OREGON STATE UNIVERSITY

college of pharmacy

Strategies identified to improve oral contraceptive success with obese women

PORTLAND, Ore. – The findings of a new study suggest two ways to effectively address the problem that birth control pills may not work as well in obese women, compared to women of a normal body mass index.

Birth control pills are a one-size-fits-all method, researchers say, but as the population has increased in weight, concern has grown about how well the pill works for obese women. Studies have consistently found that obesity has a negative impact on drug levels in the body, which may in turn affect how well the pill prevents pregnancy. 

“Birth control pills have been shown in a large population study to fail at a higher rate in women who are obese,” said Ganesh Cherala, an assistant professor in the Oregon State University/Oregon Health & Science University College of Pharmacy.

“Our original studies were focused on why this might occur,” Cherala said, “and we found that obesity changes how a woman’s body clears contraceptive hormones.”

It takes longer for the pill to reach a steady state level in obese women, with possible impacts on efficacy of the birth control, and putting them at greater risk for a pill failure if they forget to take a pill or take it later.

In order to offset these changes, Cherala and Dr. Alison Edelman, an associate professor of obstetrics and gynecology at Oregon Health & Science University, studied two alternative strategies. They found that either a slight increase in the pill dose, from a very low dose to a low dose pill; or using the pill continuously without a “period week” off, appeared to counteract the changes that obesity causes.

This, in turn, may provide improved pregnancy prevention for women of differing weights who use the pill, the researchers said. Their work is published in Contraception, a professional journal, and was supported by the National Institutes of Health.

“Since oral contraception remains one of the most popular forms of birth control in the United States and the majority of our population is obese or overweight, it’s important to find methods of contraception that work for all women, no matter what their weight,” Edelman said.

“The strategies that we studied can be, and are currently being used by women, but now we know that they help to counteract the adverse effects of weight on contraceptive hormones,” she said.

For obese women, simply shifting to an alternative form of birth control is an option, the researchers said. But they also pointed out that oral contraceptives are the most preferred form of birth control and that a woman’s individual preference influences her adherence and continuation with any method.

Media Contact: 
Source: 

Ganesh Cherala, 503-418-0447

Antibiotic use prevalent in hospice patients despite limited evidence of its value

CORVALLIS, Ore. – New research suggests that use of antibiotics is still prevalent among terminal patients who have chosen hospice care as an end-of-life option, despite little evidence that the medications improve symptoms or quality of life, and sometimes may cause unwanted side effects.

The use of antibiotics is so engrained in contemporary medicine that 21 percent of patients being discharged from hospitals directly to a hospice program leave with a prescription for antibiotics, even though more than one fourth of them don’t have a documented infection during their hospital admission.

About 27 percent of hospice patients are still taking antibiotics in the final week of their life.

This raises serious questions about whether such broad and continued antibiotic use is appropriate in so many hospice cases, experts say, where the underlying concept is to control pain and protect the remaining quality of life without aggressively continuing medical treatment.

Additional concerns with antibiotic use, the study concluded, include medication side effects and adverse events, increased risk of subsequent opportunistic infections, prolonging the dying process and increasing the risk of developing antibiotic resistant microorganisms.

The findings were just published in Antimicrobial Agents and Chemotherapy by researchers from Oregon State University and the Oregon Health & Science University. It was supported by the National Institutes of Health.

“Hospice care is very patient centered and in terminal patients it focuses on palliative care and symptom relief, not curative therapy,” said Jon Furuno, an associate professor in the Oregon State University/Oregon Health & Science University College of Pharmacy.

“It’s not for everyone, and it’s a serious decision people usually make in consultation with their family, nurses and doctors. These are tough conversations to have.

“Having decided to use hospice, however, the frequency and prevalence of antibiotic use in this patient population is a concern,” Furuno said. “Antibiotics themselves can have serious side effects that sometimes cause new problems, a factor that often isn’t adequately considered. And in terminally-ill people they may or may not work anyway.”

Issues such as this, Furuno said, continue to crop up in the evolving issue of hospice care, which is still growing in popularity as many people choose to naturally allow their life to end with limited medical treatment and often in their own homes. Hospice is covered by Medicare for people with a life expectancy of less than six months, helps to control medical costs and reduce hospital stays, and its services are now used by more than one third of dying Americans.

