Year: 2021

Categories : Injury & TraumaTags :

CT Scans Improve Outcomes for Concussion Patients

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A study found that CT scans for concussion patients provide crucial information on their risk for long-term impairment and their potential to make a complete recovery, and points to the need for more follow-up.

In the UC San Francisco-led study, researchers examined CT scans of 1935 patients, aged 17 and over, whose neurological exams met criteria for concussion, or mild traumatic brain injury (TBI). Outcomes for moderate and severe TBI have been linked to CT imaging features, but this may be the first time this link has been identified in patients with concussion. This contradicts previous research which had found no prognostic significance of specific types of CT abnormalities.

“Radiologists who routinely read trauma scans know intuitively that patterns of intracranial injury on CT are not random,” said first author Esther Yuh, MD, PhD, of the UCSF Department of Radiology and Biomedical Imaging. “We showed there are patterns of injury, that some of these are associated with worse outcome than others, and that they provide a window into mechanisms of injury that is reproducible across large studies.”

The study was published online in JAMA Neurology.

“Although concussions are referred to as mild traumatic brain injuries, there is nothing mild about some concussions,” explained senior author Geoffrey Manley, MD, PhD, professor and vice chair of neurological surgery at UCSF and chief of neurosurgery at Zuckerberg San Francisco General Hospital. “Patients with concussion may suffer from prolonged headache, poor sleep and impaired concentration, and they are at higher risk of self-medicating with drugs and alcohol. Concussion can also contribute to depression and anxiety, and increase the risk for suicide. We need to view concussion not as an event but as a disease requiring physician follow-up after a patient is discharged from the hospital.”

The participants were enrolled by the brain injury research initiative TRACK-TBI, of which Manley is the principal investigator. To enrich the number of so-called complicated concussions, the researchers drew exclusively from patients who had been seen at hospitals with level 1 trauma centres. This meant 37 percent of study participants had a positive CT, significantly more than the 9 percent of positive CTs from patients in US emergency departments.

The most common patterns of injury, affecting more than half of CT-positive patients, were combinations of subarachnoid haemorrhage (SAH), subdural haematoma (SDH), and/or contusion, which may be caused by injuries such as falls from standing. About 7 percent had intraventricular haemorrhage (IVH) or petechial haemorrhage, caused by head rotation as in some sporting, scooter and automobile accidents; and 5 percent had epidural haematoma (EDH), often seen in sports injuries such as being hit with a baseball.

Average age of the patients was 41 and 66 percent were male. They were followed-up at two weeks, and at three-, six- and 12 months following injury. Patients in the SAH/SDH/contusion group failed to make a complete recovery at 12 months post-injury and had a range of outcome impairments, from mild to more severe.

Patients in the IVH/petechial haemorrhage group tended toward more severe impairments, in the lower-moderate disability range, a level potentially affecting multiple areas of function, such as employment, social and leisure activities, up to 12 months post-injury. Patients with EDH fared significantly better and demonstrated complete recovery by their six-month assessment.

Results from CENTER-TBI, a parallel brain injury research group that had enrolled 2594 participants at European trauma centres. validated the findings. “The confirmation of the findings in an independent cohort confirms the fidelity of our results,” said Manley, adding that patients with EDH were one exception, with incomplete recovery lingering for months longer than those patients followed by TRACK-TBI. However, more severe outcomes were not seen at any point in either study.

The researchers noted that even among concussion patients with positive CT scans, only 39 percent get follow-up care, which should be routine. They also cautioned that their findings are not a call for increased CT use, which has radiation dose concerns and is restricted to known or suspected concussions.

Indeed, a recently approved rapid hand-held blood test may reduce the amount of CT scans. Manley found this test was more sensitive than CT in detecting concussion. The blood test measures biomarkers associated with TBI, which were nearly 52 times higher in MRI-identified concussion patients than in healthy participants.

