Hyperbaric oxygen treatment provides long-term relief for patients suffering from late radiation-induced injuries after treatment of cancer in the lower abdominal area. Five years after hyperbaric oxygen therapy, the positive effects remain. This has been shown in a study conducted at the University of Gothenburg, published in eClinicalMedicine.
Radiation therapy is a component of many cancer treatments in organs such as the prostate, colon, ovaries and cervix. While tumour cells are destroyed, 5-10% of patients experience severe side effects due to healthy tissue being affected by the radiation therapy.
Symptoms may include urinary incontinence, bleeding and severe pain from the lower abdomen that becomes both physically and socially disabling. These problems can occur several years after radiation therapy and cause chronic and increasing discomfort.
Researchers have previously shown that patients experience significantly less discomfort after hyperbaric oxygen treatment. The question in the current study was whether the relief would last over several years. The time aspect is important for future decisions on broader use of the method.
From severe problems to a normal life
Initially, all participants had severe symptoms. The group that was randomly assigned to hyperbaric oxygen treatment fared significantly better than the control group in terms of incontinence, bleeding and pain. The positive effects were sustained over the five year follow-up period.
Nicklas Oscarsson, senior consultant in anaesthesiology and intensive care, and researcher at the University of Gothenburg and Sahlgrenska University Hospital was the principle investigator of the study:
“Patients who respond to treatment go from being very distressed by their symptoms and restricted by their need to have quick access to a toilet, to being able to live a fully normal life. Now we know that this pronounced improvement last for at least five years. The treatment can therefore lead to the healing of an otherwise chronic injury,” he states.
The effects achieved are due to cells sensing and adapting to high oxygen levels. The increased levels of oxygen provided in a hyperbaric chamber increases vascular growth and stops chronic inflammation, reducing severe side effects.
For the oxygen treatments, participants spent 90 minutes a day in a hyperbaric chamber on 30-40 occasions, at a pressure of 1.4 atmospheres (equivalent to 14m underwater). The control group received the usual treatment, which normally includes medication and physiotherapy, for example.
The capacity already exists today
“We have reason to believe that there are many patients with severe symptoms who are never referred to hyperbaric oxygen therapy. Today we already have the capacity to treat more patients, but we need to be better at sharing our knowledge with our colleagues and with patient associations,” says Nicklas Oscarsson.
Severe side effects after radiation therapy are one of the main limitations on the dose of radiation that can be given in cancer treatment. The availability of a treatment that can reduce the number of people affected by these side effects opens the door to increased radiation doses and thus more curable tumours. One area for further investigation, according to the researchers, is whether early treatment with hyperbaric oxygen can prevent the occurrence of severe side effects.
The results are based on surveys and analyses of the participants who have been involved all the way, 70 adults. The treatments were conducted at five university hospitals in the Nordic countries: Rigshospitalet in Denmark, Turku in Finland, Haukeland in Norway, and Karolinska and Sahlgrenska in Sweden.
Researchers at Tulane University have identified a potential new way to treat idiopathic pulmonary fibrosis (IPF), a deadly and currently incurable lung disease that affects more than 3 million people worldwide.
IPF is rapidly progressive and causes scarring in the lungs, making it difficult to breathe. Approximately 50% of patients die within three years of diagnosis, and current treatments can only slow the disease – not stop or reverse it.
In a study published in the Journal of Clinical Investigation, Tulane scientists found that an FDA-approved cancer drug may help the immune system clear out the damaged cells that cause the lung scarring, potentially restoring lung function in patients with the disease.
In healthy lungs, specialised cells called fibroblasts help repair lung tissue. But in people with IPF, some fibroblasts and nearby epithelial cells stop functioning properly. These so-called “senescent” cells no longer divide or die as they should. Instead, they build up and contribute to stiff, scarred lungs.
Tulane researchers discovered that these senescent cells appear to accumulate when the immune system’s natural ability to remove them is blocked. The culprit: a protein called CTLA4, which acts as an emergency brake on immune system activity.
By using ipilimumab — an immunotherapy drug currently used to treat various cancers — the researchers were able to block CTLA4 in mice. This released the “brakes” on certain immune cells called T cells, reactivating their ability to clear out the senescent fibroblasts. As a result, the mice showed significantly improved lung tissue regeneration and reduced scarring.
