(Press-News.org) SPOKANE, Wash.—Safety concerns related to the widely used painkiller diclofenac may be tied to a little-studied drug-metabolizing enzyme whose expression can vary as much as 3,000 times from one individual to the next, according to new research.
Published in the journal Clinical Pharmacology & Therapeutics, findings from the study could be used to develop ways to identify individuals at risk of serious side effects from diclofenac and to determine safer dosing standards for specific populations, including women, young children and people of certain ethnicities.
Used to combat pain and inflammation associated with arthritis, diclofenac was available in the U.S. as an over-the-counter drug until 2013, when the Federal Drug Administration restricted it to prescription-only use following reports of the drug causing heart damage. More than 10 million prescriptions per year are written for it in the U.S. It is also one of the most widely used non-steroid, anti-inflammatory drugs worldwide. This includes many countries in Asia, Africa and the Middle East that still allow over-the-counter use of diclofenac.
“Most patients who are using diclofenac have arthritis, and many of them are at risk of heart disease,” senior author Bhagwat Prasad, an associate professor in the Washington State University College of Pharmacy and Pharmaceutical Sciences. “So there is a concern that taking diclofenac may be putting them at even greater risk of cardiovascular events such as heart attack and stroke.”
Previous findings by the WSU team had found a high degree of variability in the expression of UGT2B17, an enzyme that is a known player in diclofenac metabolism. That study showed that the enzyme is present at much lower levels in women than in men, which the researchers thought could explain the increased risk of heart damage seen in women taking diclofenac. They also found that the enzyme is mostly absent in children under the age of nine and discovered large ethnicity-based differences in the number of people who lack the gene for the enzyme altogether, which ranges from around 20% of Caucasians up to around 90% of Japanese people.
In this new study, the WSU researchers used human liver and intestinal samples along with computer-based modeling to quantify the degree to which this enzyme contributes to diclofenac metabolism relative to other related enzymes. They found it to be a major player, supporting the idea that low levels of the UGT2B17 enzyme may be the cause of heart damage tied to diclofenac use.
“No one knew why this heart toxicity is happening in some individuals,” said first author Deepak Ahire, a graduate student in the WSU College of Pharmacy and Pharmaceutical Sciences. “Our study showed, for the first time, that UGT2B17 is important in diclofenac metabolism and suggests that differences in UGT2B17 expression are what makes people’s response to diclofenac so variable, leading to toxicity in some whereas for others the drug simply does not work.”
Ahire said that their study found that this enzyme metabolizes diclofenac mainly in the intestine, unlike other related enzymes that are active mostly in the liver. As a result, the effect the researchers are seeing is specific to diclofenac tablets taken by mouth, which provides for the quickest absorption and pain relief. Just under half of prescriptions written for the drug in the U.S. are for oral diclofenac, Prasad said.
The researchers’ findings suggest that it may be feasible to use genetic testing to help healthcare providers evaluate safety risks before prescribing diclofenac. Prasad also noted that drug regulatory authorities in countries where diclofenac is still available over the counter should consider doing efficacy testing to determine the optimal dose of the drug for their local market.
The WSU researchers are currently in the process of confirming their findings in a pilot clinical trial. Their next step would be to pursue collaborations with large hospitals to study the connection between diclofenac and heart damage in patients’ electronic medical records.
The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, a component of the National Institutes of Health.
END
Study points to cause of safety concerns in widely used painkiller diclofenac
2023-04-24
ELSE PRESS RELEASES FROM THIS DATE:
Cryo-imaging lifts the lid on fuel cell catalyst layers
2023-04-24
Proton-exchange membrane fuel cells (PEMFC), which are being developed for use in electric vehicles, rely on nanoparticles called catalysts to trigger electricity-producing reactions between hydrogen and oxygen. Most PEMFC catalysts contain platinum – a scarce and precious metal. There is therefore a pressing global need to develop catalysts that can generate the most power while minimizing platinum content.
Manufacturers integrate these catalysts in complex assemblies called catalyst layers. Until now, they had to do so without a detailed picture of the resulting structure, as traditional imaging processes almost always cause some degree of damage. Vasiliki Tileli, head ...
Study finds significant variation in anatomy of human guts
2023-04-24
New research finds there is significant variation in the anatomy of the human digestive system, with pronounced differences possible between healthy individuals. The finding has implications for understanding the role that the digestive tract’s anatomy can play in affecting human health, as well as providing potential insights into medical diagnoses and the microbial ecosystem of the gut.
“There was research more than a century ago that found variability in the relative lengths of human intestines, but this area has largely been ignored since then,” says Amanda Hale, co-first author of the study and a Ph.D. ...
