Author: patienttalk

Posted on Pain Management

Killing pain without hurting the body: Novel compound that is potentially safer than current drugs

Pharmacodynamics and Pharmacokinetics of AD732: A Novel Pyrazole Derivative

Novel compound “AD732” shows analgesic and anti-inflammatory properties, but with fewer side effects than standard non-steroidal painkillers CREDIT Ritsumeikan University, Japan

Muscular pain, osteoarthritis, inflammatory bowel disease, and headaches have something in common—they are the result of various inflammatory processes that occur inside our body. The standard treatment, among other recourses, includes administration of non-steroidal anti-inflammatory drugs (NSAIDs). By inhibiting either of the enzymes (cyclooxygenase-1 or -2, also known as COX-1/COX-2) present in abundance at biological sites of inflammation, NSAIDs minimize pain and combat inflammation. But there’s a flip side—they can also cause serious side effects that result in heart failure, kidney malfunction, and stomach ulceration. It appears that to kill pain, we hurt our bodies.

This is why, for some time, efforts have been directed at finding safer non-steroidal anti-inflammatory and analgesic drugs. Most recently, a compound labeled AD732 has been synthesized, which shows promise in this direction. Now, in a new study published in the European Journal of Pharmaceutical Sciences (paper made available online on November 21, 2021, and published in Volume 168 of the journal on January 1, 2022), researchers led by Dr. Kikuko Amagase from Ritsumeikan University, Japan, and Prof. Adnan A. Bekhit, from the University of Alexandria, Egypt, have explored the therapeutic efficacy and side effects of this compound in rat models. “In a previous study, we synthesized this compound AD732. In this study, we compared it with two standard pharmaceutical drugs—indomethacin, a prototype NSAID, and celecoxib, a COX-2 inhibitor.” explains Dr. Amagase. “We aimed to assess its efficacy and adverse effects while relieving both acute and chronic pains.”

The researchers tested AD732’s anti-inflammatory properties in rat models of paw edema and granuloma. They tested its analgesic properties in a rat model of hyperalgesia and with hot plate tests, where a rat is placed on a temperature-controlled heated plate and its responses are monitored for signs of pain. The results were encouraging. AD732 showed higher anti-inflammatory and analgesic effects than the standard agents, while showing no ulcerogenic effects and causing minimal harm to kidney function.

Further, upon in vitro investigation of its mechanism of action, the scientists found that AD732 was a less potent inhibitor of COX-2 than celecoxib, which may indicate a lower potential for cardiovascular toxicity. Their inference is premised on prior studies, where highly potent COX-2 inhibitors have been noted to cause serious cardiac damage. For instance, rofecoxib (popularly known by the brand names “Vioxx,” “Ceoxx,” and “Ceeoxx”), a selective COX-2 inhibitor, drew flak from the New England Journal of Medicine for significantly increasing the risk of heart attacks and was subsequently withdrawn from the market in 2004.

But despite being a less selective inhibitor of COX-2, AD732 had proved very therapeutically effective, as previously mentioned, particularly in inhibiting rat paw edema. This seems, to an extent, to be counterintuitive. Dr. Bekhit muses, “Our findings on AD732’s lower COX-2 inhibition could indicate that this is not the sole mechanism contributing to its anti-inflammatory actions.” Further in-depth research is needed to determine its precise mechanism of action.

Nevertheless, as Dr. Amagase explains, “It may be concluded that compound AD732 appears to be a safer and more effective molecule with promising potential for the management of pain and inflammation, even in difficult diseases such as ulcerative colitis and Crohn’s disease.”  Perhaps, soon, we will be able to kill pain without hurting our bodies.

Posted on Diabetes

Gap in diabetes technology use among Black and white Medicare beneficiaries is worsening

Black Patients with RA Less Likely to Receive a Biologic, More Likely to Be Treated with Glucocorticoids Than Whites


The gap in the use of insulin pumps and continuous glucose monitors (CGMs) among Black and white Medicare beneficiaries widened from 2017-2019, according to new research published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.