“The CTLA4 protein normally functions to prevent excessive inflammation by blocking overactive T cells,” said senior author Dr. Victor Thannickal, professor and Harry B. Greenberg Chair of Medicine at Tulane University’s John W. Deming Department of Medicine. “Too much of this ‘blocker protein’ may result in losing the ‘good’ inflammation that is needed to remove senescent cells. What we’re doing is blocking the blocker.”
The researchers zeroed in on CTLA4 as a potential therapeutic target when they analyzed both human and mouse IPF lung tissue and found unusually high levels of CTLA4 on the T cells in the areas where scarring was most prevalent.
Mice that received ipilimumab showed significantly improved lung repair ability and recovered faster than mice that did not receive the drug.
“This opens up an entirely new direction for potential treatment of IPF,” said lead author Santu Yadav, PhD, assistant professor of medicine at the Tulane University School of Medicine. “Instead of using drugs to kill senescent cells, we are re-activating our own immune system to clear them out.”
More research is needed to determine the efficacy of drugs that target CTLA4 or other so-called “checkpoint proteins” to rejuvenate the immune system. A primary concern is determining a safe dosing strategy that allows for the immune system to attack senescent cells without causing harmful levels of inflammation.
IPF is a disease of aging and is rarely seen before age 50. These findings also offer hope that this approach could work for other similar aging related diseases.
“If it works in IPF, this immune rejuvenating approach to treatment may be effective in other diseases such as Alzheimer’s or cardiovascular diseases in which senescent cells are known to accumulate,” Thannickal said. “Can the right drug activate T cells in a way that clears senescent cells without causing collateral damage? If so, we may be closer to combating many aging related diseases and perhaps even aging itself.”
Retina showing reticular pseudodrusen. Although they can infrequently appear in individuals with no other apparent pathology, their highest rates of occurrence are in association with age-related macular degeneration (AMD), for which they hold clinical significance by being highly correlated with end-stage disease sub-types, choroidal neovascularisation and geographic atrophy. Credit: National Eye Institute
A new study by Brown University researchers suggests that gold nanoparticles might one day be used to help restore vision in people with macular degeneration and other retinal disorders.
In a study published in the journal ACS Nano and supported by the National Institutes of Health, the research team showed that nanoparticles injected into the retina can successfully stimulate the visual system and restore vision in mice with retinal disorders. The findings suggest that a new type of visual prosthesis system in which nanoparticles, used in combination with a small laser device worn in a pair of glasses or goggles, might one day help people with retinal disorders to see again.
“This is a new type of retinal prosthesis that has the potential to restore vision lost to retinal degeneration without requiring any kind of complicated surgery or genetic modification,” said Jiarui Nie, research leader and now a postdoctoral researcher. “We believe this technique could potentially transform treatment paradigms for retinal degenerative conditions.”
Nie performed the work while working in the lab of Jonghwan Lee, an associate professor in Brown’s School of Engineering and a faculty affiliate at Brown’s Carney Institute for Brain Science, who oversaw the work and served as the study’s senior author.
Retinal disorders like macular degeneration and retinitis pigmentosa affect millions of people in the U.S. and around the world. These conditions damage light-sensitive cells in the retina called photoreceptors — the “rods” and “cones” that convert light into tiny electric pulses. Those pulses stimulate other types of cells further up the visual chain called bipolar and ganglion cells, which process the photoreceptor signals and send them along to the brain.
This new approach uses nanoparticles injected directly into the retina to bypass damaged photoreceptors. When infrared light is focused on the nanoparticles, they generate a tiny amount of heat that activates bipolar and ganglion cells in much the same way that photoreceptor pulses do. Because disorders like macular degeneration affect mostly photoreceptors while leaving bipolar and ganglion cells intact, the strategy has the potential to restore lost vision.
In this new study, the research team tested the nanoparticle approach in mouse retinas and in living mice with retinal disorders. After injecting a liquid nanoparticle solution, the researchers used patterned near-infrared laser light to project shapes onto the retinas. Using a calcium signal to detect cellular activity, the team confirmed that the nanoparticles were exciting bipolar and ganglion cells in patterns matched the shapes projected by the laser.
