Due to the sizeable interest in the use of cannabis-based medications in treating drug resistant epilepsy and comparative lack of clinical guidance on prescription, an expert working group in Australia recently developed an interim “consensus advice” for prescribers and published it in the British Journal of Clinical Pharmacology.
The working group was made up of paediatric and adult epilepsy specialists, clinical pharmacists, pharmacologists, and cannabis researchers. Epilepsy occurs in 1–2% of the population, and about one in three people with epilepsy are considered drug resistant to standard antiseizure medications.
Since there are few clinical data available on comparative efficacy of cannabinoids with registered epilepsy treatments, the authors recommend cannabinoids only in drug resistant epilepsy, in carefully selected compliant patients with specific epilepsy phenotypes.
The document provides an overview of the different cannabis medicines currently available for treating epilepsy in children and adults, with information on dose, drug interactions, toxicity, and type and frequency of symptom and seizure relief. The consensus advice will be updated as new evidence emerges and will provide the structure for a more definitive guideline in the future.
“In the absence of a registration dossier, scientific experiments and case reports are helpful to provide some guidance to optimised dosing. However as in this guidance, observational data obtained from clinical practice – which often includes information not included in scientific experiments or even early clinical trial data, such as treating patients with other comorbidities, taking multiple medications, and patient diversity – can be very helpful to clinical practice,” said senior author Jennifer H. Martin, MBChB, MA, PhD, FRACP, a researcher at the University of Newcastle and the Director of the Australian Centre for Cannabis Clinical and Research Excellence.
Researchers have found that found that patients developing persistent postural-perceptual dizziness (PPPD) are likely to have exacerbating factors soon after the onset of balance disorder symptoms. The results were reported in Laryngoscope Investigative Otolaryngology.
When people experience vestibular symptoms, it can develop into persistent postural-perceptual dizziness (PPPD), a chronic disorder where patients experience dizziness and non-spinning vertigo, particularly during moving, maintaining an upright posture, and when exposed to complex visual stimuli. However, not all individuals suffering from vestibular symptoms go on to develop PPPD, and it unclear whether people showing exacerbating factors for PPPD tend to develop PPPD or not.
Assistant Professor Kayoko Kabaya led a team that analysed medical records of patients who were tested for vestibular symptoms for the first time to identify predictive factors for developing PPPD later on, and to see if the presence of exacerbating factors early on increases the likelihood of developing chronic PPPD. “PPPD is often severe and resistant to treatment. We believe that it is important to provide preventive interventions before PPPD develops, and wanted to identify the characteristics of patients who are prone to PPPD,” explained Dr Kabaya.
In their study, the severity of the symptoms experienced by the patients was scored with a questionnaire which involved questions on the exacerbating factors. Additionally, the perceived handicap due to dizziness was evaluated using a self-assessment scale. There was three months of follow-up, and the symptom scores of patients developing PPPD during the follow-up were compared with that of patients who did not develop PPPD.
More than half of the patients reported experiencing exacerbating factors shortly after the vestibular symptoms. About 10% of these patients developed PPPD during the follow-up period, and the exacerbating factors were found to have a more severe effect on the vestibular symptoms. Notably, the symptom scores of those who developed PPPD were significantly higher than that of those who did not.
“Our results suggest that patients who develop PPPD are likely to have its exacerbating factors at the early stages of the disease following the onset of vestibular symptoms,” said Dr Kabaya.
The researchers believe the results could lead to preventive measures against the disease. “PPPD is a disease that causes long-term social loss and occurs following acute vestibular symptoms. Based on our finding that patients with exacerbating factors during acute vestibular symptom are more likely to develop PPPD, our study could encourage the development of intervention protocols for such patients before they develop PPPD,” said Dr Kabaya.
It is said that seeing is believing, and researchers have found that using patients’ own medical imaging such as CT scans may discourage risk-related behaviours more than non-visual information. The meta-analysis, which appears in PLOS Medicine, found that when patients see imaging results about their risk of disease, they may be more likely to reduce risky behaviours.
Modifiable behaviours such as smoking, poor diet and physical inactivity are linked to non-communicable disease. Encouraging behavioural changes can help reduce the global burden of such diseases, which account for two-thirds of deaths around the world. The investigators were interested to see whether the growing use of medical imaging technologies could help.