In addition to challenging the belief that CT features in concussion are not relevant, the researchers are also challenging the idea that concussion is “what the patient brings to the injury,” said Manley, who is also affiliated with the UCSF Weill Institute for Neurosciences. “In moderate and severe TBI, it is anecdotally taught that outcome is determined by ‘what the injury brings to the patient,’ while concussion is determined by baseline characteristics like age, sex and years of education. While the study confirms the importance of these characteristics, we show that in some concussion cases, poor outcomes are also attributed to ‘what the injury brings to the patient.'”

Source: University of California, San Francisco

Journal information: Yuh EL et al., Pathological computed tomography features associated with adverse outcomes after mild traumatic brain injury, JAMA Neurology, July 19, 2021.

Categories : Neurology PaediatricsTags :

Internal Body Sensing Ability Varies with Age

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A Chinese study has found that the ability to sense nervous signals such as heartbeat varies with age, peaking in young adulthood, but does not seem to be associated with autism.

Interoception is the ability to process and integrate internal signals originating from one’s body, such as heartbeats and breathing patterns. This ability is important for maintaining homeostasis. Recent findings have suggested that autism spectrum disorders are associated with a wide range of sensory integration impairments including interoceptive accuracy.

However, it is still not clear whether individuals with subclinical features of autism, which only moderately impact daily life, also exhibit similar impairments in interoceptive accuracy. It is also not clear how interoceptive ability and its association with autistic traits varies with age.

In order to address this issue, Dr Raymond Chan’s team from the Institute of Psychology of the Chinese Academy of Sciences (CAS) has developed an innovative paradigm involving eye-tracking measures to examine the multidimensional interoception and autistic traits in different age groups.

In so doing, they recruited 114 healthy university students aged 19–22 and explored the correlations among autistic traits and interoceptive accuracy using an “Eye-tracking Interoceptive Accuracy Task” (EIAT), which presents two bouncing shapes and requires participants to look at the one whiches bounces in time with their heartbeat.

Since this task requires no verbal report or button-pressing, it enables the exploration of interoceptive accuracy in preschool children and individuals with psychiatric disorders or speech impairments.

However, while autistic traits correlated significantly with the ability to describe and express emotion (alexithymia) but not with the different dimensions of interoception such as interoceptive accuracy (performance of interoceptive ability on behavioural tests), interoceptive sensibility (subjective sensitivity to internal sensations on self-report questionnaires) and interoceptive awareness (personal insight into interoceptive aptitude).

They then recruited 52 preschool children aged four to six, 50 adolescents aged 12–16 and 50 adults aged 23–54 to specifically examine the relationship of autistic traits and interoceptive accuracy across these three age groups. The researchers found that interoceptive accuracy evolves from childhood to early adulthood, and then declines with age. The highest average accuracy was seen in 12-16 year olds. The dataset showed that the developmental trajectory of interoceptive accuracy has a reverted U-shape trend peaking around early adulthood.

The findings suggest that interoceptive accuracy significantly differs between typically-developing preschool children, adolescents and adults. The study also highlights the need for future study into preschool children with suspected autism spectrum disorders.

Source: Medical Xpress

Categories : LungTags :

Protein’s Involvement in Emphysema Could Yield a Treatment Target

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Researchers from Japan have found a protein that promotes the development of the early stages of emphysema, which could prove to be a target for treatment of the serious disease.

Chronic obstructive pulmonary disease (COPD) causes illness and death worldwide, and is characterised by destruction of the alveolar walls in the lungs, known as emphysema, resulting in lung function declining and to date little is known about how it develops. The Global Initiative for chronic obstructive lung disease (GOLD) has defined COPD as “a common, preventable, and treatable disease that is characterised by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.”

It is known that COPD can be triggered by certain environmental factors, such as cigarette smoking, which result in lung inflammation. The development of inflammation involves the movement of molecules inside cells, and this “intracellular trafficking” is known to play a part in some diseases. The team searched for COPD-related proteins that are involved in trafficking and identified a protein called FCHSD1, which not known to have any lung function but is associated with some diseases.