The experiments showed that neither the nanoparticle solution nor the laser stimulation caused detectable adverse side effects, as indicated by metabolic markers for inflammation and toxicity. Using probes, the researchers confirmed that laser stimulation of the nanoparticles caused increased activity in the visual cortices of the mice — an indication that previously absent visual signals were being transmitted and processed by the brain. That, the researchers say, is a sign that vision had been at least partially restored, a good sign for potentially translating a similar technology to humans.
For human use, the researchers envision a system that combines the nanoparticles with a laser system mounted in a pair of glasses or goggles. Cameras in the goggles would gather image data from the outside world and use it to drive the patterning of an infrared laser. The laser pulses would then stimulate the nanoparticles in people’s retinas, enabling them to see.
The approach is similar to one that was approved by the Food and Drug Administration for human use a few years ago. The older approach combined a camera system with a small electrode array that was surgically implanted in the eye. The nanoparticle approach has several key advantages, according to Nie.
For starters, it’s far less invasive. As opposed to surgery, “an intravitreal injection is one of the simplest procedures in ophthalmology,” Nie said.
There are functional advantages as well. The resolution of the previous approach was limited by the size of the electrode array — about 60 square pixels. Because the nanoparticle solution covers the whole retina, the new approach could potentially cover someone’s full field of vision. And because the nanoparticles respond to near-infrared light as opposed to visual light, the system doesn’t necessarily interfere with any residual vision a person may retain.
More work needs to be done before the approach can be tried in a clinical setting, Nie said, but this early research suggests that it’s possible.
“We showed that the nanoparticles can stay in the retina for months with no major toxicity,” Nie said of the research. “And we showed that they can successfully stimulate the visual system. That’s very encouraging for future applications.”
Photo by Mikhail Nilov: https://www.pexels.com/photo/paramedics-using-a-defibrillator-on-a-patient-8942635/
Patients who receive an add-on medication soon after a heart attack have a significantly better prognosis than those who receive it later, or not at all. These are the findings of a new study from researchers at Lund University in Sweden and Imperial College London.
Their analysis suggests that treating patients earlier with a combination of statins and the cholesterol-lowering drug ezetimibe could prevent thousands of new heart attacks in the UK over a decade.
Cardiovascular disease is by far the most common cause of death worldwide, with heart attack (‘myocardial infarction’) being the most common acute event.
For those who survive a heart attack, the risk of a new heart attack is greatest in the first year after the initial event because the blood vessels are more sensitive, making it easier for blood clots to develop.
Our findings suggest that a simple change in treatment guidelines could have a huge impact on patients and reduce the demand on the NHS.
Professor Kausik Ray, School of Public Health
Reducing LDL or “bad” cholesterol in the blood can stabilise changes in the vessels, decreasing the risk for new events.
The current treatment guidelines for patients are high-potency statins immediately after a heart attack, to lower their cholesterol levels.
However, the majority of patients do not reach recommended cholesterol levels using only statins, and so need an add-on treatment, such as ezetimibe.
“Today’s guidelines recommend stepwise addition of lipid-lowering treatment. But it’s often the case that this escalation takes too long, it’s ineffective and patients are lost to follow-up,” says Margrét Leósdóttir, Associate Professor at Lund University and senior cardiology consultant at Skåne University Hospital in Malmö, Sweden. “By giving patients a combination treatment earlier, we could help to prevent many more heart attacks.”
Co-investigator Professor Kausik Ray, from Imperial College London’s School of Public Health, said: “This study shows that we could save lives and reduce further heart attacks by giving patients a combination of two low-cost drugs.
“But at the moment patients across the world aren’t receiving these drugs together. That’s causing unnecessary and avoidable heart attacks and deaths – and also places unnecessary costs on healthcare systems.
“Our study shows the way forward; care pathways must now change for patients after this type of heart event.”
Reducing heart attacks
In the latest study, the international team examined outcomes for heart attack patients if they received a combination of statins with the add-on therapy ezetimibe (within 12 weeks after a heart attack), statins with ezetimibe added later (between 13 weeks and 16 months), or just statins with no ezetimibe at all.
Based on Swedish registry data from 36 000 patients who had a heart attack between 2015 and 2022, the researchers used advanced statistical models to emulate a clinical trial.
