Toward One Drug to Treat All Coronaviruses

Safe and effective vaccines offer hope for an end to the COVID-19 pandemic. However, the possible emergence of vaccine-resistant SARS-CoV-2 variants, as well as novel coronaviruses, make finding treatments that work against all coronaviruses as important as ever. Now, researchers reporting in ACS’ Journal of Proteome Research have analyzed viral proteins across 27 coronavirus species and thousands of samples from COVID-19 patients, identifying highly conserved sequences that could make the best drug targets.

Drugs often bind inside “pockets” on proteins that hold the drug snugly, causing it to interfere with the protein’s function. Scientists can identify potential drug-binding pockets from the 3D structures of viral proteins. Over time, however, viruses can mutate their protein pockets so that drugs no longer fit. But some drug-binding pockets are so essential to the protein’s function that they can’t be mutated, and these sequences are generally conserved over time in the same and related viruses. Matthieu Schapira and colleagues wanted to find the most highly conserved drug-binding pockets in viral proteins from COVID-19 patient samples and from other coronaviruses, revealing the most promising targets for pan-coronavirus drugs.

The team used a computer algorithm to identify drug-binding pockets in the 3D structures of 15 SARS-CoV-2 proteins. The researchers then found corresponding proteins in 27 coronavirus species and compared their sequences in the drug-binding pockets. The two most conserved druggable sites were a pocket overlapping the RNA binding site of the helicase nsp13, and a binding pocket containing the catalytic site of the RNA-dependent RNA polymerase nsp12. Both of these proteins are involved in viral RNA replication and transcription. The drug-binding pocket on nsp13 was also the most highly conserved across thousands of SARS-CoV-2 samples taken from COVID-19 patients, with not a single mutation. The researchers say that novel antiviral drugs targeting the catalytic site of nsp12 are currently in phase II and III clinical trials for COVID-19, and that the RNA binding site of nsp13 is a previously underexplored target that should be a high priority for drug development.

Source: American Chemical Society

No Evidence Muscle Relaxants Can Ease Low Back Pain

Alan Mozes wrote . . . . . . . . .

Although tens of millions of Americans turn to muscle relaxants for lower back pain relief, a new Australian review finds little evidence that such drugs actually work.

That’s the conclusion of a deep-dive into 31 prior investigations, which collectively enlisted more than 6,500 lower back pain patients. Enrolled patients had been treating lower back pain with a wide range of 18 different prescription muscle relaxants.

But while the studies suggested that muscle relaxants might ease pain in the short term, “on average, the effect is probably too small to be important,” said study author James McAuley. “And most patients wouldn’t be able to feel any difference in their pain compared to taking a placebo, or sugar pill.”

Another concern: Beyond their ineffectiveness, “there is also an increased risk of side effects,” cautioned McAuley, director of the Centre for Pain IMPACT with the University of New South Wales’ School of Health Sciences in Sydney.

Such side effects can include dizziness, drowsiness, headache and/or nausea, in addition to the risk that patients will develop a lingering addiction.

McAuley said his team was surprised by the findings, “as earlier research suggested that muscle relaxants did reduce pain intensity. But when we included all of the most up-to-date research the results became much less certain.”

One problem is that much of the research “wasn’t done very well, which means that we can’t be very certain in the results,” McAuley said.

For example, none of the studies explored long-term muscle relaxant use. That means the Australian team could only assess muscle relaxant effectiveness during two time frames: throughout an initial two-week regimen and between 3 to 13 weeks. In the first instance, they found low evidence of an insignificant pain relief benefit; in the second instance, they found no pain intensity or disability relief benefit whatsoever.

McAuley’s take-away: “There is a clear need to improve how research is done for low back pain, so that we better understand whether medicines can help people or not.

“Low back pain is extremely common. It is experienced by 7% of the global population at any one time. Most people, around 80%, will have at least one episode of low back pain during their life,” McAuley noted.

But because it’s often very difficult to isolate a precise cause, many treatments — including NSAIDs, opioids, exercise therapy and/or counseling — aim to control pain rather than provide a cure. Muscle relaxants — prescribed to 30 million Americans in 2020 — fall into that category, McAuley said.

Given that muscle relaxants provide neither a cure nor pain relief, there’s “a clear need to develop and test new effective and cost-effective treatments for people with low back pain,” he said.

In the meantime, McAuley says a move is underway to “de-medicalize” lower back pain treatment by embracing techniques that focus on alternatives to medicine or surgery.

For example, “we know that people with low back pain should avoid staying in bed,” he noted, “and they should try to be active, and continue with usual activities, including work, as much as they can.