The researchers deleted the FCHSD1 protein in mice and studied these mice against normal mice when emphysema was induced. In normal mice, a large increase was seen in FCHSD1 after treatment, while mice lacking FCHSD1 were protected from the development of emphysema. These mice showed less airspace expansion from damaged air sacs, and had less inflammation and reduced apoptosis.

The researchers went on to investigate the molecular mechanism by which FCHSD1 acts. In response to stress, a protein called NRF2 moves into the nucleus to protect it. However, FCHSD1 binds to NRF2, stopping it from moving to the nucleus. “Mice with a FCHSD1 deficiency showed enhanced nuclear translocation of NRF2 and a smaller reduction in SIRT1 levels, which is seen to occur as emphysema develops,” explained lead author Takahiro Kawasaki, “and this reduced inflammation and apoptosis of lung cells.”

Increasing the activity of NRF2 to counteract FCHSD1 could therefore be a potential therapy for COPD. Treatments are currently available that target NRF2, and inhibiting FCHSD1 while targeting NRF2 could enhance these treatments and prevent systemic complications. “Our findings may also lead to a specific therapeutic strategy to ameliorate, or even halt, the progression of emphysema by inhibiting FCHSD1,” said Takashi Satoh, senior author of the paper.

Source: EurekAlert!

Categories : COVID Diseases, Syndromes and ConditionsTags :

A Report of Two Sequential Cases of Facial Palsy after COVID Vaccines

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The case of a patient who experienced two facial palsies, both immediately after receiving the Pfizer-BioNTech vaccine, strongly suggests that they are linked to the vaccine, wrote in the journal BMJ Case Reports.

The case report of two separate unilateral facial nerve palsies, where muscles on one side of the face become weak or paralysed, occurring shortly after each dose of a COVID vaccine, is the first in medical literature.

“The occurrence of the episodes immediately after each vaccine dose strongly suggests that the Bell’s palsy was attributed to the Pfizer-BioNTech vaccine, although a causal relationship cannot be established,” the authors said.

Single episodes of unilateral facial nerve palsies were reported in the initial clinical trials of Pfizer-BioNTech, Moderna and Oxford/Astra Zeneca and there have been subsequent case reports.

In phase 3 trials, four cases of facial palsy of unknown cause (Bell’s palsy) were reported in volunteers who received the Pfizer-BioNTech mRNA vaccine and none in the placebo group, and three cases were reported in volunteers who received the Moderna mRNA vaccine compared with one in the placebo group. Three cases of facial nerve palsy were also reported in volunteers who received the Oxford/AstraZeneca vaccine, and there were three cases in the placebo group.

This case report describes a 61-year-old Caucasian male with no previous history of facial nerve palsy who experienced an episode of Bell’s palsy on the right side of his face five hours after receiving his first dose of the Pfizer-BioNTech vaccine, and a more severe episode of Bell’s palsy on the left side of his face two days after receiving the second dose. The patient had a high BMI, hypertension, hypercholesterolaemia and type 2 diabetes.

After the first episode, the patient went to the emergency department, with incomplete eye closure and no forehead movement and was diagnosed with Bell’s palsy. Blood tests and a CT head scan revealed no pathologies and he was discharged with a course of steroids, and the right-sided facial nerve palsy completely resolved.

Two days after his second shot, he developed a more severe left-sided facial nerve palsy. The symptoms included dribbling, difficulty swallowing and again, incomplete left eye closure. He went to the emergency department, where he was again prescribed a course of steroids. He was also referred to an emergency Ear Nose and Throat clinic, which continued the steroids and referred him to ophthalmology.

The authors reported that the patient is almost back to normal. “The patient has been advised to discuss future mRNA vaccines with the GP on a case-by-case basis, taking into account risk versus benefit of having each vaccine,” they said.

Bell’s palsy is believed to be related to facial nerve inflammation and oedema from viral infection. In 2004 the inactivated intranasal influenza vaccine was shown to significantly increase the risk of Bell’s palsy and was discontinued. Increased incidence of Bell’s palsy has also been seen following administration of other influenza and meningococcal vaccines. The annual incidence is 15 to 20 per 100 000 and the lifetime risk is 1 in 60, with an 8% to 12% recurrence rate.