Reducing health disparities is a major public health goal in the United States, and these disparities include the use of diabetes technology. All Medicare beneficiaries with type 1 diabetes should have equal access to diabetes therapy, but research shows there are inequities associated with race and ethnicity.

“This study highlights the complexity of the causes of health disparities in diabetes. Previous studies in non-Medicare beneficiaries point to socio-economic status as the key driver of unequal adoption of diabetes technology, but our study shows many other contributing factors,” said Robert Vigersky, M.D., Chief Medical Officer of medical device manufacturer Medtronic Diabetes in Northridge, Calif. “Other factors include unconscious bias among healthcare providers who may feel that people of color may not be able to use these technologies. In addition, there are cultural barriers, low health literacy and limited access to healthcare, particularly to endocrinologists.”

The researchers determined the prevalence of diabetes technology use by race and ethnicity using data from the Medicare fee-for-service database between 2017-2019. They found CGM and insulin pump use grew among all groups between 2017-2019, but the increase was greatest for white patients.

The prevalence of insulin pump use was low for Black beneficiaries in 2017 and slightly increased from 2017 to 2019 (from 3.9% to 4.6%). It was higher in 2017 for white beneficiaries and increased substantially from 2017 to 2019 (from 14.0% to 18.2%). About 25% of white beneficiaries were using CGMs in 2019, compared to 12% of Black beneficiaries – a gap that has widened since 2017.

“We need to address the social determinants of health, including race and ethnicity, before all aspects of diabetes care become more equitable,” said Vigersky, who is Past President of the Endocrine Society.

Posted on Diabetes, Exercise

Uncovered: Key to how exercise protects against consequences of ageing

Staining showing mitochondria within individual muscle fibres.


Staining showing mitochondria within individual muscle fibres. CREDIT Monash University

Monash University, Australia scientists have discovered an enzyme that is key to why exercise improves our health. Importantly this discovery has opened up the possibility of drugs to promote this enzyme’s activity, protecting against the consequences of ageing on metabolic health, including type 2 diabetes.

The proportion of people worldwide over 60 years old will double in the next three decades and by 2031, more than six million Australians will be over 65 years old. The incidence of type 2 diabetes increases with age so this ageing population will also result in an increased incidence of the disease globally.

One of the main reasons for the increased prevalence of type 2 diabetes with age is the development of insulin resistance, or an inability for the body to respond to insulin, and this is often caused by reduced physical activity as we age.

However, the precise mechanisms by which physical inactivity facilitates the development of insulin resistance has remained a mystery. 

Now researchers from Monash University in Australia have discovered how physical activity actually enhances insulin responsiveness and in turn promotes metabolic health. Importantly, the enzymes they have discovered that are key to this mechanism have the potential to be targeted by drugs to protect against consequences of ageing such as muscle wasting and diabetes.

The team of scientists at the Monash University Biomedicine Discovery Institute (BDI), led by Professor Tony Tiganis, reveals that reductions in skeletal muscle reactive oxygen species (ROS) generation during ageing is instrumental in the development of insulin resistance. According to Professor Tiganis, skeletal muscle constantly produces ROS and this is increased during exercise. 

“Exercise-induced ROS drives adaptive responses that are integral to the health-promoting effects of exercise,” he said. 

In a paper published today (15 December) in the journal, Science Advances, the research team show how an enzyme called NOX-4 is essential for exercise-induced ROS and the adaptive responses that drive metabolic health.

In mice the researchers found that NOX4 is increased in skeletal muscle after exercise and that this then leads to increased ROS which elicits adaptive responses that protect mice from the development of insulin resistance, which otherwise occurs with ageing or diet induced-obesity. 

Importantly, the scientists have shown that the levels of NOX4 in skeletal muscle are directly related to age-associated decline in insulin sensitivity.  “In this study we have shown, in animal models, that skeletal muscle NOX 4 abundance is decreased with ageing and that this leads to a reduction in insulin sensitivity,” Professor Tiganis said.

“Triggering the activation of the adaptive mechanisms orchestrated by NOX4  with drugs, might ameliorate key aspects of ageing, including the development of insulin resistance and type 2 diabetes,” he said. 

