Colourised scanning electron micrograph of a breast cancer cell. Credit: NIH
A novel therapeutic approach that combines human epidermal growth receptor factor 2 (HER2)-targeted therapies with the cholesterol-lowering drug lovastatin can reduce the number of cancer treatments required to prevent tumour growth. Monitored by immuno-PET scans, this combination therapy has the potential to personalise treatment for cancer patients and spare them from harmful side effects. This research was published in The Journal of Nuclear Medicine.
Antibody-drug conjugates (ADCs) have become an eminent cancer treatment because of their ability to precisely target tumours with potent efficacy. HER2-ADC therapies have been effective in treating breast, lung, bladder, and stomach cancers. Although usually well-tolerated, multiple doses of the drugs can result in severe side effects, including low blood counts, liver damage, and lung damage. Strategies that reduce toxic side effects caused by ADCs and predictive biomarkers of ADC toxicity are currently an unmet clinical need.
“In this study, we sought to determine whether a single dose of HER2-ADCs could be administered in combination with lovastatin (which temporarily elevates cell-surface HER2) to achieve therapeutic efficacy similar to that of a multiple dose regime,” said Patricia Pereira, PhD, assistant professor at the Washington University School of Medicine. “We also used HER2-targeted immuno-PET to monitor changes in HER2 expression after ADC therapy.”
Researchers injected mice with cultured gastric cancer cells and patient-derived gastric cancer cells. When tumours grew sufficiently, the mice were divided into groups and received various treatment schedules (no treatment, multiple doses of ADC, multiple doses of ADC with lovastatin, single dose of ADC, or single dose of ADC with lovastatin). Immuno-PET was used to investigate the dosing regimen and the efficacy of the treatment schedules.
A single dose of ADC therapy combined with lovastatin was found to reduce tumour volume at rates similar to those resulting from multiple doses of ADC in a preclinical setting. The study results showed that immuno-PET can noninvasively monitor HER2 tumour levels after treatment with HER2-targeted ADC therapies.
“This preclinical work is significant because it has the potential to improve therapy for patients with HER2-positive cancers,” noted Pereira. “It not only simplifies treatment by exploring single-dose schedules of antibody-drug conjugates but can also reduce side effects by minimizing the number of doses required. Additionally, it personalises therapy using molecular imaging, enhancing treatment efficacy.”
She continued, “The findings suggest a future where molecular imaging techniques play a critical role in guiding drug development and cancer treatment decisions, particularly as various ADCs are being tested and approved for cancer treatment. Currently, there is no perfect way to select tumours or monitor their response to ADCs. This research indicates that molecular imaging can bridge this gap by providing real-time insights into therapy response.”
Research on long-term memories has largely focused on the role of neurons but in recent years, research is revealing that other cell types are also vital in memory formation and storage. A new study reveals the crucial role of vascular system cells (pericytes) in the formation of long-term memories of life events – memories that are lost in diseases such as Alzheimer’s. The research, published in the journal Neuron, shows that pericytes, which wrap around the capillaries work in concert with neurons to help ensure that long-term memories are formed.
Pericytes help maintain the structural integrity of the capillaries. Specifically, they control the amount of blood flowing in the brain and play a key role in maintaining the barrier that stops pathogens and toxic substances from leaking out of the capillaries and into brain tissue.
“We now have a firmer understanding of the cellular mechanisms that allow memories to be both formed and stored,” says Cristina Alberini, a professor in New York University’s Center for Neural Science and the paper’s senior author. “It’s important because understanding the cooperation among different cell types will help us advance therapeutics aimed at addressing memory-related afflictions.”
“This work connects important dots between the newly discovered function of pericytes in memory and previous studies showing that pericytes are either lost or malfunction in several neurodegenerative diseases, including Alzheimer’s disease and other dementia,” explains author Benjamin Bessières, a postdoctoral researcher in NYU’s Center for Neural Science.
The discovery, reported in the new Neuron article, of the pericytes’ significance in long-term memory emerged because Alberini, Bessières, Kiran Pandey, and their colleagues examined the role of insulin-like growth factor 2 (IGF2) – a protein that was known to increase following learning in brain regions, such as the hippocampus, and to play a critical role in the formation and storage of memories.
They found that IGF2’s highest levels in the brain cells of the hippocampus do not come from neurons or glial cells, or other vascular cells, but, rather, from pericytes.
A cheap and widely available prescription drug can improve symptoms of irritable bowel syndrome in patients seen in GP surgeries, according to research findings published in The Lancet and presented today at UEG Week 2023.
Amitriptyline, a tricyclic which is commonly used at low doses for a range of health concerns, has been found to improve irritable bowel syndrome (IBS) symptoms too, according to the results of the ATLANTIS trial.
The study was conducted in primary care, with GPs prescribing the drug and patients managing their own dose based on the severity of their symptoms, using an adjustment document designed for the trial. Most people with IBS are seen and managed in primary care by their GP, which means that the results of this trial are likely to be applicable to many people with the condition.
Led by researchers at the Universities of Leeds, Southampton, and Bristol and funded by the National Institute for Health and Care Research (NIHR), the study showed that patients taking amitriptyline were almost twice as likely to report an overall improvement in symptoms as those taking a placebo.