While most cases of Bell’s palsy recover on their own over time, the symptoms can cause significant temporary disability, affecting facial expression and eating and drinking. Risk factors for the condition include diabetes, obesity, hypertension, pregnancy, pre-eclampsia and upper respiratory disease.

Source: EurekAlert!

Categories : HospitalsTags :

Tshwane Hospital, Left Unscathed by Unrest, Continues the COVID Fight

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Amidst the unrest which badly disrupted the provision of healthcare in many areas, Dr George Mukhari Academic Hospital was one of the lucky Gauteng metros left unscathed.

The hospital’s Acting CEO Dr Keneilwe Letebele said that protests did not extend as far as Ga-Rankuwa, north of Pretoria, which left the healthcare facility untouched by the violence and looting.

“Up until now, our hospital has not been adversely affected, possibly because there were not much protest marches happening in our vicinity,” said Dr Letebele.

Being out of the thick of the protests let the hospital remain focussed on dealing with COVID cases. Lessons they had learnt from the first two waves had helped them mitigate the high number of fatalities in the third waves.

“The situation is quite challenging but we have learnt some valuable lessons from the first and second wave experiences regardless of some differences.

“These lessons have helped us to adapt to the situation. What is important is that when the first wave engulfed us, it was a first experience for everyone but now we know what to expect and how to address some challenges,” she said.

Dr Letebele noted that they have 60 additional beds at their newly-built Alternative Building Technology (ABT) unit, which adds to the existing 280 beds dedicated to COVID.

However, the high number of healthcare workers testing positive for COVID had left them short of staff.

“Capacity is reduced due to staff being COVID positive. However, the department has increased the number of staff to manage the surge (in cases),” she said.

Meanwhile, Vuyo Mhaga, the spokesperson for Gauteng Premier David Makhura, said scientists have warned that although COVID numbers were beginning to fall in the province, it was not enough – and it might even reverse given current events.

“The province is concerned that there might be a change in the downward trajectory of new infections due to recent protest action.

“Daily new infections remain very high. Some of those infected do require hospital care. These protests might cause the province to take longer to flatten the curve,” said Mhaga.

Meanwhile, health bodies including the South African African Health Products Regulatory Authority (SAHPRA) have issued a joint statement warning against using looted medications.

“We would like to urge the public not to utilise any medicines that are not accessed through authorised health care institutions. You may report such illegal activity to SAHPRA or to law enforcement agencies,” the medical bodies said.

They also said that looting and violence from the unrest only worsened the COVID pandemic and set back the provision of equitable healthcare.

“We appeal to citizens looting and destroying the healthcare infrastructure and disrupting the provision of health care to consider the long-term consequences of their actions on the health of communities.

“Without health care services, the requisite medicines and vaccines, we will have unnecessary deaths and cause further pandemonium, including severe damage to the economy,” the bodies said.

Source: IOL

Categories : COVID PaediatricsTags :

Child Mask Study Which Reported High CO2 Levels Retracted

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A study which generated controversy by suggesting that masks may harm children through exposure to high carbon dioxide levels was retracted on Friday.

The research letter released in JAMA Pediatrics on June 30 had reported finding in a lab environment unacceptably high levels of CO2 by German standards in air inside masks worn by children.

The journal editors cited “numerous scientific issues” in the retraction notice, which also included questions over the applicability of the CO2 measurement device and the validity of the study’s conclusions.

“In their invited responses to these and other concerns, the authors did not provide sufficiently convincing evidence to resolve these issues, as determined by editorial evaluation and additional scientific review,” the notice read. “Given fundamental concerns about the study methodology, uncertainty regarding the validity of the findings and conclusions, and the potential public health implications, the editors have retracted this Research Letter.”

The study drew prompt criticism following its publication. Joseph Allen, MPH, DSc, who studies the impact of carbon dioxide on human health at Harvard School of Public Health in Boston, described the study as “terribly flawed”, predicting its retraction on Twitter. He pointed out that the study made no account of the flood of air taken in when children inhale, his key complaint.