The results show that patients who received a combination treatment of statins and ezetimibe within 12 weeks of a heart attack and were able to lower cholesterol to the target level early, had a better prognosis and less risk of new cardiovascular events and death than those who received the add-on treatment later, or not at all.
From the analysis, the researchers believe many new heart attacks, strokes and deaths could be prevented every year internationally if the treatment strategy were to be changed.
Under a scenario in which 100% of patients would receive ezetimibe early, they estimate 133 heart attacks could be avoided in a population of 10 000 patients in 3 years.
The researchers suggest that in the UK, which records an estimated 100 000 hospital admissions from heart attacks a year,[1] this would equate to an estimated 5000 heart attacks being prevented over a ten year period.[2]
Improving guidance
Dr Leósdóttir said: “Combination therapy is not applied up-front for two main reasons. General recommendations are not included in today’s guidelines and a precautionary principle is applied to avoid side effects and overmedication.
However, there are positive effects from applying both medicines as soon after the infarction as possible. Not doing this entails an increased risk. In addition, the drug we have examined in the study causes few side effects and is readily available and inexpensive in many countries.”
Margrét Leósdóttir hopes that the research results will in time provide support for changes in the recommendations. A treatment algorithm has already been introduced at her hospital in Sweden to help doctors to prescribe appropriate lipid-lowering treatment for patients who have had a myocardial infarction.
It has been noted that patients achieve their treatment goals earlier and two months after the infarction twice as many patients have reduced their bad cholesterol to the target level, compared with previously.
“Several other hospitals in Sweden have also adopted the algorithm and there are similar examples from other countries that have produced as good results. My hope is that even more will review their procedures, so that more patients will get the right treatment in time, and we can thereby prevent unnecessary suffering and save lives.”
A medical breakthrough could result in the first treatment for rare but serious diseases in which genetic defects disrupt cellular energy production. Researchers at the University of Gothenburg have identified a molecule that helps more mitochondria function properly.
Mitochondrial diseases caused by POLG mutations vary in severity. In young children, these diseases can quickly result in brain damage and life-threatening liver problems while others suffer muscle weakness, epilepsy, and organ failure later in childhood. POLG mutations recently received media attention when Prince Frederik of Nassau in Luxembourg died in March 2025 at just 22 years of age.
The POLG gene regulates the production of DNA polymerase gamma, an enzyme that copies mitochondrial DNA. Without it, the mitochondria cannot function normally and, as a result, fail to provide the cell with energy.
A breakthrough
Maria Falkenberg and Claes Gustafsson, professors at Sahlgrenska Academy at the University of Gothenburg, have led the work behind the study now being published in the journal Nature.
“We demonstrate that the molecule PZL-A can restore the function of mutated DNA polymerase gamma and improve the synthesis of mitochondrial DNA in cells from patients. This improves the ability of the mitochondria to provide the cell with energy,” says Maria Falkenberg.
“This is a breakthrough as for the first time we can demonstrate that a small molecule can help improve the function of defective DNA polymerase. Our results pave the way for a completely new treatment strategy,” says Claes Gustafsson.
From lab to medication
More than twenty years of basic research led to the discovery of PZL-A. The molecule was identified following the analysis of hundreds of chemical compounds in collaboration with Pretzel Therapeutics, where another one of the lead authors of the study, Simon Giroux, has led the chemical development of the molecule. So far, the molecule has been studied in cells from patients as well as in animal models.
Sebastian Valenzuela, a doctoral student at Sahlgrenska Academy, has analysed the molecule’s structure, including by means of cryo-electron microscopy.
“We demonstrate exactly where the molecule binds, between two separate chains of the enzyme. The binding site is extremely specific, which helps us understand how the enzyme works and how we can influence it,” says Sebastian Valenzuela, first author of the study.
Pretzel Therapeutics has just embarked on phase I studies with a refined version of the molecule in order to test its safety on healthy volunteers. Since a lack of mitochondrial DNA is also seen in other mitochondrial, age-related, and neurodegenerative diseases, substances similar to PZL-A may gain broader therapeutic use.
Scientists at the University of South Australia have come up with an innovative solution to improve the effectiveness of cannabidiol to treat epilepsy, multiple sclerosis and other neurodegenerative diseases.