Gareth Hollands and University of Cambridge colleagues conducted a meta-analysis of 21 randomised controlled trials involving over 9000 adult participants. Participants were either shown visual examples of personalised risk information following an imaging procedure, such as computed tomography, ultrasound, or radiography, in addition to health information or advice, or they received health information or advice with no visual feedback. The trials reported on behaviours such as smoking, medication use and levels of physical activity.
The strongest evidence was for smoking reduction, a healthier diet, increased physical activity, and increased oral hygiene behaviours. Single studies also reported increased skin self-examination and foot care following visualised feedback. Improvement in other behaviours examined were not statistically significant. The authors conclude that the growth of medical imaging technology could be capitalised on to help people modify their lifestyles and reduce disease risk.
Hollands said: “Medical imaging scans are used ever more widely by healthcare professionals. By gathering together the existing research, this study suggests that showing the scan results to patients to highlight the state of their health could motivate them to behave in a healthier way.”
Paracetamol may help protect against kidney damage in patients with malaria, according to a study recently published in Clinical Infectious Diseases.
The study found that for patients with severe malaria caused by the malaria parasite Plasmodium knowlesi (the most common cause of malaria in Malaysia), taking paracetamol regularly for 3 days led to improvements in kidney function when tested one week later.
The findings are important because they will help provide the best possible treatment to patients with severe malaria, said study leader Dr Daniel Cooper.
“Even minor kidney injury can have long-term effects, so anything we can do to minimise kidney injury from malaria will be beneficial for these patients’ long-term outcomes,” Dr Cooper said.
In collaboration with international partners, the study involved 396 people with knowlesi malaria in Sabah, Malaysia.
Assistant Professor Bridget Barber said that in severe malaria, red blood cells can rupture, releasing haemoglobin which can have a toxic impact on kidneys, and it is now believed that paracetamol can help to mitigate these toxic effects.
“These results are consistent with other studies conducted in patients with other forms of malaria, including in adults in Bangladesh, and in children in Africa. Importantly, these findings also suggest that paracetamol may help to protect the kidneys in other conditions that are also associated with rupture of red blood cells,” A/Prof Barber said.
A project sequencing the Candida glabrata genome has revealed insights into the pathogenic fungus’s virulence and resistance, which researchers found to have been enhanced by transmission through humans as they travel between continents. The project’s findings appear in Genetics.
C. glabrata is an opportunistic human fungal pathogen that causes superficial mucosal and life-threatening bloodstream infections in individuals with a compromised immune system. It most commonly affects the urinary tract, genitals, mouth, and the bloodstream. If it is not caught, these infections can become deadly. It is also very resistant to certain antifungal drugs, so understanding why resistance occurs is key to knowing how to treat it effectively.
Using samples from eight hospitals in Scotland to sequence the genome of C. glabrata, new insights on the species were made. This includes information on how it reproduces and its genetic diversity. Genes increasing its infectivity also confer an advantage for survival, and the drug-resistance genes often evolve within patients.
These findings provide scientists with an advantage in treating fungus, allowing research to focus in ways that were not possible before. It also helps aid understanding on how the pathogen spreads, which is important to identifying infections.
Dr Rhys Farrer, one of the Principal Investigators at the MRC Centre for Medical Mycology at the University of Exeter, said: “Our study sheds new light on the genetic diversity of Candida glabrata. We have demonstrated that this deadly human fungal pathogen is being spread between continents, probably by humans, and recombining to form new populations, which is likely contributing to its high virulence and increasing drug resistance.”
A study using real-world data has shown that multiple sclerosis (MS) sufferers taking cladribine were less likely to experience disease relapse than those who took other oral disease-modifying therapies.
Relapse and discontinuation outcomes favoured cladribine tablets over oral fingolimod, dimethyl fumarate, and teriflunomide. The findings were reported Helmut Butzkueven, PhD, of Monash University at ACTRIMS Forum 2022, the annual meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis.
For the study, researchers drew on data from the MSBase registry of more than 79 000 people with MS worldwide. Few clinical trials or real-world studies are available that compare the effectiveness of cladribine tablets to other oral disease-modifying therapies, the researchers noted.