Unnecessary and inappropriate antibiotic use is already a concern across all segments of society, researchers said in the report, and more efforts are clearly needed to address the issue in hospice patients. The design of the study probably leads to it underestimating the significance of the problem, the researchers wrote in their conclusion.

Media Contact: 
Source: 

Jon Furuno, 503-418-9361

Research may yield new ways to treat antibiotic-resistant TB

CORVALLIS, Ore. – Scientists in the United States and India have successfully modified the precursor to one of the drugs used to treat tuberculosis, an important first step toward new drugs that can transcend antibiotic resistance issues that experts consider a serious threat to global health.

The findings, reported in the Journal of Biological Chemistry, indicate that a new compound, 24-desmethylrifampicin, has much better antibacterial activity than rifampicin against multi-drug-resistant strains of the bacteria that cause tuberculosis.

Rifampicin and related drugs are important antibiotics, the key to an effective “drug cocktail” that already takes about six months of treatment to cure tuberculosis, even if everything goes well. But two forms of tuberculosis, referred to as “multi-drug-resistant,” or MDR, and “extensively drug-resistant,” or XDR, have become resistant to rifampicin.

In 1993, resurging levels of tuberculosis due to this antibiotic resistance led the World Health Organization to declare it a global health emergency. Today more than 1 million people around the world are dying each year from tuberculosis, and after AIDS it remains the second most common cause of death by infectious disease.

“We believe these findings are an important new avenue toward treatment of multi-drug-resistant TB,” said Taifo Mahmud, a professor in the College of Pharmacy at Oregon State University, and a corresponding author on the new publication.

“Rifampicin is the most effective drug against tuberculosis, and it’s very difficult to achieve a cure without it,” Mahmud said. “The approach we’re using should be able to create one or more analogs that could help take the place of rifampicin in TB therapy.”

A combination of genetic modification and synthetic drug development was used to create the new compound, which so far has only been developed in laboratory, not commercial quantities. Further development and testing will be necessary before it is ready for human use, researchers said.

Drug resistance in rifampicin and related antibiotics has occurred when their bacterial RNA polymerase enzymes mutate, Mahmud said, leaving them largely unaffected by antibiotics that work by inhibiting RNA synthesis. The new approach works by modifying the drug so it can effectively bind to this mutated enzyme and once again achieve its effectiveness.

“We found out how the antibiotic-producing bacteria make this compound, and then genetically modified that system to remove one part of the backbone of the molecule,” Mahmud said. “Understanding this whole process should allow us to create not just this one, but a range of different analogs that can be tested for their efficacy as new antibiotics.”

In human history and before the advent of antibiotics, tuberculosis was one of the great infectious disease killers in the world. At its peak in the 1800s in Europe, it was the cause of death of one in four people. It’s still a major concern in the developing world, where drugs are often not available to treat it, and it often causes death in tandem with HIV infection.

As the bacterial strains of this disease that are multi- or extensively-drug-resistant increase in number, so too does the difficulty of treating it. Instead of a six-month regimen, these drug-resistant strains can take 18 months to several years to treat, with antibiotics that are more toxic and less effective.

Collaborators on this research were from the University of Delhi and the Institute of Genomics and Integrative Biology in India. The research has been supported by the M.J. Murdock Charitable Trust and the Medical Research Foundation of Oregon.

The approach used in this research “holds great potential to generate more rifamycin analogs to combat the threat of MDR strains of M. tuberculosis, and/or other life-threatening pathogens,” the researchers wrote in their conclusion.

Media Contact: 
Source: 

Taifo Mahmud, 541-737-9679

Statin use associated with less physical activity

CORVALLIS, Ore. – One of the longest studies of its type has found that use of statins in older men is associated with less physical activity, a significant issue for a population that’s already sedentary.

The findings, published today in JAMA Internal Medicine, raise concerns about a decline in much-needed physical activity among men who take some of the most widely prescribed medications in the world. Almost one-third of older Americans take statins, usually to reduce their cholesterol levels.

The research did not identify why men who took statins exercised less – it just confirmed that they did. Possible causes include the muscle pain that can be a side effect of statin use, and also disruption of the mitochondrial function in cells, which could contribute to fatigue and muscle weakness.