Cannabidiol (CBD), a non-psychoactive cannabis compound, is widely prescribed for its analgesic, anti-inflammatory and neuroprotective properties, but its clinical applications to date have been limited by its poor water solubility and absorption in the human body.
By developing a phospholipid complex – a class of lipids (fats) that contain phosphorus – UniSA researchers have increased the solubility of cannabidiol by up to six times and improved its absorption in the gastrointestinal tract.
Currently, only a small fraction of orally ingested CBD reaches the bloodstream, limiting its therapeutic effects.
“For this reason, a number of different formulations have been explored, including the production of synthetic CBD, self-emulsifying delivery systems, and encapsulating CBD in gelatine matrix pellets, but all of them have only resulted in minor improvements in bioavailability,” Prof Garg says.
His research team identified the optimal phospholipid composition to form nanosized CBD-PLC particles. Compared to pure CBD, the phospholipid complex improved dissolution rates from 0% to 67.1% within three hours, demonstrating a significant enhancement in drug release.
In cellular uptake studies, CBD-PLC exhibited 32.7% higher permeability than unmodified CBD, ensuring greater absorption through the intestinal wall.
Another critical advantage of this new delivery system is its stability. Traditional CBD formulations degrade over time when exposed to heat, light or oxygen, reducing potency and shelf life.
However, testing over 12 months showed that CBD-PLC retained its performance under varied storage conditions, making it a more reliable option for pharmaceutical applications.
The study’s first author, UniSA PhD candidate Thabata Muta, says the discovery has significant implications for the future of CBD-based therapeutics.
“Improved bioavailability means that lower doses can achieve the same therapeutic effect, potentially reducing side effects and making treatment more cost effective,” Thabata says.
The research team believes that this innovation could be applied beyond CBD, providing a blueprint for enhancing the absorption of other poorly water-soluble drugs.
With the global CBD market projected to grow from USD 7.59 billion in 2023 to USD 202.45 billion by 2032, the findings of this study come at a crucial time, according to the study authors.
The team is now exploring opportunities for commercialisation and clinical trials to validate their new formulation.
Mass General Brigham and MIT investigators have developed a long-acting contraceptive implant that can be delivered through tiny needles to minimise patient discomfort and increase the likelihood of medication use.
Their findings in preclinical models provide the technological basis to develop self-administrable contraceptive shots that could mimic the long-term drug release of surgically implanted devices.
The new approach, which would reduce how often patients need to inject themselves and prove valuable for patients with less access to hospitals and other medical care providers, is described in Nature Chemical Engineering.
“Needle size and liquid viscosity are crucial considerations for commercial translation of injectables,” said senior author Giovanni Traverso, MD, PhD, MBBCH, of the Division of Gastroenterology in the Department of Medicine at Brigham and Women’s Hospital. “Our engineering challenge was finding a way to maximise comfort for patients by using smaller needles, which cause less bruising or bleeding, and to make the viscosity low enough for easy application with the syringe by hand.”
Traditional contraceptive implants are small, flexible rods that are surgically inserted under the skin to slowly deliver drugs over time, removing the hassle of remembering to take a pill. But the surgery required for implants makes them less accessible to some patients.
Traverso’s team developed a new approach to deliver the contraceptive drug levonorgestrel (LNG) through Self-assembling Long-acting Injectable Microcrystals (SLIM). SLIM act like tiny puzzle pieces that, once injected inside the body, undergo solvent exchange to assemble into a single solid implant that slowly releases the drug as the surface erodes. Unlike similar self-administering technologies, the solvent exchange assembly enables delivery by much smaller needles.
The researchers will continue their work to optimize the dosing, duration, and injectability of the SLIM system, including understanding how it performs in the human body. The design could also be applied to other hydrophobic drugs, which make up most new pharmaceuticals. The researchers plan to investigate how different drug properties impact the SLIM system’s effectiveness.
“We anticipate that SLIM could be a new addition to the current suite of family planning options available to women, especially for people in low-resource settings where options for contraception and health care facilities are limited,” said Traverso.
Mycobacterium tuberculosis drug susceptibility test. Photo by CDC on Unsplash
By Catherine Tomlinson
Both TB treatment and TB preventive therapy involve taking lots of pills, usually for several months. Researchers are working on new long-acting formulations that might, for example, reduce an entire course of TB preventive therapy to a single injection.