“One of these compounds is found naturally, for instance, in cruciferous vegetables, such as broccoli or cauliflower, though the amount needed for anti-ageing effects might be more than many would be willing to consume.” 

Posted on Arthritis

Stopping arthritis before it starts

Frank Petrigliano and Denis Evseenko


Frank Petrigliano, MD, (left) and Denis Evseenko, MD, PhD CREDIT USC Photo/ Photo by Ricardo Carrasco III

More than a million Americans undergo knee and hip replacements each year. It’s a last resort treatment for pain and mobility issues associated with osteoarthritis, a progressive disease caused by degeneration of the protective layer of cartilage that stops our bones grinding together when we sit, stand, write, or move around.

But what if doctors could intervene and repair damaged cartilage before surgery is needed?

For the first time, researchers at the Keck School of Medicine of USC have used a stem cell-based bio-implant to repair cartilage and delay joint degeneration in a large animal model. The work will now advance into humans with support from a $6 million grant from the California Institute of Regenerative Medicine (CIRM).

The research, recently published in npj Regenerative Medicine, was led by two researchers at the Keck School of Medicine of USC – Denis Evseenko, MD, PhD, associate professor of orthopaedic surgery, director of the skeletal regeneration program, and vice chair for research of orthopaedic surgery; and Frank Petrigliano, MD, associate professor of clinical orthopaedic surgery and chief of the USC Epstein Family Center for Sports Medicine.

Osteoarthritis occurs when the protective cartilage that coats the ends of the bones breaks down over time, resulting in bone-on-bone friction. The disorder, which is often painful, can affect any joint, but most commonly affects those in our knees, hips, hands and spine. 

To prevent the development of arthritis and alleviate the need for invasive joint replacement surgeries, the USC researchers are intervening earlier in the disease.

“In some patients joint degeneration starts with posttraumatic focal lesions, which are lesions in the articular (joint) cartilage ranging from 1 to 8 cm2 in diameter,” Evseenko said. “Since these can be detected by imaging techniques such as MRI, this opens up the possibility of early intervention therapies that limit the progression of these lesions so we can avoid the need for total joint replacement.”

That joint preservation technology developed at USC is a therapeutic bio-implant, called Plurocart, composed of a scaffold membrane seeded with stem cell-derived chondrocytes—the cells responsible for producing and maintaining healthy articular cartilage tissue. Building on previous research to develop and characterize the implant, the current study involved implantation of the Plurocart membrane into a pig model of osteoarthritis. The study resulted in the long-term repair of articular cartilage defects.

“This is the first time an orthopaedic implant composed of a living cell type was able to fully integrate in the damaged articular cartilage tissue and survive in vivo for up to six months,” Evseenko said. “Previous studies have not been able to show survival of an implant for such a long time.”

Evseenko said molecular characterization studies showed the bio-implant mimicked natural articular cartilage, with more than 95 percent of implanted cells being identified as articular chondrocytes. The cartilage tissue generated was also biomechanically functional—both strong enough to withstand compression and elastic enough to accommodate movement without breaking.

With support from the $6 million translational grant from CIRM, the researchers are using this technology to manufacture the first 64 Plurocart implants to be tested in humans.

“Many of the current options for cartilage injury are expensive, involve complex logistical planning, and often result in incomplete regeneration,” said Petrigliano. “Plurocart represents a practical, inexpensive, one-stage therapy that may be more effective in restoring damaged cartilage and improve the outcome of such procedures.”

Posted on Multiple Sclerosis

New insights into impact of multiple sclerosis treatments on Covid-19 vaccine effectiveness

Treatments used to help people with multiple sclerosis (MS) manage their condition can reduce the effectiveness of Covid-19 vaccines, according to research from Cardiff University and Queen Mary University of London.

Disease-modifying therapies (DMTs) are a group of treatments for people with MS and affect the immune system. As vaccines work by triggering the body to produce an immune response, it was suspected that some DMTs could reduce the effectiveness of Covid-19 vaccines. The study, published in the journal Annals of Neurology, provides the largest peer-reviewed, published evidence of the effect of DMTs on immune responses to Covid-19 vaccines.