Now the trial team is recommending that GPs support their patients with IBS to use amitriptyline to manage their symptoms – and has made the dose adjustment document available for clinicians and patients.
Co-chief Investigator Alexander Ford, Professor of Gastroenterology in the University of Leeds’s School of Medicine, said: “Amitriptyline is an effective treatment for IBS and is safe and well tolerated. This new rigorously conducted research indicates that general practitioners should support patients in primary care to try low-dose amitriptyline if their IBS symptoms haven’t improved with recommended first-line treatments.”
Most treatments for IBS, which affects around 1 in 20 people, only have a modest effect and people often have ongoing troublesome symptoms.
Amitriptyline was originally used at high doses to treat depression, but is now superseded by newer and better antidepressants.
Previous small trials of low-dose tricyclic antidepressants for IBS suggested a possible benefit in patients seen in hospital clinics, who often have more difficult to treat symptoms, but this new study is the first randomised controlled trial of low-dose amitriptyline versus a placebo tablet for IBS in primary care. It is also the largest trial of amitriptyline for IBS undertaken worldwide.
GPs already prescribe low-dose amitriptyline to treat chronic nerve and back pain, and to help prevent migraine attacks. NICE guidelines currently state that GPs could consider using a low dose tricyclic, like amitriptyline, for IBS but, until now, the evidence for a benefit has been uncertain.
Based on the results of the trial, which showed a clear benefit of amitriptyline, GPs can offer low-dose amitriptyline to people with IBS as part of shared decision making if symptoms don’t improve with first-line treatments.
Co-chief Investigator Hazel Everitt, Professor of Primary Care Research at the Primary Care Research Centre, University of Southampton, said: “Prior to ATLANTIS, GPs haven’t often prescribed amitriptyline for IBS as the research evidence was uncertain, but our new research provides good evidence of benefit.
“GPs already prescribe low-dose amitriptyline for other conditions, such as chronic pain and poor sleep, and when we interviewed GPs as part of this research, they were willing to prescribe it for IBS if the research evidence supported this. Participants were also keen to have another option to try to help their IBS symptoms and most were happy to self-adjust their dose depending on symptoms and side effects.’’
Some 463 people with IBS took part, recruited from 55 general practices across the UK.
Participants were put at random into two groups – those receiving amitriptyline and those receiving a placebo. Participants controlled how many tablets of the trial medication they took, receiving support via the patient dose adjustment document that was developed with patient representatives especially for this trial. This enabled participants to increase or decrease the number of tablets based on their IBS symptoms and any side effects experienced.
IBS scores were measured using the IBS-SSS scale. Amitriptyline participants scored a 99-point improvement compared with a 69-point improvement among placebo participants.
Participants taking amitriptyline reported a bigger improvement in their symptom scores after six months compared with those taking a placebo. Those taking amitriptyline were almost twice as likely as those taking a placebo to report an overall improvement in IBS symptoms, with amitriptyline performing better across a wide range of IBS symptom measures.
Researchers monitored participants’ anxiety or depression scores and found that they were not altered – suggesting that the beneficial effects of the medication were via the gut, not because of any effect as an antidepressant.
No safety concerns were identified and side effects in people on amitriptyline were mostly mild, such as a dry mouth in the morning.
Matthew Ridd, GP and Professor of Primary Health Care at the Centre for Academic Primary Care, University of Bristol, said: “Pragmatic trials like this are always challenging to do in primary care and the team worked hard to overcome the additional challenges of the Covid-19 pandemic. It’s fantastic that we’ve found that amitriptyline is an effective and safe option for patients with IBS to try.”
Amanda Farrin, Professor of Clinical Trials and Evaluation of Complex Interventions, who leads the Complex Intervention Division of the Leeds Clinical Trials Research Unit, said: “The participants in the ATLANTIS trial had moderate to severe symptoms and an average duration of IBS of 10 years. The fact that amitriptyline had such a big effect over a placebo is significant because it can help improve the quality of life of patients with this condition.”
Professor Andrew Farmer, Director NIHR’s Health Technology Assessment (HTA) Programme, said: “The results of this study are hugely encouraging. It shows that a drug already widely available to treat a number of other conditions appears to be safe and effective for people with IBS. The findings the research team have shared around the adjustment of dosages can be tremendously helpful to GPs in guiding them when treating patients.
“IBS affects a significant number of people in the UK and can have a debilitating effect on their day-to-day lives. This is another excellent example of how high-quality research can lead to positive changes in health and social care practice and treatments for the benefit of patients and healthcare professionals.”
A three-year clinical trial has shown that the sublingual immunotherapy (SLIT) is safe in peanut-allergic children ages one to four, with a greater likelihood of desensitisation and remission the earlier the treatment began. SLIT approach where the treatment is given as a small amount of liquid under the tongue, instead of peanut flour that is mixed with other food and then eaten like it is during oral immunotherapy, or OIT.
Published in the Journal of Allergy and Clinical Immunology, this is the first randomised, controlled trial to investigate – in this young age group – the efficacy and feasibility of SLIT.