Physical activity in older adults helps to maintain a proper weight, prevent cardiovascular disease and helps to maintain physical strength and function,” said David Lee, an assistant professor in the Oregon State University/Oregon Health & Science University College of Pharmacy, and lead author of the study.

“We’re trying to find ways to get older adults to exercise more, not less,” Lee said. “It’s a fairly serious concern if use of statins is doing something that makes people less likely to exercise.”

Muscle pain is found in 5-30 percent of people who take statins, Lee said, and some people also report feeling less energetic, weak or tired.

In an analysis of 3,071 community-living men, age 65 or older, from six geographic regions in the United States, researchers found that men who took statins averaged about 40 minutes less of moderate physical activity over a one-week period, compared to those who weren’t taking the medication.

That would equate to the loss of 150 minutes a week of slow-paced walking, Lee said.

“For an older population that’s already pretty sedentary, that’s a significant amount less exercise,” he said. “Even moderate amounts of exercise can make a big difference.”

Of some significance, the study also found that new statin users had the largest drop in physical activity. An increase in sedentary behavior, which is associated with all-cause mortality and also death from cardiovascular disease, was also observed in statin users.

Some previous studies with older adults and statins had found similar results, but those analyses were short-term. This research followed men for almost seven years after initial baseline studies were done, and compared changes in physical activity among users and non-users of statins. In parts of the experiments, men wore accelerometers for a week to track by the minute their level of activity.

“Given these results, we should be aware of a possible decrease in physical activity among people taking a statin,” Lee said.

“This could decrease the benefit of the medication,” he said. “If someone is already weak, frail, or sedentary, they may want to consider this issue, and consult with their doctor to determine if statin use is still appropriate.”

This study was done with older men, and generalization of the findings to older women may not be appropriate, the researchers noted in their study.

The research was done by scientists from OSU; the Oregon Health & Science University; the Department of Veterans Affairs Medical Center in Portland, Ore.; the California Pacific Medical Center Research Institute in San Francisco; the Stanford Prevention Research Center; and the Department of Medicine at the University of California.

The study was supported by the National Institutes of Health and the Medical Research Foundation of Oregon.

Media Contact: 
Source: 

David Lee, 503-494-2258

Multimedia Downloads
Multimedia: 

Maintaining activity levels

Maintaining activity

Extended-release medication offers promise for alcohol, opioid dependence

The study this story is based on is available online: http://bit.ly/1i9n2tD

 

PORTLAND, Ore. – A comparatively new form of a medication for alcohol and opioid dependence that’s injected once a month instead of taken orally once a day appears to be significantly more effective than some other medications – because more patients actually continue the prescribed regimen.

The findings, published in the Journal of Substance Abuse Treatment by researchers from Oregon State University and other institutions, offer support for a wider use of medications that may help reduce or prevent substance abuse and related hospital admissions.

The cost savings could offset the cost of the medication, researchers said.

In the past, there has been fairly low use of medications to treat alcohol and opioid dependence. Several treatment options are available, with differing mechanisms of action, and they generally work to reduce the pleasurable feelings associated with drug and alcohol use, thereby discouraging the use of them.

The medication in the study that was found to be more effective than some past approaches was extended-release Naltrexone, which is administered once a month by injection in a medical setting. The research was supported by Alkermes, Inc., the manufacturer of that medication.

“Some of these medications are opioid antagonists, which reduce the euphoric effects of alcohol and some drugs,” said Dan Hartung, an associate professor in the Oregon State University/Oregon Health & Science University College of Pharmacy, and lead author on the study.

“Historically, oral medications for substance abuse have not often been prescribed or found to have a high degree of success, mostly because patients stopped taking them,” Hartung said. “But there are patients who are committed to treating their problems and data showed that they clearly appear to have success with extended-release Naltrexone, which is administered just once a month.”

The issue may be of increased importance, experts said, because of health and prescription drug coverage that is now being made available through the Affordable Care Act. It may make such medications available to many people who previously did not have access to them, and in the process achieve some goals of reducing hospital admissions.

The new meta-analysis combined findings from five other papers, comprising a total of 1,565 patients who received extended-release Naltrexone compared to other therapies for six months, among nearly 60,000 overall patients – the only comprehensive analysis of its type that has been completed.

