance in the treatment of any type of cancer that tends to move through the lymphatic system, Alani said. This includes melanoma, but also breast, head and neck, prostate, pancreatic, lung and gastric cancers.

Up to 80 percent of melanomas metastasize through the lymphatic system, the researchers said in their report, and the tumor cells even secrete growth factors to further streamline their progress. The enlarged lymphatic vessels “act as a freeway for the metastatic cells to gain access and spread to distal lymph nodes and organs,” they wrote in the study.

The major drawback of existing therapies, they said, is the inability to deliver therapeutic concentrations of drugs to the lymphatic system without creating systemic toxicity. Use of drugs one at a time also tends to breed resistance to them.

The nanoparticles used to carry these cancer drugs are stable, increase the drug circulation time, and can deliver multiple drugs in a single step to the desired target, the research showed. They offer a novel therapeutic option for effective melanoma treatment, the scientists wrote in their conclusion.

Other collaborators on this research included Kingston University in London and Pacific University in Hillsboro, Ore.

 

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Adam Alani, 503-346-4702

Barriers to health care increase disease, death risk for rural elderly

CORVALLIS, Ore. – A new study of adults ages 85 or older has found that rural residents have significantly higher levels of chronic disease, take more medications, and die several years earlier than their urban counterparts.

The findings were just published in The Journal of Rural Health by researchers from Oregon State University and the Oregon Health & Science University.

The research confirms some of the special challenges facing older populations in rural or remote areas, who often have less access to physicians, long distances to travel for care, sometimes a lower socioeconomic and educational level, and other issues. It also reflects health problems that might have been reduced if they were treated earlier or more aggressively, researchers say.

Data from several different study groups found that rural residents measured significantly higher on the Modified Cumulative Illness Rating Scale, with about an 18 percent higher disease burden.

“It’s been known for some time that health care is harder to access in rural areas, and this helps us better understand the extent of the problem,” said Leah Goeres, a postdoctoral scholar who led the research at the Oregon State University/Oregon Health & Science University College of Pharmacy.

“Many physicians do the best they can in rural areas given the challenges they face,” Goeres said. “But there are fewer physicians, fewer specialists, a higher caseload. Doctors have less support staff and patients have less public transportation. A patient sometimes might need to wait months to see a doctor, and have to drive significant distances. Adverse effects can increase from taking multiple medications.

“These are real barriers to choice and access, and they affect the quality of care that’s available.”

Also worth noting, Goeres said, is that especially in very old populations, illness can lead to more illness and quickly spiral out of control. A patient in an urban setting might receive prompt treatment for a mild ulcer, whereas the same person in a rural setting might have to wait while the condition worsens and may even lead to cancer.

“It’s of particular concern that rural older adults start with more disease burden, which significantly increased over the next five years, but the average number of medications they used decreased over the same time period,” said David Lee, an assistant professor in the OSU College of Pharmacy who oversaw the research.

“This may be due to difficulty accessing health care, leading to more disease burden over time, yet less use of medications,” Lee said. “The opposite trends are seen in urban older adults.”

This research was done in Oregon with three cohorts of older adults, one rural and two urban, and 296 people altogether. It was supported by the Oregon Alzheimer’s Disease Tax Checkoff Fund and the National Institutes of Health.

The findings of the new study include:

  • The rural population of Oregon contains a greater proportion of older adults than the urban population.
  • The use of many medications can be especially risky for people in their 80s and 90s, leading to a concern called “polypharmacy” when a person takes five or more medications.
  • Rural participants were found to use an average of 5.5 medications, compared to 3.7 for urban participants.
  • At baseline measurements, valuable medications to aid bone mineralization were often used less in rural populations, but pain-killing opioids were used more often.
  • Medication use for high blood pressure went up significantly over time for rural populations, but not urban ones, in which their use had already been higher.  
  • The rate of disease accumulation was significant in the rural cohort, and negligible in their urban counterparts.
  • The median survival time of the rural cohort was 3.5 years, compared to 7.1 years for the urban older adults.
  • Risk factors of chronic diseases were low education, poor socioeconomic status, a history of chronic disease, being female, and older age. These factors are associated with a typical rural population.
  • Living with someone, and/or having a large social network are protective factors against chronic disease, and may be more common in an urban or suburban population.
  • Both urban and rural residents used a large number of over-the-counter agents, including vitamins, minerals and herbal supplements.

Increased access to health care, health education, increased supervision from clinicians, and better management of both prescription and over-the-counter medications could all be of value in helping rural residents to live longer and healthier livers, the researchers said in their conclusion.

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David Lee, 503-494-2258

Advent of recreational marijuana raises wealth of questions – and some answers

CORVALLIS, Ore. – The emergence of the legal recreational use of marijuana, in Oregon and elsewhere, has raised a wide range of questions about this drug – especially after decades of prolonged debates, some groups calling it harmless and others a “gateway” drug that should still be illegal.

