Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis

Skilton, Mica; Krishan, Ashma; Patel, Sanjay R.; Sinha, Ian; Southern, Kevin W

doi:10.1002/14651858.cd009841.pub3

Cited by 19 publications

(13 citation statements)

References 93 publications

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“…Ivacaftor (Kalydeco ® ) was the first CFTR modulator available and is a CFTR potentiator that augments anion transport by increasing CFTR channel‐open probability 6 . It was shown to improve FEV1 lung function, reduce pulmonary exacerbations, the need of hospitalization and IV (intravenous) antibiotics in patients with gating mutation G551D 7 . Post hoc analysis further revealed the potential benefit ivacaftor has in improving weight gain in both age‐adjusted paediatric and adult patients 8 .…”

Section: What Is Known and Objectivementioning

confidence: 99%

A current review of the safety of cystic fibrosis transmembrane conductance regulator modulators

Gavioli¹,

Guardado²,

Haniff³

et al. 2020

J Clin Pharm Ther

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What is known and objective Treatment with cystic fibrosis transmembrane conductance regulator (CFTR) modulators has led to improved clinical outcomes and an increase in lifespans of cystic fibrosis (CF) patients. As CF patients continue to live longer, they are at risk for developing adverse drug reactions associated with polypharmacy and CFTR modulators. Comment The authors aim to describe safety concerns of the current combination CFTR modulators, based upon a literature review, including notable safety concerns and recommendations for drug‐drug interactions. What is new and conclusion Cystic fibrosis transmembrane conductance regulator agents are generally well tolerated with low discontinuation rates when compared to placebo. Elevations in liver enzymes and drug‐drug interactions are the most notable safety concerns. Additionally, lumacaftor/ivacaftor has shown more respiratory‐related adverse events and drug‐drug interactions compared to elexacaftor/tezacaftor/ivacaftor and tezacaftor/ivacaftor. Postmarketing studies are needed to determine long‐term safety concerns.

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Section: What Is Known and Objectivementioning

confidence: 99%

A current review of the safety of cystic fibrosis transmembrane conductance regulator modulators

Gavioli¹,

Guardado²,

Haniff³

et al. 2020

J Clin Pharm Ther

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“…Recent clinical studies show that CFTR potentiators (e.g., Ivacaftor) successfully correct these defects in patients with these mutations [75,76,77,78]. Class IV mutations lead to disruptions in the chloride conducting capacity of the CFTR protein because of missense mutations and protein misfolding (e.g., R117H) [79,80]. Class V mutations include missense mutations that lead to a decrease in CFTR protein synthesis, resulting in a low abundance on the cell surface (e.g., A455E) [81].…”

Section: Cystic Fibrosismentioning

confidence: 99%

Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation

Khan

Ali

Sweezey

et al. 2019

Genes

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Genetic defects in cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene cause CF. Infants with CFTR mutations show a peribronchial neutrophil infiltration prior to the establishment of infection in their lung. The inflammatory response progressively increases in children that include both upper and lower airways. Infectious and inflammatory response leads to an increase in mucus viscosity and mucus plugging of small and medium-size bronchioles. Eventually, neutrophils chronically infiltrate the airways with biofilm or chronic bacterial infection. Perpetual infection and airway inflammation destroy the lungs, which leads to increased morbidity and eventual mortality in most of the patients with CF. Studies have now established that neutrophil cytotoxins, extracellular DNA, and neutrophil extracellular traps (NETs) are associated with increased mucus clogging and lung injury in CF. In addition to opportunistic pathogens, various aspects of the CF airway milieux (e.g., airway pH, salt concentration, and neutrophil phenotypes) influence the NETotic capacity of neutrophils. CF airway milieu may promote the survival of neutrophils and eventual pro-inflammatory aberrant NETosis, rather than the anti-inflammatory apoptotic death in these cells. Degrading NETs helps to manage CF airway disease; since DNAse treatment release cytotoxins from the NETs, further improvements are needed to degrade NETs with maximal positive effects. Neutrophil-T cell interactions may be important in regulating viral infection-mediated pulmonary exacerbations in patients with bacterial infections. Therefore, clarifying the role of neutrophils and NETs in CF lung disease and identifying therapies that preserve the positive effects of neutrophils, while reducing the detrimental effects of NETs and cytotoxic components, are essential in achieving innovative therapeutic advances.

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“…This question is best addressed with Ivacaftor (Kalydeco), which has now been administered to individuals with CFTR gating mutations for more than seven years [41]. At this pre-conference meeting it was shown that robust Ivacaftor-induced improvements in ion transport, airway surface liquid height and ciliary beating in vitro by cultured human bronchial epithelial cells correlated well with clinical parameters, including reduced sweat chloride concentration, improved lung function (measured by forced expiratory volume in one second; FEV 1 ), increased mucus clearance and reduced lung inflammation and exacerbations [42] (IS-G, PCM). Clearly, targeting the cause of CF relieves clinical manifestations.…”

Section: The Clinical Benefit Of Allosteric Modulation Of Cftr Functionmentioning

confidence: 99%

CFTR: New insights into structure and function and implications for modulation by small molecules

Kleizen

Hunt²,

Callebaut³

et al. 2020

Journal of Cystic Fibrosis

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Structural biology and functional studies are a powerful combination to elucidate fundamental knowledge about the cystic fibrosis transmembrane conductance regulator (CFTR). Here, we discuss the latest findings, including how clinically-approved drugs restore function to mutant CFTR, leading to better clinical outcomes for people with cystic fibrosis (CF). Despite the prospect of regulatory approval of a CFTR-targeting therapy for most CF mutations, strenuous efforts are still needed to fully comprehend CFTR structure-and-function for the development of better drugs to enable people with CF to live full and active lives.

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Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis

Abstract: Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis.

Cited by 19 publications

References 93 publications

A current review of the safety of cystic fibrosis transmembrane conductance regulator modulators

A current review of the safety of cystic fibrosis transmembrane conductance regulator modulators

Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation

CFTR: New insights into structure and function and implications for modulation by small molecules

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