It found that even though extended-release Naltrexone is expensive – about $1,100 a month – the total health care utilization and costs were generally lower for patients taking it, compared to those using other alcohol-dependence treatments.

They found that significant savings were produced by fewer days of detoxification facility use and inpatient utilization.

Alcohol and drug use disorders affect more than 21 million Americans, the researchers noted in their study – or about 8 percent of the nation’s population. Research in New York found that substance abuse more than doubled the number of preventable hospital re-admissions. But despite this, treatment of alcohol dependence with medications ranks the lowest among 25 health and behavioral conditions.

“There has always been some reluctance on the part of health care practitioners, as well as the patients they are treating, to use prescription medication to treat a substance abuse problem,” Hartung said.  “Medication-assisted therapy is underutilized. With more people having access to these medications, now would be a good time to do further research on the comparative efficacy and use of them.”

Although most studies of extended-release Naltrexone have been six months in duration, longer-term data suggest effectiveness is maintained for longer durations of therapy. Very limited research has been done comparing the efficacy of various drugs for these purposes.

Nationally, even at addiction treatment centers, only 24 percent used pharmacotherapy for alcohol dependence and 34 percent for opioid dependence. Barriers to use include financing, concerns about cost, medical staffing, education and attitudes.

“Given rising pressures to reduce potentially preventable hospital readmissions and other reducible cost and morbidity causes,” the researchers wrote in their conclusion, “the optimization of patient care and management of resources warrant systemic change in the delivery of addiction treatment, in the advancing era of health care reform.”

Media Contact: 
Source: 

Dan Hartung, 503-494-4720

Exact outline of melanoma could lead to new diagnostic tools, therapies

CORVALLIS, Ore. – Researchers at Oregon State University have identified a specific biochemical process that can cause normal and healthy skin cells to transform into cancerous melanoma cells, which should help predict melanoma vulnerability and could also lead to future therapies.

More than 70,000 cases of melanoma, the deadliest form of skin cancer, develop in the U.S. every year.

The work was published today in PLoS Genetics, in work supported by the National Institutes of Health.

“We believe this is a breakthrough in understanding exactly what leads to cancer formation in melanoma,” said Arup Indra, an associate professor in the Oregon State University/Oregon Health & Science University College of Pharmacy. “We’ve found that some of the mechanisms which ordinarily prevent cancer are being switched around and actually help promote it.

“In melanoma, the immune system is getting thrown into reverse,” he said. “Immune cells that previously were attracted to help deal with a problem are instead repulsed.”

The key to this process, the researchers said, is a protein called retinoid-X-receptor, or RXR. When present in an adequate amount, the RXR protein aids the proper operation of the immune response in the skin. Primary players in this are skin cells called melanocytes, which produce protective pigments, or melanin, in response to exposure to ultraviolet radiation in sunlight – in simple terms, a suntan.

Even with this protection, however, both melanocytes and other skin cells called keratinocytes routinely suffer genetic damage. Sometimes the damage can be repaired, and at other times the immune response – in the presence of adequate levels of RXR in the melanocytes – will kill the defective skin cells before they become malignant.

When expressed levels of RXR are too low in the melanocytes, however, this protective process breaks down. The chemicals that can help control mutated cells are actually suppressed, and the conditions for cancer promoted. DNA-mutated melanocytes begin to thrive at the same time other skin cells die and free up space for the growing, mutating melanocytes. The ultimate result can be the malignancy known as melanoma, which in turn can spread from the skin throughout the body.

“When there isn’t enough RXR, the melanocytes that exist to help shield against cancer ultimately become part of the problem,” Indra said. “It’s routine to have genetic damage from sunlight, because normally those cells can be repaired or killed if necessary. It’s the breakdown of these control processes that result in cancer, and that happens when RXR levels get too low.”

This process has not before been outlined in its entirety, Indra said, and the new findings open several possibilities. One would be a diagnostic test to determine when RXR levels are lower than they should be – which would set the stage for melanoma and possibly other cancers, but also with careful monitoring facilitate earlier diagnosis.

Beyond that, mechanisms may be developed to stabilize or stimulate the levels of RXR expression, and form the basis for a therapy. This might be done through diet or a “nanocarrier” drug that could deliver RXR to cells, Indra said.

“It’s quite possible that a new and effective therapy can now be developed, based on increasing levels of RXR,” Indra said.

