Three decades-old antibiotics could offer an alternative to opioid-based painkillers

Three decades-old antibiotics administered together can block a type of pain triggered by nerve damage in an animal model, UT Southwestern researchers report. The finding, published online today in PNAS, could offer an alternative to opioid-based painkillers, addictive prescription medications that are responsible for an epidemic of abuse in the U.S.

Over 100 million Americans are affected by chronic pain, and a quarter of these experience pain on a daily basis, a burden that costs an estimated $600 billion in lost wages and medical expenses each year. For many of these patients – those with cancer, diabetes, or trauma, for example – their pain is neuropathic, meaning it's caused by damage to pain-sensing nerves.

To treat chronic pain, prescriptions for opioid painkillers have increased exponentially since the late 1990s, leading to a rise in abuse and overdoses. Despite the desperate need for safer pain medications, development of a new prescription drug typically takes over a decade and more than $2 billion according to a study by the Tufts Center for the Study of Drug Development, explains study leader Enas S. Kandil, M.D., associate professor of anesthesiology and pain management at UTSW.

Seeking an alternative to opioids, Kandil and her UT Southwestern colleagues – including Hesham A. Sadek, M.D., Ph.D., professor of internal medicine, molecular biology, and biophysics; Mark Henkemeyer, Ph.D., professor of neuroscience; Mahmoud S. Ahmed, Ph.D., instructor of internal medicine; and Ping Wang, Ph.D., a postdoctoral researcher – explored the potential of drugs already approved by the Food and Drug Administration (FDA).

The team focused on EphB1, a protein found on the surface of nerve cells, which Henkemeyer and his colleagues discovered during his postdoctoral training nearly three decades ago. Research has shown that this protein is key for producing neuropathic pain. Mice genetically altered to remove all EphB1 don't feel neuropathic pain, he explains. Even mice with half the usual amount of this protein are resistant to neuropathic pain, suggesting EphB1's promise as a target for pain-relieving drugs. Unfortunately, no known drugs inactivate EphB1.

Exploring this angle further, Ahmed used computer modeling to scan a library of FDA-approved drugs, testing if their molecular structures had the right shape and chemistry to bind to EphB1. Their search turned up three tetracyclines, members of a family of antibiotics used since the 1970s. These drugs – demeclocycline, chlortetracycline, and minocycline – have a long history of safe use and minimal side effects, Ahmed says.

To investigate whether these drugs could bind to and inactivate EphB1, the team combined the protein and these drugs in petri dishes and measured EphB1's activity. Sure enough, each of these drugs inhibited the protein at relatively low doses. Using X-ray crystallography, Wang imaged the structure of EphB1 with chlortetracycline, showing that the drug fits neatly into a pocket in the protein's catalytic domain, a key portion necessary for EphB1 to function.

In three different mouse models of neuropathic pain, injections of these three drugs in combination significantly blunted reactions to painful stimuli such as heat or pressure, with the triplet achieving a greater effect at lower doses than each drug individually. When the researchers examined the brains and spinal cords of these animals, they confirmed that EphB1 on the cells of these tissues had been inactivated, the probable cause for their pain resistance. A combination of these drugs might be able to blunt pain in humans too, the next stage for this research, says Kandil.

Unless we find alternatives to opioids for chronic pain, we will continue to see a spiral in the opioid epidemic. This study shows what can happen if you bring together scientists and physicians with different experience from different backgrounds. We're opening the window to something new."

Enas S. Kandil, M.D., Associate Professor, Anesthesiology and Pain Management, UT Southwestern

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UT Southwestern Medical Center

Posted in: Medical Science News | Medical Research News | Pharmaceutical News

Tags: Anesthesiology, Animal Model, Antibiotic, Cancer, Cardiology, Chronic, Chronic Pain, Crystallography, Diabetes, Drugs, Education, heat, Medicine, Minocycline, Molecular Biology, Nerve, Neuropathic Pain, Neuroscience, Opioids, Pain, Pain Management, pH, Prescription Drug, Protein, Receptor, Research, Tetracycline, Trauma, X-Ray

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Analysis finds racial and ethnic disparities in the odds of testing positive for COVID-19

An analysis of Kaiser Permanente members in Northern California early in the COVID-19 pandemic found racial and ethnic disparities in the likelihood of testing positive for the coronavirus, but no significant disparities in mortality among those who were hospitalized.

According to the study published Feb. 8 in Annals of Internal Medicine, Latino patients were nearly 4 times as likely as white patients to become infected with the virus, while Asian and Black patients were 2 times as likely to get COVID-19 as white patients. The odds of hospitalization were also higher for Latino, Asian, and Black patients with COVID-19 than for white patients. However, the study did not find racial disparities in mortality among patients hospitalized after infection.

The authors of the study said the findings reinforce the urgent message to health systems to mitigate the spread of COVID-19 in their highest-risk communities by seeking to reduce transmission among the most vulnerable.