The US Centers for Disease Control do not list any known risk wearing facing masks poses to children, and in fact, recently recommended that unvaccinated children wear masks when school reopen later this year. A previous study with adult volunteers had shown short-term but acceptable rises in CO2 when wearing masks,

While many areas of the US have dropped mask mandates, Los Angeles is reinstating its indoor mask mandate regardless of vaccination status as COVID cases and hospitalisations rise, presumably due to the spread of the Delta variant.

Source: MedPage Today

Categories : Cardiovascular Disease New Compounds and TreatmentsTags :

A Treatment for Heart Attack from Spider Venom

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Photo by Adrián Valverde on Unsplash
Photo by Adrián Valverde on Unsplash

A protein found in the venom of one of the world’s deadliest spiders has been shown to preserve heart cells, and could be developed into a potentially life-saving treatment for heart attack victims.

A drug candidate developed from a molecule found in the venom of the Fraser Island (K’gari) funnel web spider can prevent damage caused by a heart attack and extend the life of donor hearts used for organ transplants. This would not be the first investigation into a clinical application for spider venom, however. Tarantula spider venom has also been investigated as a potent anaesthetic.

The discovery was made by a team led by Dr Nathan Palpant and Professor Glenn King from The University of Queensland (UQ) and Professor Peter Macdonald from the Victor Chang Cardiac Research Institute.

Dr Palpant, from UQ’s Institute for Molecular Bioscience (IMB), said the drug candidate worked by stopping a ‘death signal’ sent from the heart in the wake of an attack.

“After a heart attack, blood flow to the heart is reduced, resulting in a lack of oxygen to heart muscle,” Dr Palpant said. “The lack of oxygen causes the cell environment to become acidic, which combine to send a message for heart cells to die.

“Despite decades of research, no one has been able to develop a drug that stops this death signal in heart cells, which is one of the reasons why heart disease continues to be the leading cause of death in the world.”

Using beating human heart cells exposed to heart attack stresses, Dr Palpant tested the drug candidate, a protein called Hi1a, to see if the drug improved the cells’ survival.

“The Hi1a protein from spider venom blocks acid-sensing ion channels in the heart, so the death message is blocked, cell death is reduced, and we see improved heart cell survival.”

At present, there are no drugs in clinical use that prevent the damage caused by heart attacks.

Professor Macdonald of Victor Chang Cardiac Research Institute said that this incredible result had been decades in the making.

“This will not only help the hundreds of thousands of people who have a heart attack every year around the world, it could also increase the number and quality of donor hearts, which will give hope to those waiting on the transplant list,” said Professor MacDonald, who is also a senior cardiologist at St Vincent’s Hospital in Sydney.

“The survival of heart cells is vital in heart transplants — treating hearts with Hi1a and reducing cell death will increase how far the heart can be transported and improve the likelihood of a successful transplant,” added Prof MacDonald. “Usually, if the donor heart has stopped beating for more than 30 minutes before retrieval, the heart can’t be used — even if we can buy an extra 10 minutes, that could make the difference between someone having a heart and someone missing out. For people who are literally on death’s door, this could be life-changing.”

The discovery builds on earlier work by Professor King, who identified a small protein in the venom of the Fraser Island (K’gari) funnel-web spider that was shown to markedly improve recovery from stroke.

“We discovered this small protein, Hi1a, amazingly reduces damage to the brain even when it is given up to eight hours after stroke onset,” Professor King said.

“It made sense to also test Hi1a on heart cells, because like the brain, the heart is one of the most sensitive organs in the body to the loss of blood flow and lack of oxygen.

“For heart attack victims, our vision for the future is that Hi1a could be administered by first responders in the ambulance, which would really change the health outcomes of heart disease.”

“This is particularly important in rural and remote parts of Australia where patients and treating hospitals can be long distances apart — and when every second counts.”

Also, this could help for the transfer of donor hearts for cardiac transplantation — allowing these donor hearts to be transported over longer distances and therefore increasing the network of available donors and recipients.

