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1.
Br J Hosp Med (Lond) ; 82(11): 1-6, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34817261

RESUMO

Cystic fibrosis is a life-limiting, inherited, multi-organ disease which affects many systems of the body. Until recently, treatments were only able to ameliorate symptoms, but the introduction of precision medications which modulate the underlying defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene has changed this. Notably improvements in nutrition and lung function, reduced use of antibiotics and reduced occupation rates for hospital beds have been seen. This article summarises the discussion of a group of healthcare professionals from different specialties and an expert patient, representing their personal views and experience of treating patients who are using CFTR modulators. The discussion was sponsored by an unrestricted grant from Chiesi Limited (Manchester, UK).


Assuntos
Fibrose Cística , Quinolonas , Aminofenóis , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Mutação , Qualidade de Vida
2.
IET Nanobiotechnol ; 15(8): 664-673, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34694721

RESUMO

Zinc sulphide (ZnS) nanoparticles were synthesized by the coprecipitation method. The ZnS nanoparticle surface was polymerized with allyl glycidyl ether (AGE), and 3-aminophenol was then deposited as a ligand on nanosorbent. The modified nanosorbent was investigated with Fourier transform infrared spectroscopy and thermogravimetric analysis. The particle size of the modified nanosorbent was studied with scanning electron microscopy. Some characteristic factors of the adsorption process such as pH and time were investigated for famotidine using the modified nanosorbent. The equilibrium adsorption study of famotidine by 3-aminophenol-grafted AGE/ZnS was analysed by adsorption isotherms of the Langmuir, Freundlich, and Temkin models. The famotidine-releasing process was investigated in simulated biological fluids (intestinal fluid at pH of 7.4 and gastric fluid at pH of 1.2) and demonstrated 65% and 73% famotidine release during periods of 30 h (pH = 7.4) and 60 min (pH = 1.2), respectively. These results reveal the optimal performance of 3-aminophenol-grafted AGE/ZnS for sustained drug delivery.


Assuntos
Nanopartículas de Magnetita , Nanopartículas , Adsorção , Aminofenóis , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio , Cinética , Polímeros , Espectroscopia de Infravermelho com Transformada de Fourier , Sulfetos , Compostos de Zinco
3.
J Environ Sci (China) ; 108: 134-144, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34465427

RESUMO

Biodegradation mechanisms and microbial functional diversity during coupled p-nitrophenol (PNP) and p-aminophenol (PAP) degradation were studied in a bioelectrochemical system. PNP in the biocathode and PAP in the bioanode were almost completely removed within 28hr and 68hr respectively. The degradation followed the steps including hydrating hydroxyalkylation, dehydrogenating carbonylation, and hydrolating ring cleavage, etc. Metagemomic analysis based on the KEGG and eggNOG database annotations revealed the microbial composition and functional genes/enzymes related to phenol degradation in the system. The predominant bacteria genera were Lautropia, Pandoraea, Thiobacillus, Ignavibacterium, Truepera and Hyphomicrobium. The recognized biodegradation genes/enzymes related to pollutant degradation were as follows: pmo, hbd, & ppo for phenol degradation, nzba, amie, & badh for aromatic degradation, and CYP & p450 for xenobiotics degradation, etc. The co-occurrence of ARGs (antibiotic resistant genes), such as adeF, MexJ, ErmF, PDC-93 and Escherichia_coli_mdfA, etc., were annotated in CARD database during the biodegradation process. The Proteobacteria & Actinobacteria phylum was the primary host of both the biodegradation genes & ARGs in this system. The microbial functional diversity ensured the effective biodegradation of the phenol pollutants in the bioelectrochemical system.


Assuntos
Aminofenóis , Nitrofenóis , Biodegradação Ambiental
4.
Curr Opin Pulm Med ; 27(6): 554-566, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34420018

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to describe on-going and upcoming real-world studies that will aid the cystic fibrosis (CF) community in understanding the long-term efficacy, safety and challenges in utilizing this therapy and managing care. RECENT FINDINGS: The triple combination of elexacaftor, tezacaftor and ivacaftor (ETI) has been demonstrated to improve lung function, weight and quality of life in children and adults with CF with at least one copy of Phe508del. Treatment with ETI will potentially be available for approximately 90% of the CF population and change the face of CF. SUMMARY: In spite of early demonstrations of short-term efficacy and safety, for medications that may be given for much of someone's life, continued assessment of these outcomes is necessary. Furthermore, the CF community must evaluate and address the issues that arise with increased longevity including parenthood, preventive care management and the potential comorbidities of aging.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Adulto , Aminofenóis/uso terapêutico , Criança , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Combinação de Medicamentos , Humanos , Mutação , Qualidade de Vida
5.
N Engl J Med ; 385(9): 815-825, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34437784

RESUMO

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear. METHODS: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group. RESULTS: After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del-gating or Phe508del-residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).