"We need to continue to explore the reasons why some communities have higher infection rates, which in a pandemic can be deadly," said lead author Gabriel Escobar, MD, an investigator with the Kaiser Permanente Northern California Division of Research. "It's also our responsibility as clinicians and health care leaders to improve the way we reach out to these communities."

While research from other health systems has also found racial disparities related to COVID-19, this analysis was the first to follow a cohort of patients from virus testing through the complete course of the disease, the authors said.

"COVID-19 has dramatically altered the patterns of health care delivery across the world making it more difficult than ever to trace patients' experiences and outcomes," said coauthor Vincent Liu, MD, MS, a research scientist with the Northern California Division of Research and critical care specialist with The Permanente Medical Group. "Kaiser Permanente's comprehensive health data from testing to medical care and hospitalization allow us to carefully assess the impact of racial and ethnic differences at each stage."

The study examined a total of 3.5 million Kaiser Permanente members in Northern California, 2.6% of whom, or 91,212 people, received a COVID-19 test between Feb. 1 and May 31, 2020. Of the total, 4%, or 3,686, tested positive.

The study confirmed other research linking specific comorbidities with increased mortality from COVID-19, and that nonwhite patients were more likely to have chronic health conditions. However, the authors noted that there are complex reasons why that might be. "Many factors may contribute to comorbidity and intrinsic risk, including the totality of ways in which societies foster racial discrimination, through mutually reinforcing inequitable systems (structural racism)," they wrote.

Unadjusted hospital mortality rates were highest among white patients (17%), followed by Black patients (12.7%), Asian patients (10.5%), and Hispanic patients (9.7%). After adjusting for age, severity of illness, and comorbidities, racial and ethnic differences were no longer significantly different.

Neighborhood and age as risk factors

Along with following the outcomes for those who tested positive, the analysis also looked at the role of geographic location, finding infections clustered in areas with higher proportions of nonwhite members, regardless of their health risks for COVID-19.

The researchers found race was a major factor in likelihood of infection, but contributed in a minor way to hospitalization, admission, and death. For those adverse outcomes, age was the major predictor.

The findings bring an important message to health care leaders, said coauthor Stephen Parodi, MD, associate executive director of The Permanente Medical Group and national infectious disease leader at Kaiser Permanente. "Health care systems are in a position to take action in their communities in response to these inequities," Dr. Parodi said. "Specifically, we must continue to pursue initiatives such as community education, contact tracing, and public health partnerships. We are deepening community connections to address social determinants in response to an unprecedented health threat that is taking an unequal toll."

Clinicians also have a role in reducing inequities, and Kaiser Permanente has taken steps to support clinicians in doing so, said coauthor Yi-Fen "Irene" Chen, MD, associate executive director of The Permanente Medical Group. "The pandemic has moved many medical visits to telehealth, which has many benefits, but we must remain aware of the digital divide that could make this technology harder to access in some traditionally underrepresented communities," Dr. Chen said. "Addressing such issues is part of Kaiser Permanente's longstanding commitment to health equity."

Dr. Chen noted the importance of addressing equity in vaccination. "Now that COVID-19 vaccines are available, physicians and health care providers must employ culturally tailored messaging for communities that experience health disparities, to make sure they are optimally informed and protected," she said.

Source:

Kaiser Permanente

Posted in: Medical Research News | Disease/Infection News | Healthcare News

Tags: Chronic, Chronic Disease, Coronavirus, Critical Care, Education, Health Care, Health Disparities, Health Systems, Hospital, Medicine, Mortality, Pandemic, Public Health, Research, Virus

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Fostamatinib in chronic immune thrombocytopenia: No comparison—added benefit not proven

Fostamatinib is approved for the treatment of chronic immune thrombocytopenia in adults who are refractory to other treatments (in particular to treatment with corticosteroids). The German Institute for Quality and Efficiency in Health Care (IQWiG) examined in an early benefit assessment whether fostamatinib offers an added benefit for these patients in comparison with eltrombopag or romiplostim.

The drug manufacturer recognized both drugs as appropriate comparator therapy, but presented neither direct nor indirect comparisons between fostamatinib and the appropriate comparator therapy. IQWiG therefore concluded that an added benefit is not proven.

Comparisons with appropriate comparator therapy necessary

The approval studies, the data of which the manufacturer cited in its dossier, compared fostamatinib with placebo. Randomized controlled trials with direct comparisons between fostamatinib and eltrombopag or romiplostim are not available. The manufacturer did not identify any suitable data for an adjusted indirect comparison.

Comparisons with the appropriate comparator therapy are necessary, however, to understand the benefit and harm that the different treatment options have for the patients in relation to each other. They are the backbone of the early benefit assessment: There is no other way to determine an added benefit of the drug in comparison with the current standard treatment.

G-BA decides on the extent of added benefit

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