Tag: side effects

Categories : Cardiovascular Disease Pain ManagementTags :

Researchers Quantify Risk Factors for Oral Diclofenac

On By ModernMedia

Safety concerns related to the widely used analgesic diclofenac may be tied to a little-studied drug-metabolising enzyme which can vary as much as 3000 times across individuals, according to new research published in the journal Clinical Pharmacology & Therapeutics.

The findings could be used to develop ways to identify those at risk of serious side effects from the drug. They may help determine safer dosing standards for specific populations, including women, young children and people of certain ethnicities.

Used to treat arthritis-associated pain and inflammation, diclofenac was available over-the-counter in the US until 2013, when the Food and 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 US. It is also one of the most widely used non-steroidal anti-inflammatory drugs worldwide, and is still over-the-counter in many countries. 

“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 at Washington State University. “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. They found that the enzyme is present at much lower levels in women than in men, which could explain the increased risk of heart damage seen in women taking diclofenac. The enzyme was also mostly absent in children under age 9 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 modelling 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 metabolises diclofenac mainly in the intestine, unlike other related enzymes that are active mostly in the liver. Thus the observed effects are limited to diclofenac tablets taken by mouth, which provides for the quickest absorption and pain relief.

The findings suggest genetic testing could 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.

Source: Washington State University

Categories : Cardiovascular DiseaseTags :

1 in 5 Patients at High Cardiovascular Risk Refuse Statins, Especially Women

On By ModernMedia
Photo by Priscilla du Preez on Unsplash

Heart disease is the leading cause of death worldwide, and statins are a vital medication against it – but they are notoriously unpopular, leading to poor adherence. Investigators from Brigham and Women’s Hospital conducted the first population-based study on patients’ nonacceptance of statin therapy recommendations, and published their results in JAMA Network Open.

The study found that in patients at high risk of developing cardiovascular disease, over 20% refused to take statin medications. They were particularly surprised to see that women were about 20% more likely than men to refuse statin therapy when it was first suggested by their physician, and 50% more likely than men to never accept the recommendation. The study also showed that all patients who refused statin therapy developed higher LDL cholesterol levels, likely increasing their risk even further.

“Our study highlights the alarming number of patients who refuse statins and signals that physicians must have discussions with patients about why,” says Alex Turchin, MD, MS, an associate professor at Harvard Medical School and director of quality in the Brigham’s Division of Endocrinology, Diabetes, and Hypertension. “We need to better understand what our patients’ preferences are and to be able to provide more patient-centered care.”

After Turchin began noticing that many of his patients with high cholesterol, including those with diabetes, were opting not to take safe and beneficial medications like statins that can lower cholesterol and bring down the risk of heart attack and stroke, he developed a system to more closely study the phenomenon by analysing the text of provider notes.

The study focused on high-risk patients who either had coronary artery or vascular disease, diabetes, very high cholesterol, or had suffered a stroke. All were recommended statin medications by their physicians to reduce their risk of heart attack and stroke and reduce cholesterol levels. The retrospective study included more than 24 000 patients who were seen at Mass General Brigham between January 1, 2000, and December 31, 2018.

“Even in this higher-risk patient population, so many people did not accept statin therapy,” Turchin said. The study found that while about two-thirds of the patients who were being recommended statin therapy eventually tried it, about one-third never did. And it took three times as long for people in the study who initially said no to taking statin medications to reduce their LDL cholesterol levels to less than 100, compared to people who initially said yes.

The study’s biggest surprise, however, was the much higher rate of refusal by women than men. Turchin and his colleagues wonder if this might be due in part to a false misconception that heart disease impacts men more than women, and plan to further research the reasons underlying these results.

“Ultimately, we need to talk to our patients and find out in more detail why they would prefer not to take statins,” Turchin says. He is currently looking at the impacts of nonacceptance of statin therapy on outcomes that matter to most to patients including heart attacks, strokes, and death. “I think people underestimate how much of a difference modern medicine has made in extending people’s lives, and their quality of life, and medications can play a big role in that.”

Source: Brigham and Women’s Hospital

Categories : Medical Research & TechnologyTags :

Why Some Drugs Have Side Effects

On By ModernMedia
Photo by Myriam Zilles on Unsplash

Researchers have discovered how unwanted side effects can result from how some drugs affect various membrane-spanning proteins in addition to their intended target. The findings, published in PNAS, illuminate one of the main problems of drug discovery and point to new strategies to overcome it.

Any class of drug can have side effects, but those that interact directly with cellular membranes have been especially problematic. “Those drugs tend to affect many membrane proteins, and we suspected that there’s some kind of non-specific mechanism at work,” said first author Dr Radda Rusinova, assistant professor of research in physiology and biophysics at Weill Cornell Medicine. “We wanted to see whether it could be linked to the cell membrane.”

Dr Rusinova and her colleagues used sensitive assays that allowed them to compare how different drugs affected the activities of two channel proteins that span membranes: the gramicidin ion channel and a potassium channel called KcsA. Gramicidin was used to measure the magnitude of drugs’ effect on the membrane while KcsA reflected effects these drugs could have on typical membrane proteins.  They found that membrane-associated drugs can affect KcsA in at least three ways: by interacting directly with the proteins, by interfering with the proteins’ structural connections to the membrane, or by causing broad changes in membrane characteristics such as thickness or elasticity.

Changes in membrane characteristics have well-known effects on the gramicidin ion channel, an antibiotic isolated from bacteria that has long been used as a standard tool for studying such changes. “Gramicidin is a probe essentially for changes in bilayer and membrane properties, and will report on the magnitude of the changes,” said Dr. Rusinova.