The study included 50 peanut-allergic children between the ages of one and four, randomised to receive 4mg peanut SLIT versus placebo. Participants were randomised 1:1 to receive either peanut SLIT or placebo. Desensitization to peanut was assessed by double-blind, placebo-controlled food challenge (DBPCFC) after three years of treatment.
Findings showed that peanut SLIT can be highly effective in treating peanut-allergic toddlers with almost 80% tolerating 15 peanuts without allergic symptoms after completing the treatment. With most typical peanut-allergic reactions being caused by one peanut or less, these results would translate into strong protection against exposures to peanut. In addition, researchers showed that remission of the peanut allergy may be possible after peanut SLIT with 63% of the toddlers maintaining their protection three months after stopping the treatment. These new findings show that early intervention with peanut SLIT is promising and warrants further development.
Led by Edwin Kim, MD, associate professor of paediatrics at the UNC School of Medicine, said: “From our prior studies in older children, we were optimistic that peanut SLIT could have a similar treatment effect in toddlers.
“However, what we found was even better. The desensitisation levels we saw were higher than expected and on par with levels we normally would only expect with oral immunotherapy. Just as important, rather than wearing off quickly, we were excited to see that over 60% stayed protected three months after stopping the treatment.”
One of the presumed strengths of the SLIT approach when compared to OIT has been its overall safety and simple administration. While most treatment side effects with OIT are mild to moderate, severe reactions requiring emergency treatment do occur and there remains a critical need to develop treatments with more manageable side effects.
“Peanut OIT is currently available and being offered by increasing numbers of allergists, however we are quickly learning that in addition to its known risk of allergic reactions, the actual doing of OIT can be very difficult for many families,” said Kim. “Peanut SLIT could be a good option to consider as it may be able to provide comparable levels of protection while being safe and easier to administer.”
Compared to OIT, the SLIT approach is likely to be a safer option, Kim said, with the most common side effect consisting of oral itching. Treatments that can protect children from allergic reactions while still being safe and practical for busy families can be life-changing, and researchers are hopeful that peanut SLIT can be one of those options.
“Even with the push to introduce peanut in early childhood in order to prevent the allergy, peanut allergy remains one of the most common food allergies,” said Kim. “A result of early peanut introduction is that we are diagnosing peanut allergy at younger and younger ages making it vitally important to develop treatments that can be safe and effective at preventing allergic reactions in these young children.”
Talk to your patients about safe, effective use of medicines
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Approximately one in ten patients experience an adverse drug reaction during their care1. This can lead to serious harm or even death. Sanofi is committed to reducing these numbers by working with healthcare practitioners to create a culture of patient safety.
“Patient safety is a top priority for Sanofi,” says Yusuf Dawood, Multi-Country Safety Head for Sanofi Southern Africa. “We believe that patients should be essential partners in their healthcare journeys, and we are committed to working with healthcare professionals alongside their patients to ensure optimal therapeutic outcomes. We call on all healthcare practitioners to join us in raising awareness of patient safety. By working together, we can advocate for improved communication and reduce patient harm.”
Here are some key tips for healthcare practitioners on how to improve patient safety:
Ask patients about their concerns and listen to their feedback. They can provide valuable insights into their own health and well-being and by engaging them, healthcare practitioners can ensure that potential issues are detected as soon as possible and handled appropriately.
Provide patients with clear and concise information about their care. Patients need to understand what their diagnosis is, what treatment options are available, and what the benefits and risks of each option are. They also need to know what to expect during and after their treatment, and how to manage any side effects or complications. By giving patients accurate and easy-to-understand information, healthcare practitioners can empower them to make informed choices about their care.
Communicate with patients and other members of the healthcare team. Use simple and unambiguous language, avoid jargon and acronyms, and confirm that the patient has understood the information they have been given. Use tools such as checklists, handovers, and feedback loops to ensure that the information they share is complete and accurate.
Follow safety protocols and procedures. Healthcare practitioners need to adhere to guidelines, policies, protocols, best practices and standards of care established by professional bodies and regulatory authorities, which have been designed to prevent or minimise harm to patients.
Report issues immediately. Report any patient safety issues to the appropriate authorities in the interest of public safety. Report any medication-related patient safety issues to the relevant pharmaceutical companies. This enables companies to continuously monitor the benefit-risk profile of their products and ensure the safe use of medicines.
“Patient safety should be a top priority for healthcare professionals and pharmaceutical companies because the goal of both sectors is to improve and protect the well-being of individuals,” says Dawood. “When safety is compromised, it not only jeopardises the health and trust of patients but also undermines the credibility and integrity of the entire healthcare system. By working with pharmaceutical companies like Sanofi, healthcare professionals can provide real-world feedback on drug efficacy and side effects. This collaborative approach ensures that treatments are both safe and effective.
Join Sanofi in championing patient care. Let’s collaborate, communicate, and make every patient’s journey safer.
Reference 1. Ribeiro, M. et al. (2018) ‘Increase of 10% in the rate of adverse drug reactions for each drug administered in hospitalized patients’, Clinics, 73, pp. 1–6. doi:10.6061/clinics/2018/e185.
