Tag: 6/6/24

Categories : Cancer Cardiovascular DiseaseTags :

New Discovery in Preventing Heart Damage from Chemotherapy

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Human heart. Credit: Scientific Animations CC4.0

Blocking a protein known as CDK7 could prevent heart damage associated with the commonly used cancer chemo drug doxorubicin, according to a study led by scientists at Washington State University. Importantly, the researchers also found that inhibiting CDK7 could help enhance the drug’s cancer-killing capability.

Based on an animal model, the study findings could provide a foundation for future treatment strategies to reduce chemotherapy-related heart toxicity and increase treatment effectiveness. This could ultimately help increase the lifespan of people with cancer. Heart damage related to chemotherapy treatment can surface decades after treatment and can result in heart attacks, heart failure, cardiomyopathy and other types of heart disease.

Published in the journal Cardiovascular Research, the WSU study focused on doxorubicin, a chemotherapy drug used to treat breast cancer, lymphoma, leukaemia and other cancers. Capable of killing a wide range of cancer cells, doxorubicin and other similar chemotherapy medications are known to be toxic to the heart. Despite this toxicity, the drug still sees a lot of use.

“Doxorubicin remains the mainstay treatment for certain cancer types for which targeted therapies or other better treatments are not available,” said senior study author Zhaokang Cheng, an associate professor in the WSU College of Pharmacy and Pharmaceutical Sciences.

Cheng has been working to unravel the underlying mechanisms of doxorubicin-induced heart toxicity to make the use of doxorubicin safer for patients who rely on the drug. This new study builds on findings from earlier research that showed that doxorubicin activates a protein known as CDK2. That protein then activates another known as FOXO1, which causes heart cells to die. Cheng’s team collaborated with WSU cancer biology researcher Boyang (Jason) Wu to take a closer look at CDK7, a protein that helps fuel cell growth and has been shown to play a role in the development of cancer.

The researchers found that CDK7 activated CDK2, which set off the chain of molecular signals that eventually led to heart cell death. They also showed that mice that lacked the CDK7 gene were protected from doxorubicin-induced heart toxicity. Next, they used a CDK7 inhibitor drug known as THZ1 to block the protein’s activity and examine the impact on heart health and cancer growth. A similar inhibitor is currently being tested as an anticancer drug in clinical trials, but its effect on the heart is still not clear.

“We are the first to study the effect of THZ1 on the heart and on tumor growth in the same model,” said study first author Jingrui Chen, a WSU research associate. “And what we found is that this CDK7 inhibitor drug can increase heart function and at the same time inhibit tumour growth.”

Though more research is needed, the researchers said their findings suggest that combining doxorubicin and THZ1 could help prevent heart damage and increase the effectiveness of chemotherapy treatment.

The researchers’ next step is to test the effect of THZ1 on heart damage and cancer growth in younger mice and follow them longer. This would more closely mimic long-term doxorubicin-induced heart toxicity seen in childhood cancer survivors. They also plan to look at other proteins that may somehow be involved in the signaling pathway that underlies doxorubicin-related heart damage.

Source: Washington State University

Categories : Antibiotics New Compounds and TreatmentsTags :

New Antibiotic Kills Pathogenic Bacteria but Spares Healthy Gut Microbes

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Gut Microbiome. Credit Darryl Leja National Human Genome Research Institute National Institutes Of Health

Researchers have developed a new antibiotic that reduced or eliminated drug-resistant bacterial infections in mouse models of acute pneumonia and sepsis while sparing healthy microbes in the mouse gut. The drug, called lolamicin, also warded off secondary infections with Clostridioides difficile, and was effective against more than 130 multidrug-resistant bacterial strains in cell culture.

The findings are detailed in the journal Nature.

“People are starting to realise that the antibiotics we’ve all been taking – that are fighting infection and, in some instances, saving our lives – also are having these deleterious effects on us,” said University of Illinois Urbana-Champaign chemistry professor Paul Hergenrother, who led the study with former doctoral student Kristen Muñoz. “They’re killing our good bacteria as they treat the infection. We wanted to start thinking about the next generation of antibiotics that could be developed to kill the pathogenic bacteria and not the beneficial ones.”

“Most clinically approved antibiotics only kill gram-positive bacteria or kill both gram-positive and gram-negative bacteria,” Muñoz said.

The few drugs available to fight gram-negative bacteria, which are protected by their double cell walls, also kill other potentially beneficial gram-negative bacteria. For example, colistin, one of the few gram-negative-only antibiotics approved for clinical use, can cause C. difficile-associated diarrhoea and pseudomembranous colitis, a potentially life-threatening complication. The drug also has toxic effects on the liver and kidney, and “thus colistin is typically utilised only as an antibiotic of last resort,” the researchers wrote.

To tackle the many problems associated with indiscriminately targeting gram-negative bacteria, the team focused on a suite of drugs developed by the pharmaceutical company AstraZeneca. These drugs inhibit the Lol system, a lipoprotein-transport system that is exclusive to gram-negative bacteria and genetically different in pathogenic and beneficial microbes. These drugs were not effective against gram-negative infections unless the researchers first undermined key bacterial defenses in the laboratory. But because these antibiotics appeared to discriminate between beneficial and pathogenic gram-negative bacteria in cell culture experiments, they were promising candidates for further exploration, Hergenrother said.

In a series of experiments, Muñoz designed structural variations of the Lol inhibitors and evaluated their potential to fight gram-negative and gram-positive bacteria in cell culture. One of the new compounds, lolamicin, selectively targeted some “laboratory strains of gram-negative pathogens including Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae,” the researchers found. Lolamicin had no detectable effect on gram-positive bacteria in cell culture. At higher doses, lolamicin killed up to 90% of multidrug-resistant E. coli, K. pneumoniae and E. cloacae clinical isolates.