The biggest HIV news of last year was that an injection containing an antiretroviral called lenacapavir provides six months of protection against HIV infection per shot. While it will be several years before the jabs become widely available, experts nevertheless hailed the development as a potential game-changer. In some countries, HIV treatment is already available as injections – containing the antiretrovirals cabotegravir and rilpivirine – administered every two months.
Scientists working on tuberculosis (TB) are trying to replicate the successes of the HIV field and develop similarly long-acting formulations of TB medicines. The good news is that they have several exciting products under development – the bad news is that the research is still at a very early stage and the pivotal studies that will tell us if these products work are likely still years away.
But if they work, they could make a big difference to patients. That is because TB treatment and TB preventive therapy mostly still requires swallowing lots of pills over a long period of time. There is some good evidence that many people would prefer long-acting injections.
The case for long-acting TB medicines
TB preventive therapy is used to stop someone suspected of having latent TB infection from falling ill with TB. In South Africa, such preventive therapy is recommended for all close contacts of someone sick with TB. Typically, it involves taking tablets for three or six months (a one-month course has been shown to work, but is not widely available). There is research that shows that the shorter the regimen the more likely it is to be completed.
The hope is that a long-acting product might do away with swallowing tablets altogether and reduce an entire course of preventive therapy to a single injection. This is likely to be more convenient for patients as well as come with the benefit of perfect treatment completion rates.
TB preventive therapy is a simpler target for long-acting formulations than TB treatment since it typically involves only one or two drugs and treatment durations are shorter. TB treatment typically takes six or more months to complete and usually involves taking four different drugs – often four for two months and then only two for the remaining four months in what is called the continuation phase. Some of the current thinking is that the continuation phase could potentially be replaced by long-acting formulations of TB medicines. This could shorten the duration of TB treatment to just two months of taking tablets.
Not an easy nut to crack
As explained by Dr Eric Nuermberger of Johns Hopkins University, not all TB medicines available as tablets make good candidates for translation to long-acting injectable formulations. He was presenting on long-acting TB drugs at the Conference for Retroviruses and Opportunistic Infections (CROI), recently held in San Francisco.
Nuermberger outlined three key characteristics that are needed for long-acting formulations. These are low water solubility (so the drug doesn’t dissolve to quickly), low clearance in plasma (so that the body doesn’t clear the drug too quickly), and high drug potency (so that a small volume of drug can be effective for a long period of time).
One key challenge, according to Nuermberger, is that scientists do not yet have reliable biomarkers to measure the effectiveness of long-acting TB preventive therapy in phase II trials. Biomarkers, such as blood levels of certain proteins, could in theory offer scientists a faster way to assess if TB preventative therapy is working, without having to monitor clinical trial participants for long periods of time to determine treatment outcomes.
Writing in the journal Clinical Infectious Diseases, scientists working to develop long-acting TB products explained: “The inability to culture or otherwise quantify viable bacteria during latent TB infection and the lack of validated surrogate biomarkers mean that there is no opportunity to obtain initial proof of efficacy… which is usually the domain of phase 2 trials. Instead, the development of new TPT regimens requires bridging directly from preclinical studies and phase 1 trials to phase 3 trials, which are themselves long and require large numbers of participants.”
However, they added that “[t]he search for biomarkers that act as prospective signatures of risk for developing TB disease is a very active research area and an important scientific priority for the field”.
Back at CROI, Nuermberger also told participants that most products in the pipeline remain at pre-clinical stages and are still being tested in mice. He explained that differences in how depot drugs — drugs released slowly over time — work in mice and humans make it hard to apply findings from mice to humans. But modeling is being done to help bridge this gap.
‘Expanded remarkably’
Despite these challenges, Nuermberger said “the number of long-acting drug formulations in development [for TB] has really expanded remarkably in the last few years, which is a very promising development”.
The product that is furthest along in the development pipeline, but still at a very early stage of research, is a long-acting form of bedaquiline. This drug is currently used for the treatment of drug-resistant forms of TB and falls in a class of antibiotics known as diarylquinolines.
