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Take a look at a selection of our recent media coverage:
20th March 2023
Tuberculosis treatment in those with rifampin susceptible disease with an initial 8-week course containing bedaquiline and linezolid is non-inferior to the standard regimen, with respect to clinical outcomes, according to the TRUNCATE-TB trial investigators.
According to the World Health Organisation, in 2021, globally, an estimated 10.6 million people contracted tuberculosis, leading to an estimated 1.6 million deaths. Currently, treatment of drug susceptible pulmonary tuberculosis requires a 6-month rifampin-based regimen although this can affect adherence and ultimately lead to treatment failure. However, emerging evidence suggests that a 4-month rifapentine-based regimen containing moxifloxacin was non-inferior to the standard 6-month regimen. In the current study, researchers wondered if an initial 8-week treatment regimen, which could be extended for persistent clinical disease with follow-up after treatment and prompt re-treatment for those who relapse, may be as effective as the current standard regimen.
The Two-Month Regimens Using Novel Combinations to Augment Treatment Effectiveness for Drug-Sensitive Tuberculosis (TRUNCATE-TB) trial, compared whether an initial regimen of either high-dose rifampin-linezolid or bedaquiline-linezolid (each with isoniazid, pyrazinamide, and ethambutol) was non-inferior to the current standard regime of rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks. Individuals were randomised to either the standard regime or a strategy of an 8-week regimen (rifampin-linezolid or bedaquiline-linezolid) with extended treatment if required. The primary outcome was a composite of death, ongoing treatment, or active disease at week 96 and the non-inferiority margin set at 12%.
Tuberculosis treatment strategy outcomes
A total of 674 participants were included and randomised to the different strategies.
The primary outcome event occurred in 3.9% of those in the standard regime and 11.4% in the rifampin-linezolid regimen (adjusted difference, AD = 7.4%, 95% CI 1.7 – 13.2%), hence non-inferiority was not met. In contrast, the primary outcome occurred in 5.8% of those assigned to bedaquiline-linezolid regimen (AD = 0.8%, 95% CI -3.4 to 5.1%), hence the criterion for non-inferiority (12%) was met with this regimen.
In fact, the mean total duration of treatment was 180 days in the standard-treatment group but only 85 days in the bedaquiline-linezolid strategy group, with a similar incidence of grade 3 or 4 adverse and serious events across the three groups.
The authors concluded that use of an 8-week regimen with bedaquiline-linezolid proved to be non-inferior to the standard regimen and with no apparent safety concerns.
Paton NI et al. Treatment Strategy for Rifampin-Susceptible Tuberculosis. N Eng J Med 2023
17th March 2023
A childhood lower respiratory tract infection (LRTI) nearly doubles the risk of a premature adult respiratory-related death according to the findings of a life-spanning cohort study by UK researchers.
Chronic respiratory diseases are a leading cause of death and disability worldwide and in 2017, represented the third largest cause of mortality. Moreover, adverse factors affecting lung development during foetal life as well as in early childhood, decrease the attainment of maximal lung function and accelerate function decline in adulthood. Although researchers have speculated for some time that there is a direct casual link between acute lower respiratory infection in early childhood and conditions such as chronic bronchitis in adult life, an absence of longitudinal data, makes it difficult to provide greater clarity on the relationship between childhood respiratory infections and possible early deaths from a respiratory cause.
In the current study, researchers prospectively collected data from a nationally representative cohort of all single births among married women during 1 week in March, 1946, across England, Scotland and Wales with a review to evaluating the association between the presence of a LRTI during early childhood (age < 2 years) and death from respiratory disease from age 26 through 73 years.
Childhood LRTI and premature respiratory-related death
Researchers included a total of 3,589 participants, aged 26 years (51% male) and who were included in the analysis from 1972 onwards and followed-up for a median of 47.9 years.
After adjusting for several factors including adult smoking, among these 3,589 participants, 25% had an LRTI during early childhood, which nearly doubled their risk of premature death from a respiratory-related disease by age 73 (Hazard Ratio, HR = 1.93, 95% CI 1.10 – 3.37, p = 0.021). Furthermore, in subgroup analysis, there was no evidence that an early childhood LRTI increased the risk of circulatory, cancer, external, other-cause, or all-cause mortality.