“But we needed to go further to see how a more typical cell membrane protein would react,” Dr. Rusinova said. KcsA belongs to a class of proteins – potassium channels – that drive many aspects of cell physiology in everything from bacteria to humans, making it a good comparative probe.

The comparative assay results revealed a more nuanced process than the  straightforward model currently used to explain how membrane-binding drugs can affect membrane-spanning proteins.

“The more data that Dr Rusinova got, the more it became apparent that this simple model did not actually cover the full spectrum of effects that we saw,” said senior author Dr Olaf Andersen, professor of physiology and biophysics.

“The investigators who are looking into molecules that can move into the cell membrane need to worry about at least three mechanisms for off-target effects,” Dr Rusinova said.

However, not all is bad news: in some cases, off-target effects at the cellular level cause no trouble to the organism, and in a few instances they can even be beneficial. Dr Rusinova points to two of the drugs her team tested as an example: amiodarone, a heart medication whose membrane-mediated effects actually boost its efficacy, and troglitazone, an anti-diabetic drug whose side effects included liver toxicity, ultimately forcing regulators to pull it from the market.

The investigators hope to develop more predictive models for such off-target effects. “We would like to determine the structural characteristics of a membrane protein that would make it more or less sensitive to bilayer effects,” Dr Rusinova said.

Source: Weill Cornell Medicine

Categories : COVID General InterestTags :

The Second Vaccine Dose Can Hit Hard

On By ModernMedia

The scuttlebut among healthcare workers is that the second dose of a COVID vaccine hits much harder than the first – unless you’ve had COVID, in which case the first is equally as bad.

TJ Maltese, DO, a neurologist in private practice on Long Island in New York state, was fine with the first dose of the Moderna vaccine but was flattened by the second one.

Dr Maltese got his second jab on a Friday at 4:30 pm. Within two hours his arm was sore. Overnight, he developed flu-like symptoms, and on Saturday experienced chills and body aches, with a lingering fever. He could have pushed through if he’d had to work, he said, but he rode out his symptoms on his couch with the help of the occasional painkiller.

By 9 pm on Saturday evening, Dr Maltese started to feel better, getting a good night’s sleep and on Sunday was fine again.

“I know plenty of people with minimal symptoms after the second dose, so it’s not definite you’ll feel side effects,” he wrote in a Facebook post. “But be prepared for the possibility.”

Immunology and the phase III clinical trial data from the vaccine backs up the view that the second dose is worse, and some hospitals have even altered their scheduling to allow time for recuperation after the second dose. Adverse reactions to the BCG vaccine in Brazilian school children, for example, have been reported to be common with the second dose, though still rare.  

Immunologists and infectious disease experts interviewed by MedPage Today and who shared their second-dose experiences said it’s not unexpected that second-dose reactions are more intense than the first. Typical reactions to the COVID vaccines include fever, headache and fatigue as the immune system responds to a vaccine’s antigens.

“The first time the immune system comes into contact with something, it’s getting primed,” said Purvi Parikh, MD, an immunologist at NYU Langone Health in New York City. “That goes for everything, from vaccines to allergies. It’s rare on the first time to have a strong reaction. After that, the immune system recognizes it, so you have a much stronger reaction.”

“We saw it in the trials, so it’s really not surprising,” Parikh added. “Now we’re seeing it in real time as the vaccines are being rolled out.”

More adverse effects were reported after the second dose in both Pfizer’s and Moderna’s phase III trial data. For Moderna, the rates were 54.9% versus 42.2% for placebo after the first dose and 79.4% versus 36.5% for placebo after the second dose.

Stanley Weiss, MD, an infectious disease specialist and epidemiologist at Rutgers New Jersey Medical School, told MedPage Today that because his institution served as a Moderna trial site, the primary investigator was able to give an early update on what to expect following vaccination.

“They said there was a very high rate of fatigue after the second dose, so we encouraged administrators … to figure that many healthcare workers getting the vaccine might not be well enough to work the day after the second dose,” Dr Weiss said.

Drs Weiss and Parikh both experienced a stronger response to the second COVID dose. 

Zubin Damania, MD, aka ZDoggMD, said he was knocked out by the second dose of Moderna vaccine, joking on his show that, “I couldn’t sleep, I had a fever, rigors, body aches, a headache — full-on man-flu.”

Paul Offit, MD, said that he also experienced fever and fatigue after taking the second dose of the Pfizer vaccine.

“That reaction is less common in people over 65, and I’m over 65, so I’m thinking I’m not going to suffer that, but I did,” Dr Offit said.

Older people are not expected to have as intense a reaction due to their weaker immune systems. According to Dr Parikh, “The idea is that their immune system is not as robust as a young person’s.”
The same immunological underpinnings of why reactions to the second dose are worse also apply to those who’ve had COVID.
Victoria Arthur, MD, of Lexington Pediatrics in Massachusetts, had suspected she had contracted COVID in March 2020 but could not prove it. When she received the Moderna vaccine, she felt much worse than her colleagues.

“How I felt was how everyone else was describing their second vaccine,” Dr Arthur told MedPage Today. Within three hours of her jab, she was suffering from a headache, neck pain, and cognitive fog. She awoke at 3am with nausea and stomach cramps, and spent the whole of the next day in bed. 

“I’m always grateful when I have a reaction, that means the body is doing its thing,” she said. “I’m very fortunate to have been given the vaccine, so any side effect is worth it.”

In spite of the side effects, these health care professionals all expressed gratitude at having been vaccinated.

Dr Weiss said that people shouldn’t be discouraged by the side effects from the second dose and not get vaccinated: “The benefits greatly overwhelm the risk of side effects. It’s not a reason to delay.”

Source: MedPage Today