Researchers in France and at the Knight Cancer Institute of the Oregon Health & Science University in Portland, Ore., contributed to this research.

Media Contact: 
Source: 

Arup Indra, 541-737-5775

Multimedia Downloads
Multimedia: 

Sun damage

Melanoma formation

Proteins discovered in gonorrhea may offer new approach to treatment

CORVALLIS, Ore. – Researchers at Oregon State University have discovered novel proteins in, or on the surface of the bacteria that causes gonorrhea, which offer a promising new avenue of attack against a venereal disease that is showing increased resistance to the antibiotics used to treat it.

Only a single, third-generation cephalosporin antibiotic still shows good efficacy against gonorrhea, creating a race against time to find some alternative way to treat this disease that can have serious health effects. It’s the second most commonly reported infectious disease in the United States.

Investigations based on these proteins might lead to new ways to combat the disease, including a vaccine, new types of drugs to block the growth of the bacteria, or even restoring the efficacy of some older antibiotics that have lost their usefulness, said Aleksandra Sikora, an assistant professor in the OSU College of Pharmacy.

“This could be a milestone in finding new ways to treat a global problem,” Sikora said. “It appears that one or more of these proteins, either within the bacterial cell envelope or on its surface, are essential to its growth and survival. Now we have a new target to aim at.”

World health officials have raised alarms that the growing resistance of gonorrhea to antibiotics could cause it to become untreatable. There are more than 60 million cases of this venereal disease treated around the world every year – and 300,000 just in the U.S. – in people who experience clear symptoms. But some of the worst damage is done among millions of other cases that are very mild or asymptomatic.

Such symptomless infections, most common in women, can cause pelvic inflammatory disease, ectopic pregnancy and infertility, as well as increase the transmission of the HIV virus. Gonorrhea can also affect joints and heart valves, and cause blindness in infants infected during birth.

The new findings were just published in Molecular and Cellular Proteomics, by researchers from OSU and the Fred Hutchinson Cancer Research Center. The research has been supported by OSU and the Medical Research Foundation of Oregon.

Using the evolving science of proteomics - which is the large-scale, high-throughput study of proteins and their functions - researchers identified a plethora of proteins that reside in a space in the gonorrhea bacteria, an “envelope” and its small outpouchings, or membrane vesicles.

This cell envelope shields the interior of gonorrhea from the environment and is essential for survival of the microbes, as well as their ability to cause disease. The proteins localized there help acquire nutrients, provide a permeability barrier, suppress the immune response and keep the bacteria fit.

Other proteins on the bacteria surface also help it attach to the host. The membrane vesicles are spherical structures that contain proteins and DNA, and are involved in antibiotic resistance, microbe communication and delivery of factors important for infection.

Any or all of these proteins may now offer a way to attack the survival and spread of the gonorrhea bacteria, Sikora said. None of them have yet been used for that purpose.

“Some past approaches to create a gonorrhea vaccine failed because they were focused on proteins essential to infection, which were quite unstable,” she said. “Because they were changing so constantly they were unsuitable for a vaccine. The proteins we’ve now identified offer a much more stable and vulnerable target.”

Researchers have already quantified their abundance of these cell envelope proteins and are learning their basic function, and in continued studies will screen compounds for activity against some of them.

“With this information, the chance to create either a vaccine or new drug treatments is very promising,” Sikora said.

The gonorrhea bacteria, Neisseria gonorrhoeae, is a pathogen specific to humans and no other animals. It dates to antiquity and it’s uncertain when it first developed. Many epidemics have been reported in world history.

Media Contact: 
Source: 

Aleksandra Sikora, 541-737-5811

Multimedia Downloads
Multimedia: 

Membrane vesicles

Membrane vesicles

One in five older Americans take medications that work against each other

PORTLAND, Ore. – About three out of four older Americans have multiple chronic health conditions, and more than 20 percent of them are being treated with drugs that work at odds with each other – the medication being used for one condition can actually make the other condition worse.

This approach of treating conditions “one at a time” even if the treatments might conflict with one another is common in medicine, experts say, in part because little information exists to guide practitioners in how to consider this problem, weigh alternatives and identify different options.

One of the first studies to examine the prevalence of this issue, however, found that 22.6 percent of study participants received at least one medication that could worsen a coexisting condition. The work was done by researchers in Connecticut and Oregon, and published in PLOS One.