The researchers also calculated that the population attributable risk of premature adult death from respiratory disease due to early childhood LRTI was 20·4% and which corresponded to an estimated 179, 188 excess and premature adult deaths across England and Wales between 1972 and 2019.
The authors concluded that a LRTI during early childhood was associated with almost a two times increased risk of premature adult death from respiratory disease and that it accounted for a fifth of all these deaths.
Allinson JP et al. Early childhood lower respiratory tract infection and premature adult death from respiratory disease in Great Britain: a national birth cohort study. Lancet 2023
Prenatal leukotriene receptor antagonist use does not increase the risk of neuropsychiatric events among their offspring despite previous concerns over this class of drugs according to the findings of a study by Taiwanese researchers.
The leukotriene-receptor antagonists have demonstrated favourable anti-asthmatic activity over a wide spectrum of disease severity either alone or in combination with inhaled corticosteroids but also as an effective treatment for allergic rhinitis. Despite this, in the US, the FDA issued warnings about the risk of neuropsychiatric side effects (NSE)-related to the use of one leukotriene antagonist, montelukast and which often occurred within the first 10 days of use and were most common in 4 – 6 year old children. Moreover, other evidence also hints at such an association with a 2022 study of patients initiated on montelukast observing an increased odds of adverse neuropsychiatric outcomes among those starting the drug. Nevertheless, whether prenatal leukotriene receptor antagonist use might also increase the subsequent risk of NSE in children remains unclear.
In the current study researchers identified a group of women and their offspring, where the mother had been dispensed any prescription for a leukotriene receptor antagonist during her pregnancy. They set the outcome as a primary diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD) or Tourette syndrome (TS) in the offspring of these mothers and propensity matched these mothers with non-exposed control children.
Prenatal leukotriene receptor antagonist use and neuropsychiatric outcomes
After propensity score matching, a total of 1,988 leukotriene receptor antagonist exposed children and 19,863 non-exposed children with included in the analysis.
Among the offspring, there was no significant association observed between prenatal leukotriene receptor antagonist exposure and ADHD (adjusted hazard ratio, aHR = 1.03, 95% CI 0.79 – 1.35, p = 0.82), ASD (aHR = 1.01, 95% CI 0.65 – 1.59, p = 0.96) and TS (aHR = 0.63, 95% CI 0.29 – 1.36, p = 0.24). This association remained non-significant when the prenatal leukotriene receptor antagonist use was categorised as either 1 – 4 weeks or > 4 weeks and where the cumulative dose ranged from 1 – 170 mg or > 170 mg, for each of the three outcomes.
The authors concluded that there was no significant risk of neuropsychiatric events in children following prenatal leukotriene receptor antagonist use, although they called for further work to confirm these findings.
Tsai HJ et al. Use of Leukotriene-Receptor Antagonists During Pregnancy and Risk of Neuropsychiatric Events in Offspring. JAMA Netw Open 2023
Abnormal spirometry, defined as either airflow obstruction (AFO) or preserved ratio impaired spirometry, has been identified in just over a third of patients deemed at high risk of developing COPD because of a smoking history of at least 10 pack-years according to an analysis of data from the COPDgene study.
Chronic obstructive pulmonary disease (COPD) is an increasingly important cause of morbidity, disability, and mortality worldwide with data from 2019, estimating that globally, 391·9 million people aged 30-79 years had COPD. Nevertheless, COPD often goes undetected and one study of the general population, revealed how of 95,288 screened individuals, 3699 (11%) met the COPD criteria yet 2903 (78%) of these were undiagnosed yet 71% were symptomatic. However, the prevalence of undiagnosed COPD among heavy smokers, i.e., those who are at a high risk of developing the disease is less clear and was the overall objective of the current study, where researchers assessed the extent of abnormal spirometry, based on AFO and preserved ratio impaired spirometry, among a cohort of heavy smokers.
The team included individuals with a ≥10 pack-years of smoking and for whom there was no self-reported or physician diagnosed COPD, asthma or other related disease. In addition, a subgroup of patients were followed-up for a period of 5 years.
Abnormal spirometry findings
A total of 5,055 individuals without known obstructive lung disease were enrolled in the study, ranging in age from 56 to 61. Abnormal spirometry, based on AFO and preserved ratio impaired spirometry was seen in 21 % and in 13.6% of participants respectively.