“People with recent onset low back pain should be provided with advice and education about the low back pain,” McAuley added. “[And] they should be reassured that they do not have a serious condition, and that their low back pain is very likely to improve over time, whether or not they take medicines or other treatments.”

He and his colleagues reported their findings in the July 7 issue of BMJ.

“The problem is, back pain has so many causes,” said Dr. Daniel Park, an associate professor in the department of orthopedics with Oakland University’s William Beaumont School of Medicine in Rochester, Mich.

So when it comes to treatment, “there is no one-size-fits-all,” stressed Park, who is also a spine surgeon at Beaumont Hospital-Royal Oak.

Still, Park thinks that when it comes to muscle relaxants, “there probably is a place for short-term benefit to help patients manage severe pain.”

For example, he suggests patients with “muscle strain from overdoing it,” or those with a herniated disc may actually benefit from short-term muscle relaxant use.

But patients with garden-variety back pain from a degenerative disc? Not so much.

Regardless, long-term pain relief is unlikely, regardless of the source of the problem, Park noted.

“Long-term, therapy and core strengthening will be much more beneficial,” Park said, while every effort should be made to identify the specific cause, and to minimize the risk for a chronic condition, permanent damage and enduring discomfort.

Source: HealthDay

New Drug Shows Real Promise Against Celiac Disease

Amy Norton wrote . . . . . . . . .

An experimental drug can prevent intestinal damage caused by celiac disease, an early trial has found — raising hopes that it could become the first medication for the serious digestive disorder.

With celiac disease, the immune system attacks the lining of the small intestine when a genetically susceptible person eats gluten — a protein found in wheat, rye and barley.

The symptoms of celiac include diarrhea, abdominal pain, fatigue and weight loss. Underlying it all is an aberrant immune system attack that damages hair-like structures in the intestinal lining called villi. Villi absorb nutrients from food, so people with celiac can become malnourished and develop problems like anemia and thinning bones.

Right now, the only treatment is “rigorous avoidance of even traces of gluten in the daily diet,” said lead researcher Dr. Detlef Schuppan.

But a lifelong gluten-free diet is difficult to maintain, said Schuppan, a professor at the University Medical Center of Johannes Gutenberg University, in Germany.

Gluten can lurk in many processed foods, from pasta and breakfast cereals to sauces and soups to energy bars and chips.

Beyond being a practical burden, the strict diet is a “social and psychological” one as well, Schuppan noted.

And even when patients manage to adhere to it, he said, some can still have intestinal inflammation and symptoms.

The new study, published July 1 in the New England Journal of Medicine, looked at whether an experimental drug can prevent that intestinal damage.

The drug, dubbed ZED1227, inhibits the activity of an enzyme called transglutaminase 2 (TG2) in the intestines, Schuppan explained. TG2 plays a key role in the autoimmune response that marks celiac.

The trial, which was funded by drugmaker Dr. Falk Pharma, enrolled 163 adults with celiac disease who’d been successful with a gluten-free diet for at least a year.

The researchers randomly assigned the patients to one of four groups: three were given various doses of ZED1227 to take every morning for six weeks; the fourth took placebo pills.

Thirty minutes after each morning dose, the study patients ate a biscuit containing a moderate amount of gluten, as a way to test the drug’s ability to block gluten-induced inflammation.

After six weeks, the trial found, patients on any dose of the drug showed fewer signs of intestinal damage, versus the placebo group. As for side effects, skin rash was the only symptom more common among medication users; that was seen in 8% of patients on the highest dose.

Dr. Joseph Murray, a gastroenterologist at the Mayo Clinic, called the findings “encouraging.”

The trial “proves that blocking this key enzyme is feasible,” said Murray, who is also a medical advisor to the Celiac Disease Foundation.

Whether that will also lessen patients’ symptoms and improve their quality of life remains to be seen in larger studies, Murray said.

Like Schuppan, he noted that gluten-free diets are tough to maintain, and are not always enough on their own.

“About 30% of patients continue have substantial issues despite doing their best on a gluten-free diet,” Murray said.

Those patients will be the focus of future research. Schuppan said his team is planning a trial that will test ZED1227 in celiac disease patients who are not completely responding to a gluten-free diet.

If ZED1227 or any other medication becomes available for celiac, that does not spell the end of the gluten-free diet.

According to Murray, it’s likely patients will still have to follow diet restrictions. But, especially given the difficulty of avoiding gluten entirely, medication should make people’s lives easier, he said.

“There is real hope we will have additional treatments for celiac, which heretofore has placed the entire burden of care on the patient,” Murray said.