At Oregon State University, pharmacological experts are helping to answer these questions. They are speaking to many public and professional groups around the state, as well as OSU pharmacy students, and trying to raise the level of medical knowledge about marijuana, based on the best available science.

That’s a challenge in itself, they say, because despite vehement arguments on both sides of these issues over many years, comparatively little valid scientific research has been done on marijuana. Some key questions remain unanswered, even though there’s evidence the drug has been used by humans for more than 4,000 years, and its use in the U.S. is now expanding significantly as legal restrictions weaken.

That being said, there’s a lot that is known.

First and foremost, today’s commercially available marijuana is not the same product that some may remember from the 1960s or 70s. It is far more potent.

“Marijuana today has a much higher content of THC, its psychoactive component, than it did in the past,” said Jane Ishmael, an associate professor of pharmacology in the OSU College of Pharmacy and a member of the Oregon Public Health Division’s Retail Marijuana Scientific Advisory Committee. Ishmael is an expert on drug action who teaches pharmacy students about drugs of abuse, ranging from alcohol to nicotine or even some over-the-counter and prescription products.

“The average THC content in marijuana decades ago used to be about 4 percent, but with years of improved cultivation techniques and plant improvements it’s now around 17 percent,” she said. “It’s even higher in some specific strains, meaning that today’s marijuana products can be at least four times stronger. For any older people who are considering use of marijuana again now that’s it’s legal, that’s something they should be aware of.”

An important research finding that’s more recent, Ishmael said, is how this age-old drug actually works.

Studies reported in the 1990s showed that the human body contains many receptor targets for THC and also produces “endocannabinoids.” Normally, the endocannabinoid system plays a role in regulation of appetite, pain control, pleasure and other sensations.

It was discovered that chemicals in marijuana, such as THC, bind to cannabinoid receptors in the brain and modulate the release of other neurotransmitters. These actions explain many of the biological impacts of marijuana for sensations of pleasure, its medicinal potential, and other aspects of neurobiology.

“One thing that people must understand is that marijuana is a recreational drug,” Ishmael said. “We’ve now chosen to make it legal, but like other drugs such as alcohol, that’s not synonymous with saying it’s completely safe and harmless. If people choose to use it, they should understand how it works, what it does, and when or with whom it should not be used.”

Among key points to consider, the experts said:

  • Marijuana use is inappropriate for women who are, or may become pregnant or are nursing. THC can pass directly to the baby during pregnancy and breastfeeding, and may affect the baby. There is no known safe amount of marijuana use during pregnancy.
  • For similar reasons, the laws restricting retail marijuana use to those over 21 years of age are important.
  • Marijuana, as many users will attest, causes feelings of relaxation, pleasure, or a stimulated appetite.
  • Marijuana can cause immediate difficulties in thinking and concentrating, dry mouth, blurred vision, increased heart rate and blood pressure, and feelings of anxiety or panic.  
  • Marijuana can impair coordination, slow reaction times, change perceptions of time, danger, and lowers the perception of risk. These issues, along with changes in the ability to think and concentrate, are the clear reasons why it should never be used when driving, riding a bike or operating dangerous equipment.
  • For similar reasons, a person should not ride in a vehicle, or let others ride, if it’s known the driver is under the influence of marijuana. 
  • The effects of marijuana, and the time it takes to clear the body, vary with the individual and mode of use. It has an effect much more quickly if inhaled or vaporized, and most impacts usually wear off after three to four hours when used this way.
  • If marijuana is eaten, as it is sometimes combined with foods to produce what are known as edibles, the effects will typically take longer to start and can last longer, up to 10 hours after eating.
  • Any use of marijuana in a food or candy is a common-sense parental concern in a household where children may be present. Marijuana can make children sick and should always be kept out of sight and reach of children.
  • Although THC is not believed to be a carcinogen, marijuana smoke contains the same cancer-causing chemicals as tobacco smoke, yet the health risks from second-hand exposure to marijuana smoke have been much less studied. Heavy smokers of marijuana can experience chronic bronchitis, including a chronic cough, sputum production and wheezing.
  • Considerable caution should be taken when marijuana is used in conjunction with other prescription medications that act on the central nervous system, such as drugs that have a sedative effect, or with medicines that are prescribed to treat mental illness.
  • Even though the psychoactive effects of marijuana may wear off in a few hours, metabolites from its use can still be detected in the blood or urine for up to three weeks – an issue as it relates to employers that forbid its use, or the complex legal issues of driving under the influence of marijuana.

Some reliable information is now emerging about the medicinal use of marijuana to improve symptoms in a variety of chronic conditions, the researchers said.