Factors such as age, pack-years, current smoking and a history of acute bronchitis were all significantly and positively associated with AFO. In contrast, body mass index, female gender and Black ethnicity, were inversely, but significantly associated with AFO.
In a subgroup of 2,800 participants who had 5 years of follow-up, 19% had an incident diagnosis of COPD and factors significantly associated with the diagnosis included a MMRC > 2 (dyspnoea score) and the presence of a chronic, productive cough.
The authors concluded that there was a high prevalence of undiagnosed COPD in at-risk individuals and that the associated factors could be used to identify those at risk for enable earlier diagnosis and treatment of the disease.
Trab TV et al. Prevalence of abnormal spirometry in individuals with a smoking history and no known obstructive lung disease. Respir Med 2023
16th March 2023
In a study presented at the American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023, researchers described how following a ketogenic diet, involving consumption of very low amounts of carbohydrates and high amounts of fats, appeared to increase levels of LDL cholesterol and the risk of an adverse cardiovascular event.
A ketogenic diet (KD), also referred to as a low carbohydrate, high fat (LCHF) diet, contains high amounts of fat (55 to 60%), 30 to 35% protein and 5 to 10% carbohydrate. Overall, it seems that a KD plays appears to play a significant therapeutic role in various cardiometabolic diseases and there is certainly evidence of a benefit when used as an intervention for overweight patients with type 2 diabetes. However, despite these advantages, others have raised concerns that a KD has the potential to exacerbate or cause hypercholesterolaemia in patients with or without underlying genetic hyperlipidaemia.
Nevertheless, whether a KD over time gives rise to adverse cardiovascular events is unclear given the absence of long-term data. The study presented at ACC/WCC tried to answer this question and researchers used information from data held in the UK Biobank and identified individuals meeting their their definition of a KD diet, i.e., no more than 25% of total daily calories from carbohydrates and more than 45% from fat. These individuals were then matched to a group who self-reported eating a normal diet. The main outcome of the study was the effect of a KD on serum lipids whereas a secondary outcome was the composite incidence of adverse cardiovascular events (e.g., angina, myocardial infarction, coronary artery disease, ischaemic stroke, peripheral arterial disease, or coronary/carotid revascularisation.)
Ketogenic diet outcomes
A total of 305 participants eating a KD diet were matched with 1220 eating a standard diet. The mean age of the sample was 54 and 73% were women and the mean body mass index (BMI) of 27.7 compared to 26.7 on the standard diet.
After an average follow-up of 11.8 years, a KD gave rise to higher LDL cholesterol levels compared to a standard diet (3.80 vs. 3.64 mmol/L, p = 0.004). There was also a significantly higher level of apolipoprotein B (1.09 vs. 1.04 g/L, p < 0.001).
However, after adjustment for cardiovascular risk factors, e.g., diabetes, hypertension, obesity, and smoking, researchers found that 9.8% of those on a KD and 4.3% on a standard diet experienced an adverse cardiovascular event (adjusted hazard ratio, aHR = 2.18, 95% CI 1.39 – 3.43, p < 0.001).
Despite these findings, the authors did acknowledge the limitations of their study in that the information was self-reported and based on a single time-point. They also noted how not everyone responds to a KD in the same way.
‘Keto-Like’ Diet May Be Linked to Higher Risk of Heart Disease, Cardiac Events. ACC Anywhere
15th March 2023
Acadia Pharmaceuticals announced that it has received approval for trofinetide as a treatment for adult and paediatric patients with Rett Syndrome from two years of age.
Rett syndrome is described as a neuro-developmental disorder characterised by typical early growth and development followed by a slowing of that development, loss of functional use of the hands, distinctive hand movements, slowed brain and head growth, problems with walking, seizures, and intellectual disability. The condition primarily affects females resulting in severe cognitive and physical disabilities and is estimated to affect about 1 in 12,000 girls and is only rarely seen in boys. Virtually all patients with Rett syndrome have one of > 300 distinct loss-of-function mutations in the MECP2 gene on the X chromosome, which encodes methyl-CpG binding protein-2, an essential transcriptional regulator in the brain required for normal neurodevelopment.
Before trofinetide, which is given orally, there were no recognised treatments for Rett syndrome and the drug is believed to work by normalising aberrant neural function resulting from MECP2 mutations. In an exploratory phase 2, multicentre, double-blind, placebo-controlled, dose-escalation study, trofinetide was found to provide a clinically meaningful improvement for patients with the syndrome. The approval by the FDA was based on the findings from LAVENDER, a phase 3 study of trofinetide for Rett syndrome.