Roughly 1% of the world’s population has celiac disease, according to the Celiac Disease Foundation. In the United States, it’s estimated that 2.5 million people are undiagnosed.

Source: HealthDay

Which Blood Sugar Meds Work Best Against Type 2 Diabetes?

Steven Reinberg wrote . . . . . . . . .

You have type 2 diabetes, and you are already taking an old standby drug, metformin. But you still need help controlling your blood sugar levels. Which medication would be the best?

New research pitted several diabetes drugs against each other and came up with an answer: The diabetes drugs Lantus and Victoza were better at controlling blood sugar over time than Amaryl or Januvia.

“We’ve known that type 2 diabetes is a progressive disease, and these medications, in general, do not reduce or obliterate progression, and that the ability of these medications to slow the rise in glucose varies amongst them,” explained Dr. Steven Kahn, a professor of medicine, metabolism, endocrinology and nutrition at the University of Washington in Seattle. He is a member of the executive committee that oversaw the trial.

The goal was to see which of these drugs kept average blood sugar levels in the recommended target range, at an A1C level of less than 7%. A1C blood tests are a standard means of gauging long-term blood sugar control.

“When we look at the rise in A1C over time, it’s clear that there are initial beneficial impacts of one drug over the other, but they tend to fail at a very similar rate,” Kahn said. “So, beyond the first couple of years, all the failure seems to be occurring at the same rate, but overall failure was less with Lantus and Victoza.”

Lantus (insulin glargine) and Victoza (liraglutide) are both injectable drugs, while Amaryl (glimepiride) and Januvia (sitagliptin) are pills.

The study, which was funded by the U.S. National Institutes of Health, included more than 5,000 people with type 2 diabetes, average age 57. The participants, 20% of whom were Black and 18% of whom were Hispanic, were randomly assigned to one of the four drugs along with metformin in the trial, which ran an average of four years.

The researchers found that Lantus and Victoza were the most effective in keeping A1C levels under 7%, while Amaryl or Januvia had the lowest effect and higher odds of letting A1C levels rise above 7%.

The results were similar across gender, race, ethnicity and age group.

Other findings included:

  • Patients given Victoza and Januvia were more likely to lose weight than those taking Amaryl. Those taking Lantus maintained a stable weight.
  • Victoza caused more gastrointestinal side effects, such as nausea, abdominal pain and diarrhea, than the other drugs. Amaryl was linked to a higher risk for low blood sugar than the other drugs.
  • Victoza was linked to a lower risk of heart attack, stroke and other heart and vascular complications than the other drugs.

Dr. Caroline Messer, an endocrinologist at Lenox Hill Hospital in New York City, said the study confirms that these medications are appropriate and should be used as a second-line treatment after metformin, or as a first-line treatment if metformin isn’t tolerated.

Messer noted that although some of the newer drugs are expensive, they are covered by most health insurance plans.

“I think the only disservice of the study is that I don’t want people to start thinking that you should be using insulin [Lantus] as a second-line treatment,” she explained. “I think that it does a disservice, because if people are reaching for insulin too quickly because of this trial, that would be a shame.”

The findings were presented Monday at the virtual annual meeting of the American Diabetes Association. Findings presented at medical meetings should be considered preliminary until published in a peer-reviewed journal.

Dr. Joel Zonszein, an emeritus professor of medicine at Albert Einstein College of Medicine in New York City, was not surprised by the findings, but thinks the trial is outdated.

“It certainly proves that Victoza and Lantus are better medications to improve blood sugar control when metformin is not enough,” he said.

The problem with the study is that it didn’t include other drugs that were approved by the U.S. Food and Drug Administration when the study began, so there may be more effective drug combinations that are yet to be tested, Zonszein said.

“We need to know what the best combination is for treatment of diabetes early in the disease and not to use the antiquated step-up approach — what to do when the medication fails? We have an excellent choice of medications, and there is no reason to have individuals with diabetes not well-treated,” he added.

And when managing diabetes, treating blood sugar is not the only consideration, Zonszein noted.

“We treat each patient and individualize regimens accordingly. Treatment includes obesity, high cholesterol and hypertension, among others. We aim to improve and prolong a good quality of life,” he said. “For instance, the weight loss found with Victoza is important for many, and not found with the other agents in the study. Victoza’s gastrointestinal side effects are also well-known, and these are decreased when using newer weekly drugs.”

Although blood sugar levels are important, treatment aims to avoid or delay the complications of diabetes, Zonszein said.

Because stroke and heart attack are the common causes of death among diabetes patients, treatment should include medications that prevent heart attack, stroke and other heart and vascular complications, as well as kidney disease.