“Many treatment choices that patients and their care teams have to make are not or not yet examined in classical randomised trials,” Dr Butzkueven told MedPage Today. “Sophisticated analysis of data gathered systematically and prospectively in clinical care is proving a valuable alternative to examine and compare the outcomes of different treatment choices in all kinds of scenarios.”
“Oral agents for use in relapsing MS are very convenient and effective treatment choices,” he added. “This work directly compares outcomes for people with MS who chose cladribine tablets versus other oral drugs.”
The chemotherapy drug cladribine, was recently approved by the FDA for active secondary progressive disease and relapsing MS. This was based on results from trial data showing that cladribine significantly decreased the number of MS relapses and reduced the progression of disability compared with placebo.
GLIMPSE was a longitudinal study that included data for 3475 MS patients on either cladribine, fingolimod, dimethyl fumarate or teriflunomide.
The 633 patients taking cladribine were propensity-score matched with those taking oral comparators on various factors such as age, sex and country.
In pairwise comparisons, cladribine versus fingolimod had 520 matched participants per group: the annualised relapse rate (ARR) was 0.09 compared with 0.15, respectively, the hazard ratio (HR) for time to first relapse was 0.60, and the HR for time to discontinuation was 0.22.
For cladribine versus dimethyl fumarate (450 people per group), the ARR was 0.10 compared with 0.15 the HR for time to first relapse was 0.58, and the HR for time to discontinuation was 0.10.
The cladribine versus teriflunomide (458 people per group) comparisons showed that the ARR was 0.09 compared with 0.17, the HR for time to first relapse was 0.33, and the HR for time to discontinuation was 0.10.
The reason why multiple sclerosis (MS) sufferers often complain of more severe disease symptoms after consuming dairy products may be down to the milk protein casein, which can trigger inflammation targeting the myelin sheath, according to a study published in the journal PNAS.
This link was demonstrated in mice, but there was evidence of a similar mechanism in humans. The researchers therefore recommend that certain groups of MS sufferers avoid dairy products.
“We hear again and again from sufferers that they feel worse when they consume milk, cottage cheese or yoghurt,” explained Professor Stefanie Kürten from the Institute of Anatomy at University Hospital Bonn. “We are interested in the cause of this correlation.”
The professor of neuroanatomy is considered a renowned expert on multiple sclerosis. “We injected mice with different proteins from cow’s milk,” she said. “We wanted to find out if there was a constituent that they were responding to with symptoms of disease.”
When they administered the cow’s milk constituent casein together with an effect enhancer to the animals, the mice went on to develop neurological disorders. Electron microscopy showed damage to the insulating myelin sheath, which normally prevents short circuits and significantly accelerates stimulus conduction.
In multiple sclerosis, the body’s immune system destroys the myelin sheath. Consequences range from paresthaesia and vision problems to movement disorders. With patients ending up in a wheelchair. In mice, the myelin sheath was also massively perforated, apparently triggered by casein administration. “We suspected that the reason was a misdirected immune response, similar to that seen in MS patients,” explained Rittika Chunder, a postdoctoral fellow in Prof. Kürten’s research group. “The body’s defenses actually attack the casein, but in the process they also destroy proteins involved in the formation of myelin.”
Such cross-reactivity can occur when two molecules share some similar parts, causing the immune system to mistake them for each other. “We compared casein to different molecules that are important for myelin production,” Dr Chunder said. “In the process, we came across a protein called MAG. It looks markedly similar to casein in some respects – so much so that antibodies to casein were also active against MAG in the lab animals.”
This means that in the casein-treated mice, the body’s own defences were also directed against MAG, destabilising the myelin. But to what extent can the results be transferred to people with MS? To answer this question, the researchers added casein antibodies from mice to human brain tissue. These did indeed accumulate in the cells responsible for myelin production in the brain.
The study found that the antibody-producing B cells in the blood of people with MS respond particularly strongly to casein. It is possible that at some point while consuming milk, the affected individuals developed an allergy to casein. Now, on consuming dairy products, the immune system produces masses of casein antibodies, which due to cross-reactivity with MAG, also damage the myelin sheath.
However, this only affects MS patients who are allergic to cow’s milk casein. “We are currently developing a self-test with which affected individuals can check whether they carry corresponding antibodies,” said Prof Kürten. “At least this subgroup should refrain from consuming milk, yogurt, or cottage cheese.”