According to the press release, LAVENDER evaluated the efficacy and safety of trofinetide compared to placebo in 187 female patients with Rett syndrome, five to 20 years of age. In the study, treatment with trofinetide produced a statistically significant improvement (compared to placebo) on both co-primary efficacy endpoints, measured by the change from baseline, in Rett Syndrome Behaviour Questionnaire (RSBQ) total score (p = 0.018), which is a caregiver assessment on a range of disease symptoms, and the Clinical Global Impression-Improvement (CGI-I) scale score (p = 0.003) at week 12, which represents a physician-based assessment. In the study, the most common side effects were diarrhoea (82%) and vomiting (29%).
The drug is likely to be available in the US from April 2023 although the press release provides no information on its release elsewhere.
The presence of hypertension irrespective or whether or not it is controlled, in patients with obesity, increases the risk of all-cause mortality according to a large, population study by Singaporean and Australian researchers.
Hypertension is the leading cause of global cardiovascular disease and premature death with the World Health Organisation estimating that 1.28 billion adults aged between 30 and 79 have hypertension, two-thirds of whom, live in low and middle-income countries. It has also become clear that as body mass index increases, so too does the risk of hypertension. Although the prevalence of hypertension among those with obesity has been found to be above 70%, much less is known about the impact on mortality of having hypertension and whether the level of control exerts a mitigating effect.
In the current study, researchers collected data on obese patients, which was defined as adults with a body mass index (BMI) of ≥ 30.0 kg/m2. Furthermore, individuals were then stratified by their hypertensive status as either having controlled hypertension (CH) (< 140/90 mmHg) with antihypertensive use, uncontrolled hypertension (UCH) ( ≥ 140/90 mmHg) with and without antihypertensive use or normotensive. The main outcome measure was all-cause mortality.
Controlled and uncontrolled hypertension and all-cause mortality
A total of 16,386 individuals with obesity were included and of whom, just over half (53.1%) were normotensive, a quarter (24.7%) had CH with the remainder having uncontrolled disease. These individuals were then followed-up for a median of 7.3 years.
The presence of hypertension per se increased the risk of all-cause mortality (Hazard Ratio, HR = 1.28, 95% CI 1.14 – 1.44, p < 0.001). After adjustment for potential confounders, the researchers found that among obese patients with UCH, there was an increased all-cause mortality risk (HR = 1.34, 95% CI 1.13 – 1.59, p = 0.001), compared to normotensive individuals. However, there was also a significantly increased mortality risk for those with CH (HR = 1.21, 95% CI 1.10 – 1.34, p < 0.001). In fact, further adjustment of the regression model for chronic kidney disease, still gave rise to a significant risk of all-cause mortality in those with CH (HR = 1.17, p = 0.007).
The authors concluded that the excess mortality risk among obese patients, irrespective of whether their hypertension was controlled, should urge health care providers to optimise disease control and advocate weight loss to achieve better outcomes in obesity.
Kong G et al. A two-decade population-based study on the effect of hypertension in the general population with obesity in the United States. Obesity (Silver Spring) 2023
In a press release, Pfizer has announced that zavegepant has become the first calcitonin gene-related peptide receptor antagonist nasal spray to receive approval by the FDA for the management of acute migraine.
According to a study using data from 2016, it was estimated that globally, migraine affects some 1·04 billion people and caused 45·1 million years of life lived with disability. Although there was a breakthrough in treatment of migraine during the early 1990’s with the introduction of triptans, it later emerged that the calcitonin-gene-related peptide (CGRP) pathway was important in the pathophysiology of migraine. While first generation drugs targeting this pathway, known as ‘gepants’ were effective, hepatotoxicity halted further development but did lead to new generation of gepants, which have been shown to be safe, efficacious and well tolerated.