The Belgian pharmaceutical company Janssen is currently running a phase I trial of long-acting injectable bedaquiline in Austria. Phase I trials are conducted in a small group of healthy individuals to assess the safety and tolerability of an experimental medicine. In the phase 1 bedaquiline trial, researchers are investigating the safety and tolerability of different doses of long-acting injectable bedaquiline.
Several other long-acting TB medicines are being investigated in preclinical research, including long-acting versions of the TB medicines rifabutin and rifapentine, as well as the second generation diarylquinolines, TBJ-876 and TBA-587, which are under development by the TB Alliance. The second generation diarylquinolines are being tested on their own and in combination with pretomanid and telacebec.
In addition, the University of Liverpool, Johns Hopkins University, University of Southern Denmark, University of North Carolina and the US pharmaceutical company Inflamamasome Therapeutics, are all involved in pre-clinical research on long-acting formulations. These efforts are supported financially by Unitaid, the US National Institutes of Health, and the Gates Foundation.
The treatments being developed include aqueous nanoparticle suspensions, in-situ forming implants, and rod implants. Aqueous nanoparticle suspensions are drugs turned into tiny particles and delivered in a water-based solution via injection. In-situ forming implants are injected as a liquid that then solidifies into an implant under the skin. Rod implants are small, rod-shaped devices inserted under the skin with a needle-like tool after numbing the area with a local anaesthetic.
What users prefer
At CROI, delegates also learned about patient and provider preferences for long-acting TB treatment.
Dr Marcia Vermeulen from the University of Cape Town presented the results of a survey involving over 400 patients in South Africa and India, as well as 94 healthcare providers.
Seventy-five percent of healthcare workers said they would prescribe a long-acting injectable product rather than pills for tuberculosis preventative therapy if it was priced the same or lower. Similarly, 75% of patients said they would try an injectable product for TB prevention if it became available.
“As a TB survivor, I am excited about long-acting TB treatment as it doesn’t require frequent facility visits, saving a person’s time and money, and can thereby increase adherence and improve treatment outcomes,” TB Proof’s Phumeza Tisile told Spotlight.
She added that communities should be at the heart of rollout plans because they understand the needs of people affected by TB and know how to communicate effectively to encourage involvement and adoption.
Disclosure: The Gates Foundation is mentioned in this article. Spotlight receives funding from the Gates Foundation but is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
Researchers at WashU Medicine and Stanford University developed a compound that relieves pain in mice but doesn’t affect the brain, thereby avoiding mind-altering side effects and abuse potential. The custom-designed molecule, derived from cannabis, may provide an alternative to opioids for treating chronic pain. The compound is illustrated here in cyan, nestled within a protein (green and purple) involved in sensing pain. Credit: Tasnia Tarana
In the quest to develop a safe, effective alternative to opioids, researchers have developed a compound that mimics a natural molecule found in the cannabis plant, harnessing its pain-relieving properties without causing addiction or mind-altering side effects in mice.
While more studies are needed, the compound shows promise as a nonaddictive pain reliever. The study, from Washington University School of Medicine in St. Louis and Stanford University, appears in Nature.
“There is an urgent need to develop nonaddictive treatments for chronic pain, and that’s been a major focus of my lab for the past 15 years,” said the study’s senior author Susruta Majumdar, PhD, a professor of anaesthesiology at WashU Medicine. “The custom-designed compound we created attaches to pain-reducing receptors in the body but by design, it can’t reach the brain. This means the compound avoids psychoactive side effects such as mood changes and isn’t addictive because it doesn’t act on the brain’s reward centre.”
Opioids dull the sensation of pain in the brain and hijack the brain’s reward system, triggering the release of dopamine and feelings of pleasure, which make the drugs so addictive. Despite widespread public health warnings and media attention focused on the dangers of opioid addiction, numerous overdose deaths still occur. In 2022, some 82 000 deaths in the U.S. were linked to opioids.
“For millennia, people have turned to marijuana as a treatment for pain,” explained co-corresponding author Robert W. Gereau, PhD, professor of anaesthesiology and director of the WashU Medicine Pain Center. “Clinical trials also have evaluated whether cannabis provides long-term pain relief. But inevitably the psychoactive side effects of cannabis have been problematic, preventing cannabis from being considered as a viable treatment option for pain. However, we were able to overcome that issue.”