It is possible that cow’s milk also increases the risk of developing MS in healthy individuals. Because casein can also trigger allergies in them – which is probably not even that rare. Once such an immune response exists, cross-reactivity with myelin can in theory occur. However, this does not mean that hypersensitivity to casein necessarily leads to the development of multiple sclerosis, Prof Kürten stressed. This would presumably require other risk factors. This connection is concerning worrying, said Prof Kürten, as “Studies indicate that MS rates are elevated in populations where a lot of cow’s milk is consumed.”
A recent study on the impact of the antibiotic azithromycin during severe respiratory syncytial virus (RSV) bronchiolitis overwhelmingly supports current bronchiolitis guidelines in the US, which recommend against antibiotics during acute bronchiolitis.
The anti-inflammatory properties of azithromycin can be beneficial in some chronic lung diseases, such as cystic fibrosis. With that in mind, researchers investigated its potential to prevent future recurrent wheezing among infants hospitalised with RSV. With such babies at increased risk of developing asthma later in childhood, the scientists hoped to find a therapy to reduce this risk.
The study, published in NEJM Evidence, also provided considerable evidence that severe RSV bronchiolitis in early life increases the likelihood of repeated wheezing episodes in early childhood, often leading to asthma.
“The major message is that antibiotics don’t have a role, either in the management of acute RSV bronchiolitis or to reduce subsequent wheezing,” said co-corresponding author Leonard Bacharier, MD, professor of Pediatrics at Monroe Carell Jr Children’s Hospital at Vanderbilt. “As a matter of fact, we found that antibiotics in general in our study of severe RSV bronchiolitis increased the risk of subsequent recurrent wheezing over the following two to four years.”
“We need to discourage the use of this therapy, as it is potentially harmful,” he said.
The study examined children hospitalised with RSV bronchiolitis during a single-center, double-blind, placebo-controlled trial.
An earlier pilot trial enrolled 40 infants hospitalised with RSV bronchiolitis where treatment with azithromycin, and this showed a reduction in the likelihood of recurrent wheeze over the following year.
In the current study, 200 otherwise healthy 1- to 18-month-old children who were hospitalised for RSV bronchiolitis were prospectively randomised to either oral azithromycin or a placebo for 14 days. The group was broadly representative of the population of children who experience severe RSV bronchiolitis.
Antibiotics are sometimes used in the treatment of RSV because co-occurring complications lead medical teams to prescribe them, thinking there is a bacterial component to the illness, Prof Bacharier said. “This condition can be managed by supportive care – oxygen, fluids, observation, time and love,” he stressed. “If a clinician is going to use an antibiotic in the setting of RSV bronchiolitis, there needs to be a very strong rationale for doing so. There is substantial evidence to suggest that children who receive antibiotics early in life are at an increased risk of developing asthma, and this study is consistent with that evidence.”
Sanofi’s rare disease database that helps healthcare practitioners tackle their unique challenges – and knowing that treatments are available directly improves patients’ wellbeing. This comprehensive database has also aided rare disease research.
Johannesburg, 28 February 2022: Patients with rare diseases present unique challenges to healthcare practitioners (HCPs). Obstacles to caring for them include diagnostic delays and a lack of information, expertise, and treatment options for many rare diseases. HCPs play a vital role in enhancing the quality of life for patients and families living with a rare disease by making appropriate referrals to specialists, helping to coordinate care, and assisting patients in obtaining the proper support.1,2
A disease is defined as ‘rare’ when it affects fewer than 1 in 2000 people.3
Over 7000 rare diseases have been described to date, affecting over 350 million people worldwide.3,4 While most (70-80%) of rare diseases are genetic and inherited, some may be acquired, and 70% are exclusively paediatric in onset.5
Recent surveys showed that those living with rare diseases had a significantly higher prevalence of anxiety and depression compared to the general population.5,6 Levels of high stress can become even worse for carers when the person they are supporting has a diagnosis with no available treatment option.5,6
Monique Nel, Medical Advisor – Rare Diseases at Sanofi says: “Sanofi has been dedicated to researching and developing innovative treatments for rare diseases for 40 years. Currently, Sanofi has one of the largest rare diseases pipelines in the industry, across multiple diseases and modalities.7”
“Our rare disease patient registries have grown to represent one of the largest collections of real-world data for rare diseases collected over the past 30 years. We have a presence in 68 countries worldwide, with more than 920 participating sites and more than 17 800 patients enrolled.”
