Designing Clinical Trials for Anti-Inflammatory Therapies in Cystic Fibrosis

: Several studies have indicated an association between inflammation and the recurrence of Atrial Fibrillation (AF), especially after ablation, which is a therapeutic option leading to local inflammation. On the other hand, each AF can lead to another AF, as a general rule. Thus, preventing recurrences of AF is extremely important for patient outcomes. In this paper, we attempted to review the effect of medicinal agents with anti-inflammatory properties on the prevention of AF recurrence. There are several randomized controlled trials (RCTs) and meta-analyses on the prevention of AF recurrence using agents with anti-inflammatory properties, which include steroids, colchicine, statins, and n-3 fatty acids (n-3 FA). Clinical trials evaluating the efficacy of anti-inflammatory drugs in preventing the recurrence of AF led to inconsistent results for corticosteroids, statins and n-3 FAs. These results may be related to the fact that inflammation is not the only factor responsible for triggering recurrences of AF. For example, the presence of structural, mechanical and electrical remodeling could potentially be the most important factors that trigger recurrences of AF but these factors have not been addressed in most of the reported studies. Therefore, future clinical trials are needed to compare the efficacy of anti-inflammatory drugs in AF patients with, or without other factors. For colchicine, a potent anti-inflammatory drug, there are limited studies. However, all the studies investigating colchicine in the context of AF were consistent and promising, especially when colchicine was used on a short-term basis following ablation in patients with paroxysmal AF. Therefore, colchicine could be a promising candidate for further clinical studies involving recurrent AF.

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Variation in treatment preferences of pulmonary exacerbations among Australian and New Zealand cystic fibrosis physicians

BMJ Open Respiratory Research ◽

10.1136/bmjresp-2021-000956 ◽

2021 ◽

Vol 8 (1) ◽

pp. e000956

Author(s):

Grace Currie ◽

Anna Tai ◽

Tom Snelling ◽

André Schultz

Keyword(s):

Cystic Fibrosis ◽

Clinical Trials ◽

New Zealand ◽

Treatment Options ◽

Early Response ◽

Treatment Preferences ◽

Dornase Alfa ◽

Clinical Scenarios ◽

Professional Opinion ◽

Pulmonary Exacerbations

BackgroundDespite advances in cystic fibrosis (CF) management and survival, the optimal treatment of pulmonary exacerbations remains unclear. Understanding the variability in treatment approaches among physicians might help prioritise clinical uncertainties to address through clinical trials.MethodsPhysicians from Australia and New Zealand who care for people with CF were invited to participate in a web survey of treatment preferences for CF pulmonary exacerbations. Six typical clinical scenarios were presented; three to paediatric and another three to adult physicians. For each scenario, physicians were asked to choose treatment options and provide reasons for their choices.ResultsForty-nine CF physicians (31 paediatric and 18 adult medicine) participated; more than half reported 10+ years of experience. There was considerable variation in primary antibiotic selection; none was preferred by more than half of respondents in any scenario. For secondary antibiotic therapy, respondents consistently preferred intravenous tobramycin and a third antibiotic was rarely prescribed, except in one scenario describing an adult patient. Hypertonic saline nebulisation and twice daily chest physiotherapy was preferred in most scenarios while dornase alfa use was more variable. Most CF physicians (>80%) preferred to change therapy if there was no early response. Professional opinion was the most common reason for antibiotic choice.ConclusionsVariation exists among CF physicians in their preferred choice of primary antibiotic and use of dornase alfa. These preferences are driven by professional opinion, possibly reflecting a lack of evidence to base policy recommendations. Evidence from high-quality clinical trials is needed to inform physician decision making.