As “deprescribing” medicines for older adults catches on, poll shows need for patient-provider dialogue
2023-04-24
As the movement toward “deprescribing” medications among older adults grows, a new poll shows strong interest in this idea.
A full 80% of adults aged 50 to 80 would be open to stopping one or more of the prescription medicines they’ve been taking for more than a year, if a health care provider said it was possible. Already, 26% said they have done so in the past two years.
Of those willing to stop a medicine, 67% said they would likely ask for advice about doing so at their next visit with a provider, according to the new ...
If it pays to be a jerk, why isn’t everyone that way?
2023-04-24
DURHAM, N.C. -- Throw a tantrum. Threaten, shove aside or steal from your colleagues. Science confirms, yet again, that brutish behavior can be an effective path to power. And not just in humans, but in chimpanzees, too.
A new study appearing April 24 in the journal PeerJ Life and Environment found that male chimps with more bullying, greedy and irritable personalities reached higher rungs of the social ladder and were more successful at siring offspring than their more deferential and conscientious counterparts.
But if that’s the case, researchers ask, why isn’t every chimp a bully?
A team led by researchers at the ...
New neurosurgery research: Surgical versus nonsurgical treatment of pituitary apoplexy
2023-04-24
The first prospective study comparing outcomes in patients with pituitary apoplexy—sudden bleeding or death of a pituitary tumor—found that patients managed medically fared as well as those treated surgically in the majority of cases. The multicenter international study, led by Cedars-Sinai investigators, was presented today at the American Association of Neurological Surgeons Scientific Meeting in Los Angeles.
“This is the best data to date on the question of surgery versus medical management in patients with this rare but serious condition,” said Adam Mamelak, MD, co-director ...
AAAS announces winners of the inaugural Mani L. Bhaumik Breakthrough of the Year Award
2023-04-24
The American Association for the Advancement of Science’s (AAAS) inaugural Mani L. Bhaumik Breakthrough of the Year Award — focused on standout contributors to NASA’s James Webb Space Telescope (JWST) — honors three individuals who supported vast swaths of the JWST community over decades and whose persistence amid multiple setbacks ensured the mission’s completion.
The award recognizes Major General Charles Frank Bolden Jr., USMC (Ret), a former administrator of the National Aeronautics and Space Administration (NASA); John Mather, senior project scientist of the JWST since 1995; and Bill Ochs, JWST project manager from 2011 through the telescope’s ...
Do vitamin D levels affect the body’s response to anti-cancer immunotherapy?
2023-04-24
Study’s findings suggest that maintaining normal vitamin D levels may benefit patients.
New research indicates that for patients with advanced skin cancer, it may be important to maintain normal vitamin D levels when receiving immunotherapy medications called immune checkpoint inhibitors. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.
Vitamin D has many effects on the body, including regulation of the immune system. To see whether levels of vitamin D might impact the effectiveness of immune checkpoint inhibitors, investigators analyzed the blood of 200 patients with advanced melanoma both before and every 12 weeks ...
Drug combination restores ability of leading treatment to signal for death of blood cancer cells
2023-04-24
Despite the promise of new medications that promote cancer cell death in people with acute myeloid leukemia, leukemic cells often adopt features that let them evade the drugs’ effects within a year.
Now, new research using human tissue samples and mouse models has found that resistance of leukemia cells to a widely prescribed drug called venetoclax occurs because of a rapid increase in the breakdown and turnover of mitochondria, structures inside the cell that help power its functions. In addition to their role in producing energy, mitochondria also tell cells to die under certain adverse conditions.
This process of “programmed cell ...
Increased risk of testicular cancer in people with neurodevelopmental disorders
2023-04-24
A new study by researchers at Uppsala University and Uppsala University Hospital shows that men who have a neurodevelopmental disorder, such as autism and ADHD, also have a slightly increased risk of testicular cancer, or seminoma. This is the first study to show such a link, with the results to be published in the British Journal of Cancer.
Testicular cancer is the most common form of cancer in young men, and its underlying causes are still largely unknown.
“As testicular cancer can be surgically removed, thus curing the disease, it is important to seek care in time if you feel a lump in your testicle,” notes Ingrid ...
Single CT scan in kids low risk for cancers, but 4 or more CTs increases risk
2023-04-24
For children under age 18 years, a single computed tomography (CT) scan is not associated with an increased risk of brain tumours, leukemia or lymphoma, but exposure to 4 or more scans before adulthood more than doubles the risk, according to new research https://www.cmaj.ca/lookup/doi/10.1503/cmaj.221303 in CMAJ (Canadian Medical Association Journal).
Computed tomography in children has increased worldwide in recent decades, but there is conflicting evidence about the risks of cancer from these ...