Zavegepant clinical studies
Zavegepant nasal spray is a third generation gepant and the first, non-oral gepant. In a randomised, dose-ranging, placebo-controlled, phase 2/3 trial in adults aged ≥18 years with migraine, single doses of 10 or 20 mg, of the drug were shown to be effective for the acute treatment of migraine and with a favourable safety profile. Further data on the efficacy of zavegepant and which formed the basis for the approval, came from a double-blind, randomised, placebo-controlled phase 3 trial in adults with a history of two to eight moderate or severe migraine attacks per month. The results showed that among those assigned to zavegepant, two hours after the treatment dose, a statistically significant higher proportion of zavegepant patients had freedom from pain and freedom from their most bothersome symptom. In addition, twice as many patients (16% vs 8%) given zavegepant reported pain relief after only 15 minutes. There were also significant differences (compared to placebo) for 13 of the 17 pre-specified secondary outcomes.
The trial also found that the drug was well tolerated with the most common adverse reactions reported in at least 2% of patients and at a frequency greater than placebo, were taste disorders (includes dysgeusia and ageusia), nausea, nasal discomfort and vomiting.
Pholcodine is an opioid that is approved for use in adults and children over 6 years of age as a treatment for a dry or non-productive cough, although it is also present in other products as a treatment for cough and cold symptoms. The MHRA in the UK has said that pholcodine containing cough and cold medicines are being withdrawn from the UK market as a precaution following a review and will no longer be available from pharmacies. This decision was based on the potential for an interaction, giving rise to anaphylaxis, with neuromuscular blocking agents (NMBAs). This possible interaction has already been mentioned in the summary of product characteristics for pholcodine.
The MHRA review published on the 14th March 2023, states that recently completed ALPHO study, showed that use of pholcodine during the 12 months preceding anaesthesia was significantly associated with an increased risk of peri-anaesthetic anaphylaxis to NMBAs (adjusted odds ratio = 4.2, 95% CI 2.5 to 6.9). While information on the risk from pholcodine use beyond 12 months was not available in the ALPHO study, evidence from a study in Norway, showed that IgE-mediated anaphylaxis to neuromuscular blocking agents, was still present, 3 years after withdrawal of pholcodine. However, the MHRA does add that while the risk of an anaphylactic reaction to NMBAs in less than 1 case per 10,000 procedures, it still believes that it is necessary to withdraw pholcodine as a precautionary measure.
The action by the MHRA follows a similar move by the European Medicines Agency in December 2022.
The DNA damage from vaping among individuals who have never smoked is comparable to that induced from current smoking and increases in a dose-dependent manner according to the findings of a study by a team from the Department of Population and Public Health Sciences, University of Southern California, USA.
In a 2021 Cochrane systematic review on the use of electronic cigarettes (otherwise known as ‘vaping’), researchers concluded that there did not appear to be any clear evidence of harm from nicotine electronic cigarettes, but added how the longest follow-up was two years and the overall number of studies was small. However, there does has been an increase in both hospitalisations and death due to what has been termed ‘vaping use-associated lung injury’ which is likely to be the result to cytotoxicity and neutrophilic inflammation caused by inhaled chemicals although further details remain unknown. Much of the harm associated with smoking has been linked to DNA damage due to reactive oxygen and nitrogen species. Consequently, a quantitative assessment of the extent to which such DNA damage occurs, could therefore be used to determine the relative damage caused through vaping and smoking.
In the current study, the US researchers explored the DNA-damaging effect induced by vaping and smoking compared to a group of non-smokers. The team quantified the DNA damage within oral epithelial cells using a polymerase chain reaction assay. The three groups were: exclusive vapers (who had never smoked); exclusive current smokers and non-smokers.
DNA damage in vapers and current smokers
A total of 72 individuals ranging in age from 24.3 to 26 years were included, 24 in each of the three groups.
Mean levels of DNA damage in oral epithelial cells were found to be 2.6- and 2.2-fold higher among vapers and smokers compared to non-smokers (p = 0.005 and 0.02) respectively. In addition, the level of damage was not significantly different between vapers and smokers with the extent of damage increasing in a dose-dependent manner from light to heavy users. Interestingly, the amount of nicotine present in those using electronic cigarettes did not correlate with the level of DNA damage. However, the damage was highest among those using used sweet-, mint or menthol-, and fruit-flavoured e-liquids, respectively.
The authors concluded that their findings had significant implications for public health given how the electronic cigarette flavoured liquids exhibiting the highest damage were also the most popular among younger vapers.
Tommasi S et al. Vaping Dose, Device Type, and E-Liquid Flavor are Determinants of DNA Damage in Electronic Cigarette Users. Nicotine Tob Res 2023