In cases where this “therapeutic competition” exists, the study found that it changed drug treatments in only 16 percent of the cases. The rest of the time, the competing drugs were still prescribed.

“Many physicians are aware of these concerns but there isn’t much information available on what to do about it,” said David Lee, an assistant professor in the Oregon State University/Oregon Health & Science University College of Pharmacy.

“Drugs tend to focus on one disease at a time, and most physicians treat patients the same way,” Lee said. “As a result, right now we’re probably treating too many conditions with too many medications. There may be times it’s best to just focus on the most serious health problem, rather than use a drug to treat a different condition that could make the more serious health problem even worse.”

More research in this field and more awareness of the scope of the problem are needed, the scientists said. It may be possible to make better value judgments about which health issue is of most concern, whether all the conditions should be treated, or whether this “competition” between drug treatments means one concern should go untreated. It may also be possible in some cases to identify ways to treat both conditions in ways that don’t conflict with one another.

A common issue, for example, is patients who have both coronary heart disease and chronic obstructive pulmonary disease, or COPD. Beta blockers are often prescribed to treat the heart disease, but those same drugs can cause airway resistance that worsens the COPD.

“There are several types of beta blocker that don’t cause this negative interaction, but many of the other types are still prescribed anyway,” Lee said. “It’s this type of information that would be of value in addressing these issues if it were more widely known and used.”

The chronic conditions in which competing therapies come into play include many common health concerns – coronary artery disease, diabetes, COPD, dementia, heart failure, hypertension, high cholesterol, osteoarthritis and others.

This study was done by researchers from OSU and the Yale University School of Medicine, with 5,815 community-living adults between the years 2007-09. The lead author of the study was Dr. Mary E. Tinetti at Yale University, and it was supported by the National Institutes of Health. The analysis included a nationally representative sample of older adults, and both men and women.

The research identified some of the most common competing chronic conditions, in which medications for one condition may exacerbate the other. They included hypertension and osteoarthritis; hypertension and diabetes; hypertension and COPD; diabetes and coronary artery disease; and hypertension and depression. These issues affect millions of older Americans.

“More than 9 million older adults in the U.S. are being prescribed medications that may be causing them more harm than benefit,” said Jonathan Lorgunpai, a medical student at the Yale School of Medicine and co-author of the study. “Not only is this potentially harmful for individual patients, it is also very wasteful for our health care system.”

Direct competition between medications is just one of the concerns, the report noted. Use of multiple medications can also lead to increased numbers of falls and delirium, dizziness, fatigue and anorexia.

The researchers pointed out that the presence of competing conditions does not necessarily contraindicate the use of needed medications, but rather the need for this competition to be more seriously considered in treatment.

Media Contact: 
Source: 

David Lee, 503-494-2258

Low birth weight reduces ability to metabolize drugs

PORTLAND, Ore. – Researchers have identified another concern related to low birth weight – a difference in how the body reacts to drugs, which may last a person’s entire life and further complicate treatment of illnesses or diseases that are managed with medications.

The findings add to the list of health problems that are already known to correspond to low birth weight, such as a predisposition for adult-onset diabetes, hypertension, and obesity. The implication, researchers say, is that low birth weight may not only cause increased disease, but it may also lessen the effectiveness of the drugs used to treat those diseases.

The research is among the first of its type to implicate low birth weight as a permanent factor in drug response. It was published in the European Journal of Pharmacology, by researchers from Oregon State University and Oregon Health & Science University. Funding was provided by both universities and the National Institutes of Health.

When more fully understood, low birth weight may be added to the list of factors already being considered in medication dosages, such as age, weight, gender and ethnicity. Some of that is already being done in infants. But right now it’s not one of the factors considered in adults, scientists say, and more work needs to be done before such consideration is warranted.

“Low birth weight affects the development of organs, as the fetus tries to finish development of the brain and, in a sense, sacrifice as necessary the ordinary development of organs such as the kidney,” said Ganesh Cherala, an assistant professor in the OSU/OHSU College of Pharmacy.  “But the kidney is one of the primary filtering agents in the body, and is directly involved in drug elimination.”