“The… trial is therefore outdated, and doesn’t help people or their health care providers to make decisions in 2021 — the train has left the station,” Zonszein said.

“Treatment of diabetes has shifted towards individualizing therapy, using proper medications from the get-go. We now use medications that do not cause low blood sugar or need frequent blood sugar checking. Certainly, we use medications that can help with weight loss and cause less cardiovascular complications,” he explained.

Kahn said he is all for individualized treatment for type 2 diabetes. He also wishes that drug companies would do head-to-head trials of the newer drugs to determine the best combination treatment.

Source: HealthDay

Too Many Older Americans Are Taking Daily Aspirin

Amy Norton wrote . . . . . . . . .

Many older adults are still taking a daily baby aspirin to ward off first-time heart problems — despite guidelines that now discourage it, a new study finds.

Researchers found that one-half to 62% of U.S. adults aged 70 and up were using low-dose aspirin to cut their risk of heart disease or stroke. And aspirin use was common even among those with no history of cardiovascular disease — a group for whom the drug may do more harm than good.

The study authors estimated that nearly 10 million Americans who fall into that category are using aspirin.

The numbers are concerning, said senior researcher Dr. Rita Kalyani, an associate professor of medicine at Johns Hopkins University School of Medicine, in Baltimore.

Current guidelines, she said, generally discourage people aged 70 and up from routinely using aspirin to prevent a first-time heart attack or stroke.

That’s, in part, because aspirin is not benign: It carries a risk of bleeding in the gastrointestinal tract or even the brain — risks that typically go up with age. And some recent trials have failed to show that low-dose aspirin really does lower the odds of first-time heart attacks or strokes.

That all may be confusing, and surprising, to people who’ve long believed that aspirin is a heart champion.

“It’s confusing even for health care providers,” said Dr. Wilson Pace, chief medical officer at the DARTNet Institute, in Aurora, Colo.

What is clear, Pace said, is that aspirin can benefit people with known cardiovascular disease — either clogged heart arteries or a history of heart attack or stroke.

Where things get murky is in the prevention of a first-time heart attack or stroke.

Years ago, Pace said, guidelines came out “strongly in favor” of low-dose aspirin for people considered to be at high risk of developing heart disease in the next 10 years (because of risk factors like smoking, high blood pressure or diabetes).

But based on recent studies, the thinking has changed.

Now, the latest guidelines from the American College of Cardiology/American Heart Association say aspirin can be considered for “select” patients aged 40 to 70 who are not at increased risk of bleeding.

When it comes to older adults, the guidelines caution against “routine” aspirin use for primary prevention.

That’s something of a “hedge,” said Pace, since there might be some cases where aspirin is a reasonable choice for an older adult at high risk of cardiovascular trouble.

But for the most part, he said, they do not need the drug for primary prevention.

“If you’re 75 and have diabetes, I wouldn’t start you on aspirin,” Pace said. “I’d go with a statin.”

He noted that statins, which lower LDL (“bad”) cholesterol, “clearly help prevent primary disease.”

Of course, Pace added, many older adults on aspirin actually started taking it years ago. He encouraged those patients to talk with their doctor about whether it’s still necessary.

Pace wrote an editorial published with the study June 21 in JAMA Network Open.

The findings are based on over 7,100 U.S. adults aged 60 and up who took part in a federal health survey.

Among those in their 70s, preventive aspirin use was common: Just under 62% of people with diabetes were using aspirin, as were 48.5% of those without diabetes.

And while some participants did, in fact, have a history of cardiovascular disease, most did not. Yet, their rates of aspirin use were high, the findings showed.

Among all study participants with no risk factors for cardiovascular problems, 20% were taking aspirin. And among those whose only risk factor was diabetes, 43% were on aspirin, according to the report.

But guidelines discourage aspirin use in adults aged 70 and older, Kalyani said, regardless of whether they have diabetes.

Kalyani agreed that older adults who’ve been taking aspirin for years should talk with their doctor about whether it’s still warranted.

Any decision to use preventive aspirin, she said, “has to come down to the individual.” That means patients should talk with their doctor about their personal risk of heart attack or stroke, as well as their risk of bleeding.

It’s also important to consider whether you’re doing other things to curb the risk of cardiovascular trouble — like taking a statin or controlling high blood pressure with medication and lifestyle changes, she added.

Because aspirin is readily available over-the-counter, Pace noted, people may mistakenly assume it’s harmless. But no one should start using it to prevent disease without talking to their doctor first, he said.

Source: HealthDay