The protein has been tested in human heart cells, and the team are aiming for human clinical trials for both stroke and heart disease within 2-3 years.

Source: ScienceDaily

Journal information: Meredith A. Redd, et al. Therapeutic Inhibition of Acid Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury. Circulation, 2021; DOI: 10.1161/CIRCULATIONAHA.121.054360

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

Untreated Sewage is a Driver of Antibiotic Resistance

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Photo by Jordan Opel on Unsplash
Photo by Jordan Opel on Unsplash

Contamination of urban lakes, rivers and surface water by human waste is creating pools of ‘superbugs’ in Low- and Middle-Income Countries (LMIC), according to new research. However, improving access to clean water, sanitation and sewerage infrastructure could help to improve public health.

For the study, researchers studied bodies of water in urban and rural sites in three areas of Bangladesh: Mymensingh, Shariatpur and Dhaka. In comparison to rural settings, they detected more antibiotic resistant faecal coliforms in urban surface water , consistent with reports of such bacteria in rivers across Asia. Their findings were published in mSystems.

Lead author Willem van Schaik, Professor of Microbiology and Infection at the University of Birmingham, commented: “The rivers and lakes of Dhaka are surrounded by highly-populated slums in which human waste is directly released into the water. The presence of human gut bacteria links to high levels of antibiotic resistance genes, suggesting that such contamination is driving the presence of these ‘superbugs’ in surface water.

“Interventions aimed at improving access to clean water, sanitation and sewerage infrastructure may thus be important to reduce the risk of antimicrobial resistance spreading in Bangladesh and other LMICs. While levels of antibiotic resistance genes are considerably lower in rural than in urban settings, we found that antibiotics are commonly used in fish farming and further policies need to be developed to reduce their use.”

Infections from antibiotic-resistant bacteria are on the rise globally, but the clinical issues posed by these bacteria are particularly alarming in LMICs, with significant morbidity and mortality. As in other LMICs, multidrug-resistant E. coli has a relatively high prevalence in healthy humans in Bangladesh.

With a population of around 16 million people, Dhaka’s population density ranks among the highest of any megacity, but less than 20% of its households have a sewerage connection.

Urban surface waters in Bangladesh are particularly rich in antibiotic resistance genes, the researchers discovered, with a higher number of them associated with plasmids — vehicles of genetic exchange among bacteria — indicating that they are more likely to spread through the population.

Antibiotic-resistant bacteria that colonise the human gut can be passed into rivers, lakes and coastal areas through the release of untreated wastewater, the overflow of pit latrines during monsoon season or by practices such as open defecation.

Such contaminated environments are often used for bathing, for the washing of clothes and food utensils, thereby risking human gut colonisation by antibiotic-resistant bacteria.

The researchers from the University of Birmingham and the International Centre for Diarrhoeal Disease Research, Bangladesh called for further research to quantify the drivers of antibiotic resistance in surface waters in Bangladesh.

Source: University of Birmingham

Journal information: McInnes, R.S., et al. (2021) Metagenome-Wide Analysis of Rural and Urban Surface Waters and Sediments in Bangladesh Identifies Human Waste as a Driver of Antibiotic Resistance. mSystems. doi.org/10.1128/mSystems.00137-21.

Categories : Uncategorized

No Azithromycin Benefit in Mild COVID

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Photo by Tamanna Rumee on Unsplash
Photo by Tamanna Rumee on Unsplash

A small study has found that the antibiotic azithromycin had no effect in prevention of COVID symptoms among non-hospitalised patients, and could increase hospitalisation risk, even though the antibiotic is widely used for the disease.

“These findings do not support the routine use of azithromycin for outpatient SARS-CoV-2 infection,” said lead author Catherine E Oldenburg, ScD, MPH, an assistant professor with the UCSF Proctor Foundation. 

Azithromycin, a broad-spectrum antibiotic of the macrolide class, is widely prescribed as a treatment for COVID-19 in the United States and the rest of the world. “The hypothesis is that it has anti-inflammatory properties that may help prevent progression if treated early in the disease,” said Oldenburg. “We did not find this to be the case.”