It is hoped this new information will better equip clinicians to provide guidance to people with MS on treatment options.  

The research team studied almost 500 people with MS and used a technique known as dried blood spot sampling to investigate the effects of DMTs on Covid-19 vaccine effectiveness. This approach reduced study costs as well as the need for potentially vulnerable patients to attend the clinic during the pandemic.

The findings show that people with MS taking either of two specific DMTs, fingolimod and ocrelizumab, were less likely to produce antibodies in response to AstraZeneca and Pfizer Covid-19 vaccines than people with MS not taking any DMT. If they did produce antibodies, the levels were lower than those found in people taking other DMTs, or not taking any DMT at all.  However, the researchers found that other DMTs, including some that are highly effective for MS treatment, had no detrimental effect on Covid-19 vaccine response. 

Immune cells, such as T-cells, are also an important part of our immune response to vaccines or viruses. The researchers studied T-cell responses in a small group of study participants who failed to mount an adequate antibody response to Covid-19 vaccination. They found that overall, 40 per cent of this group were able to produce a strong T-cell response, despite having a poor antibody response.

“People with MS have faced uncertainty during the Covid-19 pandemic as a direct result of their condition and the treatments they take to manage it,” says Dr Ruth Dobson, Clinical Senior Lecturer in Neurology at Queen Mary.

“Our study provides high-quality evidence that will support clinicians to advise people with MS on treatment options considering the Covid-19 pandemic. However, further trials are essential to help us understand how best to balance the risks of potentially suspending or delaying MS treatment with the need to effectively vaccinate people with MS against Covid-19.”

Dr Emma Tallantyre, Clinical Senior Lecturer in Neurology at Cardiff University, adds: “Questions about the Covid vaccine are among the most common we are currently facing from people with MS in our clinics. Highlighting groups who have mounted an inadequate Covid vaccine response has already been helpful in guiding who should receive additional doses of the vaccine, and who may need to continue to take additional infection-prevention precautions over the winter. We hope further work will allow us to individualise our management, to protect people with MS from Covid, while keeping their MS under control.”

Jo Welton, 38 was diagnosed with relapsing MS in 2009. She is a medical writer from South Wales. Day-to-day Jo mainly experiences fatigue, weakness, and pain in her left leg. She has been on disease modifying treatment (DMT) Gilenya for nearly eight years. She joined the study after being told about it by her MS team. Since, despite having two AstraZeneca vaccinations she has been told she has reduced immunity to COVID-19 and is waiting to find out if her booster vaccination has worked.

Jo says: “I have a scientific background so was interested in the study as soon as I heard about it. It was also important for me to know how much immunity I had as this impacts my day-to-day living. I’ve followed the guidelines about DMTs and MS right from the start, so this has meant I’ve been shielding for over 20 months. It’s been so difficult seeing everyone getting back to some sort of normality and not feeling like I was able to. I feel vulnerable and, although it’s not deliberate, left behind.

“Ignorance is bliss for some people, but it’s not a risk I want to take. I lost my Grandma to the virus earlier this year – this has made it even more important for me to take the necessary steps to mitigate the risk. Knowing I don’t have immunity means I can continue working remotely, socially distance, and ask friends and family to get their booster vaccine and do lateral flow tests when we meet. Having MS is hard enough without getting COVID-19 as well.”

Dr Clare Walton, Head of Research at the MS Society, says: “This is the largest published study looking at the relationship between certain high intensity disease modifying treatments (DMTs) and the AstraZeneca and Pfizer Covid-19 vaccines. It found some people with MS on these DMTs had a significantly reduced immune response to the vaccine compared to people not taking any.

“While this doesn’t mean these patients are necessarily at higher risk of severe illness if they catch COVID-19, it will be worrying for some. It’s vital that people with weakened immune systems are better supported to protect themselves from the virus, including a right to work from home and feeling assured that the general public are doing everything they can to help keep them safe. We also advise people with MS on these DMTs not to alter their treatment without speaking to someone from their MS healthcare team.”