When given orally to mice with drug-resistant septicemia or pneumonia, lolamicin rescued 100% of the mice with septicemia and 70% of the mice with pneumonia, the team reported.

Extensive work was done to determine the effect of lolamicin on the gut microbiome.

“The mouse microbiome is a good tool for modeling human infections because human and mouse gut microbiomes are very similar,” Muñoz said. “Studies have shown that antibiotics that cause gut dysbiosis in mice have a similar effect in humans.”

Treatment with standard antibiotics amoxicillin and clindamycin caused dramatic shifts in the overall structure of bacterial populations in the mouse gut, diminishing the abundance several beneficial microbial groups, the team found.

“In contrast, lolamicin did not cause any drastic changes in taxonomic composition over the course of the three-day treatment or the following 28-day recovery,” the researchers wrote.

Many more years of research are needed to extend the findings, Hergenrother said. Lolamicin, or other similar compounds, must be tested against more bacterial strains and detailed toxicology studies must be conducted. Any new antibiotics also must be assessed to determine how quickly they induce drug resistance, a problem that arises sooner or later in bacteria treated with antibiotics.

The study is a proof-of-concept that antibiotics that kill a pathogenic microbe while sparing beneficial bacteria in the gut can be developed for gram-negative infections – some of the most challenging infections to treat, Hergenrother said.

Source: University of Illinois at Urbana-Champaign, News Bureau

Categories : Healthcare Politics and RegulationsTags :

SAHPRA Releases Results Of Investigation Following Recall Of Benylin Paediatric Syrup

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Photo by cottonbro studio

On 13 April 2024, the South African Health Products Regulatory Authority (SAHPRA) initiated a precautionary recall of two batches of Benylin Paediatric Syrup (batch numbers 329303 and 329304), in response to reported high levels of diethylene glycol in an alert by the Nigerian National Agency for Food and Drug Administration and Control (NAFDAC). The recall was implemented as a precaution to protect lives while SAHPRA investigated the reported high levels of diethylene glycol.

As the national regulatory authority for health products in South Africa, SAHPRA implements health product recalls as a crucial measure to address safety concerns or quality issues in the interest of public health.

As part of the investigation of the reported high levels of diethylene glycol, SAHPRA tested samples of the two affected batches of Benylin Paediatric syrup through an independent laboratory and a method developed by the World Health Organisation for testing products for the presence of diethylene glycol. The tests did not find traces of diethylene glycol in the recalled batches. This indicates that units of batches 329303 and 329304 that were stored at the required temperature would not contain unacceptable levels of diethylene glycol.

SAHPRA also wishes to indicate that there is no record of any adverse drug reactions relating to diethylene glycol for the two recalled batches in South Africa or anywhere else where they were exported to on the continent.

SAHPRA is mandated to regulate and apply due diligence to health products to ensure that products in circulation in South Africa and those exported from SAHPRA-licensed manufacturers are safe for public consumption. SAHPRA applies this due diligence throughout the product life cycle, from registration through to post-market monitoring.

“SAHPRA will continue to closely monitor medical products that have the potential of containing unacceptable levels of diethylene glycol. And we will continue to address safety concerns or quality issues so that the health of the public is protected,” says SAHPRA CEO, Dr Boitumelo Semete-Makokotlela.

Source: SAHPRA

Categories : HospitalsTags :

Evidence-based Design or Feng Shui in Hospital Rooms might Benefit Patients

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Image-based online study shows no benefits, however, of virtual room designs incorporating the golden ratio

In an online study, virtual hospital rooms designed according to the principles of evidence-based design or the principles of Feng Shui were associated with greater potential benefit for viewers than virtual representations of standard hospital rooms. Emma Zijlstra of Hanze University of Applied Sciences in the Netherlands and colleagues present these findings in the open-access journal PLOS ONE on June 5.

Hospital designers might consider employing specific design principles in an effort to improve patients’ experiences. Growing evidence suggests there are beneficial outcomes from an approach known as evidence-based design. For instance, exposure to more daylight in hospitals is associated with lower stress and pain. Other well-known design approaches include Feng Shui, a Chinese system based on hypothetical energy flow, and the use of proportions following the golden ratio.

Despite these well-known options, experimental evidence on their relative benefits in hospitals is lacking. To help clarify, Zijlstra and colleagues randomly assigned each of 558 study participants to view online representations and information about a virtual hospital room designed with one of four approaches: Feng Shui, the golden ratio, evidence-based design or, as a control, a standard design from a real-life hospital. Only people who had previously been hospitalized at some point in their lives were invited to participate.

After experiencing the virtual rooms, participants completed a questionnaire that included standard measures of anxiety and other outcomes. Statistical analysis of their answers showed that, compared to participants who viewed the standard rooms, those who viewed rooms with evidence-based design reported less anxiety and greater senses of control, social support, distraction from negative thoughts, and pleasantness of the room.

Feng Shui design was not directly associated with lower anxiety, but participants who viewed the Feng Shui rooms did have greater senses of social support, positive distraction, and pleasantness of the room. There was no evidence for any benefits of golden ratio-based design.

On the basis of their findings, the authors suggest that rooms designed according to the principles of evidence-based design or Feng Shui might benefit patients. They note similarities between the two approaches, such as incorporation of greenery. However, they caution, it is unclear how well these online findings might translate to real-life hospital settings.

The authors add: “To our knowledge, this is the first and largest randomized controlled trial linking design principles, partly ancient and world-renowned, directly to anxiety in hospital rooms. This study showed that both Feng Shui and Evidence-Based Design are capable in effecting anxiety and it is important that large follow-up studies are conducted to examine the effect of specific design features.”

Provided by PLOS