The study was published in the Journal of the American Medical Association.

The study recruited 263 non-hospitalised participants who had tested positive for SARS-CoV-2 seven days or sooner before entering the study. Of these, 171 participants were randomised to receive\ a single, 1.2 gram oral dose of azithromycin and 92 received an identical placebo.
At day 14, 50 percent of the participants remained symptom-free in both groups. By day 21, five of the participants who received azithromycin had been hospitalised with severe COVID symptoms and none of the placebo group had been hospitalised.

From these findings, the researchers concluded that treatment with a single dose of azithromycin compared to placebo did not result in greater likelihood of being symptom-free.

“Most of the trials done so far with azithromycin have focused on hospitalised patients with pretty severe disease,” said Oldenburg. “Our paper is one of the first placebo-controlled studies showing no role for azithromycin in outpatients.”

The PRINCIPLE study being conducted in the UK investigating common medications for community treatment of moderate COVID also found no benefit to using azithromycin.

Source: University of California, San Francisco

Journal information: Catherine E. Oldenburg et al, Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection, JAMA (2021). DOI: 10.1001/jama.2021.11517

Categories : Medical Research & TechnologyTags :

Artificial Sweetener Delivers a Protective Carbon Monoxide Dose

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Photo by Sharon McCutcheon on Unsplash
Photo by Sharon McCutcheon on Unsplash

An oral prodrug has been developed which uses artificial sweeteners to deliver a protective carbon monoxide dose which protects against acute kidney injury.

Although carbon monoxide (CO) gas is toxic in large doses, with some 50 000 people suffering CO poisoning each year in the US, scientists have discovered it can reduce inflammation and protect cells against injury. The  protective effects of CO against injury in the kidneys, lungs, gastrointestinal tract and liver, among other organs has been shown in previous research. For the past five years, Wang and his collaborators have worked to design a safe way to deliver CO to human patients via prodrugs, which are inactive compounds that must undergo a chemical process in the body to release the active pharmacological agent. Their paper was published in Chemical Science.

Using two common artificial sweeteners, saccharine and acesulfame, as ‘carrier’ molecules for a prodrug, Prof Wang’s team were able to create an oral administration route for CO. They designed the molecules to release CO as they decomposed from water exposure. These are the first examples of orally active, organic CO prodrugs using a benign carrier that is approved by the Food & Drug Administration with a demonstrated safety profile.

“It’s difficult to deliver a gas, much less a poisonous gas, as a therapeutic to patients, and this work represents a pivotal step forward in developing alternative delivery forms,” said Prof Wang, a Georgia Research Alliance Eminent Scholar. “We wanted to work with a carrier that has a very well characterized safety profile, which confers a higher degree of certainty that it will be safe to use in a pill for human consumption.”

The scientists tested one of the prodrugs, CO-306, for pharmacological efficacy against acute kidney damage. CO-306, which uses saccharine as a carrier molecule, was administered to mice and it was found that it reduced biomarkers for kidney injury, indicating it could be developed working therapy. The type of kidney injury modelled mimicked those in humans that occur with extensive muscle damage, sickle cell disease, a common type of malaria, cardiopulmonary bypass surgery and severe sepsis.

Further animal model studies and safety assessments on CO-306 are planned by Wang and colleagues before they progress to human clinical studies. They also plan to test CO-306 for efficacy against other types of organ injuries.

Additionally, CO-based therapies hold promise as a method of reducing the likelihood of organ damage during transplantation and improving outcomes for transplant patients, according to Prof Wang.

“Science shows that exposing organs to CO gas can help preserve organs and prevent them from deteriorating during the process of transplantation,” he said. “Now we need to demonstrate that these prodrugs can have a similar effect.”

Source: Georgia State University

Journal information: De La Cruz, L. K., et al. (2021) Adapting decarbonylation chemistry for the development of prodrugs capable of in vivo delivery of carbon monoxide utilizing sweeteners as carrier molecules. Chemical Science. doi.org/10.1039/D1SC02711E.