These registries have helped researchers to publish studies describing the underlying biology of disease, identify risk factors impacting treatment outcomes, and share guidelines for monitoring and treatment.
A further useful resource for HCPs and patients is the list of rare diseases maintained by the Genetic and Rare Diseases Information Center (GARD) of the US National Institutes of Health.8
Says Nel: “We understand the difficulty that healthcare professionals face when it comes to patient diagnosis of a rare disease, and that a coordinated approach to diagnosis and care for people living with rare diseases is needed. Rare diseases deserve the same amount of time, resources and dedication to finding effective treatments and therapies as any other conditions, which is a mission that Sanofi strives to promote every day, to help HCPs to improve diagnosis.”
Dudding-Byth T. A powerful team: the family physician advocating for patients with a rare disease. Aust Fam Physician. 2015 Sep;44(9):634. http://www.ncbi.nlm.nih.gov/pubmed/264880401. NIH.
Bogart KR, Irvin VL. Health-related quality of life among adults with diverse rare disorders. Orphanet J Rare Dis. 2017 Dec 7;12(1):177. doi: 10.1186/s13023-017-0730-1. PMID: 29212508; PMCID: PMC5719717.
Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 2020;28:165–173. https://doi.org/10.1038/s41431-019-0508-0
The spectacular structure of the protective armour of superbug C. difficile has been revealed for the first time showing the close-knit yet flexible outer layer – like chain mail. This assembly prevents molecules getting in and provides a new target for future treatments, according to the scientists at Newcastle, Sheffield and Glasgow Universities who have uncovered it. Credit: Newcastle University, UK
The spectacular structure of the protective armour of C. difficile has been revealed for the first time showing the close-knit yet flexible outer layer – like a mediaeval knight’s chain mail.
This tight arrangement keeps molecules from getting in and provides a new target for future treatments, according to the scientists who have uncovered it.
Published in Nature Communications, the team of scientists outlined the structure of the main protein, SlpA, that forms the links of the chain mail and how they link up to form a pattern and create this flexible armour. One of the many ways that Clostridioides difficile has to protect itself from antibiotics is a special layer that covers the cell of the whole bacteria – the surface layer or S-layer. This flexible armour protects against the entry of drugs or molecules released by our immune system to fight bacteria.
Using a combination of X-ray and electron crystallography, the team determined the structure of the proteins and their arrangement.
Corresponding author and lead researcher Dr Paula Salgado said: “I started working on this structure more than 10 years ago, it’s been a long, hard journey but we got some really exciting results! Surprisingly, we found that the protein forming the outer layer, SlpA, packs very tightly, with very narrow openings that allow very few molecules to enter the cells. S-layer from other bacteria studied so far tend to have wider gaps, allowing bigger molecules to penetrate. This may explain the success of C.diff at defending itself against the antibiotics and immune system molecules sent to attack it.
“Excitingly, it also opens the possibility of developing drugs that target the interactions that make up the chain mail. If we break these, we can create holes that allow drugs and immune system molecules to enter the cell and kill it.”
Antimicrobial resistance (AMR), a growing problem, was declared by WHO as one of the top 10 global public health threats facing humanity. One of the many bacteria that have evolved resistance to antibiotics, C. diff infects the human gut and is resistant to all but three current drugs. Antibiotics only compound the problem, as the good bacteria in the gut are killed alongside those causing an infection and, as C. diff is resistant, it can grow and cause diseases ranging from diarrhoea to death due to massive lesions in the gut. Since the only way to treat C.diff is to take antibiotics, it creates a vicious cycle of recurrent infections.
This knowledge could lead to the development of C. diff specific drugs that break the protective layer, creating holes to allow drug molecules to penetrate and kill the cell.
Dr Rob Fagan, who helped carry out the electron crystallography work, said: “We’re now looking at how our findings could be used to find new ways to treat C. diff infections such as using bacteriophages to attach to and kill C. diff cells – a promising potential alternative to traditional antibiotic drugs.”