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Anti-inflammatory effects of melatonin: A systematic review and meta-analysis of clinical trials

Brain Behavior and Immunity ◽

10.1016/j.bbi.2021.01.034 ◽

2021 ◽

Vol 93 ◽

pp. 245-253 ◽

Cited By ~ 1

Author(s):

Joshua H. Cho ◽

Saumya Bhutani ◽

Carole H. Kim ◽

Michael R. Irwin

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Meta Analysis ◽

Anti Inflammatory

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Macrophage Activation and Cytokine Release Syndrome in COVID-19: Current Updates and Analysis of Repurposed and Investigational Anti-Cytokine Drugs

Drug Research ◽

10.1055/a-1291-7692 ◽

2021 ◽

Cited By ~ 1

Author(s):

Ashif Iqubal ◽

Farazul Hoda ◽

Abul Kalam Najmi ◽

Syed Ehtaishamul Haque

Keyword(s):

Immune Response ◽

Clinical Trials ◽

Macrophage Activation ◽

Fatality Rate ◽

Cytokine Storm ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Disease Condition ◽

Inflammatory Drugs ◽

Anti Inflammatory

AbstractCoronavirus disease (COVID-19) emerged from Wuhan, has now become pandemic and the mortality rate is growing exponentially. Clinical complication and fatality rate is much higher for patients having co-morbid issues. Compromised immune response and hyper inflammation is hall mark of pathogenesis and major cause of mortality. Cytokine release syndrome (CRS) or cytokine storm is a term used to affiliate the situation of hyper inflammation and therefore use of anti-cytokine and anti-inflammatory drugs is used to take care of this situation. Looking into the clinical benefit of these anti-inflammatory drugs, many of them enter into clinical trials. However, understanding the immunopathology of COVID-19 is important otherwise, indiscriminate use of these drugs could be fetal as there exists a very fine line of difference between viral clearing cytokines and inflammatory cytokines. If any drug suppresses the viral clearing cytokines, it will worsen the situation and hence, the use of these drugs must be based on the clinical condition, viral load, co-existing disease condition and severity of the infection.

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Targeted Drug Delivery Technologies Potentiate the Overall Therapeutic Efficacy of an Indole Derivative in a Mouse Cystic Fibrosis Setting

Cells ◽

10.3390/cells10071601 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1601

Author(s):

Matteo Puccetti ◽

Marilena Pariano ◽

Giorgia Renga ◽

Ilaria Santarelli ◽

Fiorella D’Onofrio ◽

...

Keyword(s):

Cystic Fibrosis ◽

Targeted Drug Delivery ◽

Fungal Infections ◽

Murine Models ◽

Multisystem Disease ◽

Aryl Hydrocarbon ◽

Target Organs ◽

Infection And Inflammation ◽

Anti Inflammatory ◽

Inflammatory Toxicity

Inflammation plays a major role in the pathophysiology of cystic fibrosis (CF), a multisystem disease. Anti-inflammatory therapies are, therefore, of interest in CF, provided that the inhibition of inflammation does not compromise the ability to fight pathogens. Here, we assess whether indole-3-aldehyde (3-IAld), a ligand of the aryl hydrocarbon receptor (AhR), may encompass such an activity. We resorted to biopharmaceutical technologies in order to deliver 3-IAld directly into the lung, via dry powder inhalation, or into the gut, via enteric microparticles, in murine models of CF infection and inflammation. We found the site-specific delivery of 3-IAld to be an efficient strategy to restore immune and microbial homeostasis in CF organs, and mitigate lung and gut inflammatory pathology in response to fungal infections, in the relative absence of local and systemic inflammatory toxicity. Thus, enhanced delivery to target organs of AhR agonists, such as 3-IAld, may pave the way for the development of safe and effective anti-inflammatory agents in CF.

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DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study

Genes ◽

10.3390/genes12030441 ◽

2021 ◽

Vol 12 (3) ◽

pp. 441

Author(s):

Fanny Pineau ◽

Davide Caimmi ◽

Sylvie Taviaux ◽

Maurane Reveil ◽

Laura Brosseau ◽

...

Keyword(s):

Cystic Fibrosis ◽

Dna Methylation ◽

Clinical Trials ◽

Lung Disease ◽

Disease Severity ◽

Genome Wide ◽

A Genome ◽

Lung Disease Severity ◽

Epigenetic Biomarker

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

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