The mind-altering properties of marijuana stem from natural molecules found in the cannabis plant referred to as cannabinoid molecules. They bind to a receptor, called cannabinoid receptor one (CB1), on the surface of brain cells and on pain-sensing nerve cells throughout the body.
Working with collaborators at Stanford University, co-first author Vipin Rangari, PhD, a WashU Medicine postdoctoral research associate in Majumdar’s laboratory, designed a cannabinoid molecule with a positive charge, preventing it from crossing the blood-brain barrier into the brain while allowing the molecule to engage CB1 receptors elsewhere in the body. By modifying the molecule such that it only binds to pain-sensing nerve cells outside of the brain, the researchers achieved pain relief without mind-altering side effects.
They tested the modified synthetic cannabinoid compound in mouse models of nerve-injury pain and migraine headaches, measuring hypersensitivity to touch as a proxy for pain. Applying a normally non-painful stimulus allows researchers to indirectly assess pain in mice. In both mouse models, injections of the modified compound eliminated touch hypersensitivity.
For many pain relievers, particularly opioids, tolerance to the medications over time can limit their long-term effectiveness and require higher doses of medication to achieve the same level of pain relief. In this study, the modified compound offered prolonged pain relief – the animals showed no signs of developing tolerance despite twice-daily treatments with the compound over the course of nine days. This is a promising sign that the molecule could be used as a nonaddictive drug for relief of chronic pain, which requires continued treatment over time.
Eliminating the compound’s tolerance resulted from the bespoke design of the compound. The Stanford collaborators performed sophisticated computational modeling that revealed a hidden pocket on the CB1 receptor that could serve as an additional binding site. The hidden pocket, confirmed by structural models, leads to reduced cellular activity related to developing tolerance compared to the conventional binding site, but it had been considered inaccessible to cannabinoids. The researchers found that the pocket opens for short periods of time, allowing the modified cannabinoid compound to bind, thus minimizing tolerance.
Designing molecules that relieve pain with minimal side effects is challenging to accomplish, said Majumdar. The researchers plan to further develop the compound into an oral drug that could be evaluated in clinical trials.
Results of a trial led by the university and reported in Nature Communications revealed that a unique investigational drug formulation called Rhenium Obisbemeda (186RNL) more than doubled median survival and progression-free time, compared with standard median survival and progression rates, and with no dose-limiting toxic effects.
“As a disease with a pattern of recurrence, resistance to chemotherapies and difficulty to treat, glioblastoma has needed durable treatments that can directly target the tumour while sparing healthy tissue,” said lead author Andrew J. Brenner, MD, PhD, professor and chair of neuro-oncology research with Mays Cancer Center at UT Health San Antonio. “This trial provides hope, with a second trial under way and planned for completion by the end of this year.”
Brenner said that the median overall survival time for patients with glioblastoma after standard treatment fails with surgery, radiation and chemotherapy is only about 8 months. More than 90% of patients have a recurrence of the disease at its original location.
Rhenium Obisbemeda enables very high levels of a specific activity of rhenium-186 (186Re), a beta-emitting radioisotope, to be delivered by tiny liposomes, referring to artificial vesicles or sacs having at least one lipid bilayer. The researchers used a custom molecule known as BMEDA to chelate or attach 186Re and transport it into the interior of a liposome where it is irreversibly trapped.
In this trial, known as the phase 1 ReSPECT-GBM trial, scientists set out to determine the maximum tolerated dose of the drug, as well as safety, overall response rate, disease progression-free survival and overall survival.
After failing one to three therapies, 21 patients who were enrolled in the study between March 5, 2015, and April 22, 2021, were treated with the drug administered directly to the tumours using neuronavigation and convection catheters.
The researchers observed a significant improvement in survival compared with historical controls, especially in patients with the highest absorbed doses, with a median survival and progression-free time of 17 months and 6 months, respectively, for doses greater than 100Gy.
Importantly, they did not observe any dose-limiting toxic effects, with most adverse effects deemed unrelated to the study treatment.
“The combination of a novel nanoliposome radiotherapeutic delivered by convection-enhanced delivery, facilitated by neuronavigational tools, catheter design and imaging solutions, can successfully and safely provide high absorbed radiation doses to tumours with minimal toxicity and potential survival benefit,” Brenner concluded.