There is evidence that marijuana can aid with some types of pain control, such as painful muscle spasms associated with multiple sclerosis and neuropathic pain. It can also help relieve nausea and vomiting associated with chemotherapy, although other drugs are now available with similar effectiveness for that purpose. And it has been shown to improve quality of life in patients struggling with loss of appetite and maintaining body weight, including AIDS patients.

“Frankly, there’s still a lot we don’t know,” Ishmael said. “Marijuana contains more than 400 chemicals and we’ve focused most research just on one of them. Hopefully some future research will help better inform us about the complete range of effects, whether positive or negative.”

Roberto Linares, a senior instructor in the OSU College of Pharmacy who is also on the Oregon Board of Pharmacy, said that the legalization of marijuana will pose many challenges for medical experts in the near future.

“Pharmacies have not yet shown interest in distributing it, in part because that could conflict with the federal laws that apply to their operation,” Linares said. “But people will be coming to their doctors, to their pharmacists and other health professionals, with a lot of reasonable questions if they choose to use legalized marijuana. That’s one reason we’re trying to put out as much valid information as we can.”

Another issue almost completely unexplored, the researchers said, is the interaction of marijuana with many other legal medications. Entire books and computer programs exist with most drugs to help pharmacists analyze precisely how they might interact with another drug. With marijuana, that’s mostly a blank page.

“One other thought that people should consider is that everyone is an individual,” Ishmael said. “People’s reactions to drugs vary widely, it’s not easily predictable. With some, the effects of marijuana use will be much more intense than with others. That should be kept in mind by anyone who is considering its use.”

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Jane Ishmael, 541-737-5783

Single-agent phototherapy system offers significant new tool to fight cancer

ORLANDO, Fla. - Researchers at Oregon State University today announced an important advance in the field of cancer imaging and phototherapy, using a single-agent system that may ultimately change the efficacy of cancer surgery and treatment around the world.

The newest approach developed at OSU uses a single chemical compound, silicon naphthalocyanine, which has both diagnostic and therapeutic value. It makes cancer cells glow when exposed to near-infrared light, so a surgeon can identify the cancer and more effectively remove it. At the same time, this compound creates heat and reactive oxygen species within any remaining cancer cells, killing them.

In tests completed with laboratory animals, tumors were completely eradicated without side effects, and did not return.

The findings were presented today at the annual meeting of the American Association of Pharmaceutical Scientists in Orlando, Florida, and were also recently published in Chemistry of Materials, a publication of the American Chemical Society.

When perfected, researchers believe that the evolving field of phototherapy may become a new and promising addition to the three primary ways that most cancer is treated today: surgery, radiation and/or chemotherapy.

Phototherapy has the potential to make some of those approaches more effective than they already are. Since this is a different form of therapy, however, it may have special value with cancers that have formed resistance to chemotherapeutic drugs, or present other problems that can’t be managed with existing therapies.

"We've now developed an improved formulation that’s biodegradable, simple, robust and reproducible," said Olena Taratula, a research assistant professor in the Oregon State University/Oregon Health and Science University College of Pharmacy, and lead author on the published study.

"This system that can make cancer cells glow is like giving the surgeon an extra pair of eyes," she said. “And the compound we're working with now is inexpensive and appears effective at killing any cancer cells that remain."

Research so far has studied ovarian cancers in laboratory animals, but the researchers said that conceptually the treatment may also be useful for other solid tumors. There were no apparent side effects on animals tested.

The system that helps deliver the silicon naphthalocyanine to cancer cells is an alternative to a dendrimer-based delivery system reported earlier this year, and uses a copolymer called PEG-PCL as the biodegradable carrier. The carrier causes the silicon naphthalocyanine to accumulate selectively in cancer cells and reach a maximum level in them after about one day, at which point surgery and phototherapy treatment would be done. The compounds are then naturally and completely excreted from the body.

"A single-agent based system is simple and very good at targeting only cancer tumors and should significantly improve outcomes,” said Oleh Taratula, an assistant professor in the Oregon State University/Oregon Health & Science University College of Pharmacy, who presented this work today at the American Association of Pharmaceutical Scientists. “It’s small, nontoxic and highly efficient."

In continued research with the OSU College of Veterinary Medicine, the treatment will be used on dogs with actual cancerous tumors, before eventually moving on to human clinical trials.

"Our strategy provides cancer imaging with a single-agent theranostic nanoplatform and subsequent phototherapeutic treatment with great potential for clinical translation," the researchers wrote in their conclusion.

Collaborators on the research include Oleh Taratula and Adam Alani, the corresponding authors and assistant professors in the OSU College of Pharmacy; and Shay Bracha, a veterinary oncologist, and Milan Milovancev, a veterinary surgeon from the OSU College of Veterinary Medicine. The work has been supported by the OSU College of Pharmacy, the OSU Venture Development Fund, OSU General Research Fund and the Medical Research Foundation of the Oregon Health and Science University.

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Oleh Taratula, 503-346-4704

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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


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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