The kidneys of low birth weight individuals have a significantly impaired ability to filter and excrete foreign compounds, Cherala said. Since the biologic impact of a medication is affected by its absorption, metabolism and excretion, low birth weight individuals might be less able to excrete drugs.

However, the biologic processes are not that simple, Cherala said. Because of liver metabolism and other issues, in many cases low birth weight individuals end up having less response to a drug, instead of more.

“A pain killer, for instance, might end up being metabolized in the liver instead of making its way to the brain where it is supposed to function,” Cherala said. “You might need more of that same drug in a low birth weight individual to have the same effect.”

The complexities of these processes need additional study before recommendations could be made to alter drug dosages based on low birth weight status, Cherala said. But this issue could be important and should be further explored, he said.

In developed countries about 8-10 percent of individuals are born with low birth weight, but the issue is of higher concern in some developing nations where 20-25 percent of babies are born with this condition. Low birth weight is generally caused by poor nutrition during pregnancy.

Media Contact: 
Source: 

Ganesh Cherala, 503-418-0447

Genetic function discovered that could offer new avenue to cancer therapies

The study this story is based on is available online: http://rsc.li/1fcWMim

 

CORVALLIS, Ore. – Researchers at Oregon State University have discovered a genetic function that helps one of the most important “tumor suppressor” genes to do its job and prevent cancer.

Finding ways to maintain or increase the effectiveness of this gene – called Grp1-associated scaffold protein, or Grasp – could offer an important new avenue for human cancer therapies, scientists said.

The findings were just published in Photochemical and Photobiological Sciences, a journal of the Royal Society of Chemistry, by researchers from OSU and Oregon Health & Science University. The work was supported by the National Institute of Environmental Health Sciences.

The Grasp gene was studied in the skin of mice in this research, but is actually expressed at the highest levels in the brain, heart and lung, studies have shown. It appears to play a fundamental role in the operation of the p53 tumor suppressor gene, which is a focus of much modern cancer research.

The p53 gene is involved in repair of DNA damage and, if the damage is too great, causing a mutated cell to die before it can cause further problems, up to and including cancer. Dysfunction of p53 genetic pathways have been linked to more than half of all known cancers - particularly skin, esophageal, colon, pancreatic, lung, ovarian, and head and neck cancers.

“DNA mutations occur constantly in our bodies just by ordinary stresses, something as simple as exposure to sunlight for a few seconds,” said Mark Leid, professor of pharmacology and associate dean for research in the OSU College of Pharmacy, and one of the lead authors on this study.

“Just as constantly, the p53 gene and other tumor suppressors are activated to repair that damage,” Leid said. “And in cases where the damage is too severe to be repaired, p53 will cause the apoptosis, or death of the mutated cell. Almost all of the time, when they are working right, these processes prevent the formation of cancers.”

But the activity and function of p53 can sometimes decline or fail, Leid said, and allow development of cancer. Promising approaches to cancer therapy are now based on activating or stimulating the p53 protein to do its job.

The new study has found that the Grasp gene is significantly involved in maintaining the proper function of p53. When “Grasp” is not being adequately expressed, the p53 protein that has entered the cell nucleus to either repair or destroy the cell comes back out of the nucleus before its work is finished.

“It appears that a primary function of Grasp is to form sort of a halo around the nucleus of a damaged skin cell, and act as kind of a plug to keep the p53 cell inside the nucleus until its work is done,” Leid said. “A drug that could enhance Grasp function might also help enhance the p53 function, and give us a different way to keep this important tumor suppressor working the way that it is supposed to.

“This could be important,” he said.

OSU experts created laboratory mice that lacked the Grasp gene, and so long as the mice were reared in a perfect environment, they developed normally. But when they were exposed to even a mild environmental stress – ultraviolet light similar to moderate sun exposure – they began to develop cellular abnormalities much more rapidly than ordinary mice. Most significantly, mutated skin cells did not die as they should have.

In normal mice, the same moderate light exposure caused a rapid increase in expression of the Grasp gene, allowing the p53 protein to stay in the nucleus and normal protective mechanisms to do their work.

Most current cancer therapies related to the p53 tumor suppression process are directed toward activating the p53 protein, Leid said. A therapy directed toward improving the Grasp gene function would be a different approach toward the same goal, he said, and might improve the efficacy of treatment.

Media Contact: 
Source: 

Mark Leid, 541-737-5809