Assuntos
Aminofenóis/uso terapêutico , Benzodioxóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/tratamento farmacológico , Indóis/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Quinolinas/uso terapêutico , Adolescente , Adulto , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Criança , Agonistas dos Canais de Cloreto/efeitos adversos , Cloretos/análise , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Genótipo , Humanos , Indóis/efeitos adversos , Masculino , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Quinolinas/efeitos adversos , Suor/química
6.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299226

RESUMO

Cystic fibrosis (CF) is caused by a defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) which instigates a myriad of respiratory complications including increased vulnerability to lung infections and lung inflammation. The extensive influx of pro-inflammatory cells and production of mediators into the CF lung leading to lung tissue damage and increased susceptibility to microbial infections, creates a highly inflammatory environment. The CF inflammation is particularly driven by neutrophil infiltration, through the IL-23/17 pathway, and function, through NE, NETosis, and NLRP3-inflammasome formation. Better understanding of these pathways may uncover untapped therapeutic targets, potentially reducing disease burden experienced by CF patients. This review outlines the dysregulated lung inflammatory response in CF, explores the current understanding of CFTR modulators on lung inflammation, and provides context for their potential use as therapeutics for CF. Finally, we discuss the determinants that need to be taken into consideration to understand the exaggerated inflammatory response in the CF lung.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/tratamento farmacológico , Pneumonia/tratamento farmacológico , Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Benzodioxóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Humanos , Indóis/uso terapêutico , Inflamação/tratamento farmacológico , Transporte de Íons , Pulmão/metabolismo , Pulmão/fisiologia , Macrófagos/metabolismo , Quinolonas/uso terapêutico , Transdução de Sinais
7.
Eur J Pediatr ; 180(9): 2731-2739, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34213646

RESUMO

Cystic fibrosis is the most prevalent inherited disease caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The impaired electrolyte homeostasis caused by the mutated or absent protein leads to symptoms in multiple organ systems. However, the pulmonary manifestation with chronic infections and eventually respiratory failure remains the most important threat. Until one decade ago, only symptomatic treatment was available. However, since 2012, different combinations of CFTR modulators are available for people with cystic fibrosis (pwCF) that carry different mutations. The advent of these drugs has impressively changed life expectancy and quality of life in people with cystic fibrosis and raised new challenges regarding long-term complications and tapering of conventional therapies.Conclusion: In this review, we provide an update on the latest developments around diagnostics, treatment, and prognosis of pwCF. What is Known: • Cystic fibrosis is an incurable and life-shortening disease asking for life-long symptomatic treatment. • Three combination CFTR modulating drugs has gained marked approval over the last 10 years. What is New: • The emerge of new (modulating) therapies contribute to the increasing life expectancy. • A high unmet need to develop new therapies for people with CF who cannot access or benefit from these drugs remains. This review gives an update on the current status.


Assuntos
Fibrose Cística , Quinolonas , Aminofenóis/uso terapêutico , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Mutação , Qualidade de Vida , Quinolonas/uso terapêutico
8.
Analyst ; 146(16): 5135-5142, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34282821

RESUMO

Nitrogen doped carbon dots were synthesized using the hydrothermal reaction of cellulose and urea, and then carbonized in a N2 atmosphere at a high temperature to prepare N-doped carbon dots decorated with manganese oxide nanospheres (N-CMOS) formed using cetyltrimethylammonium bromide (CTAB) and MnO. The introduction of N-CMOS resulted in a large specific surface area, abundant pores, favourable conductivity and an excellent electrocatalytic performance. A glassy carbon electrode modified with N-CMOS was used for the simultaneous identification of paracetamol (AP) and p-aminophenol (PAP) utilising differential pulse voltammetry. Under optimum conditions, the electrical sensor showed a wide linear range of 0.1-100 µM for PAP and 0.1-80 µM for AP, with detection limits of 0.0456 and 0.0303 µM (S/N = 3), respectively. The sensitivities for detecting PAP and AP were calculated as 1.615 and 1.971 µA µM-1 cm-2, respectively. The sensitivity and limit of detection (LOD) meet the requirements of detection of drug impurity limits in tablets. In addition, the sensor has been successfully applied to detect PAP and AP in paracetamol tablets. The constructed sensor not only possesses a superior repeatability, reproducibility and stability, but a relatively wide linear range, and a superior detection limit and sensitivity.


Assuntos
Carbono , Nanosferas , Acetaminofen , Aminofenóis , Técnicas Eletroquímicas , Eletrodos , Limite de Detecção , Compostos de Manganês , Óxidos , Reprodutibilidade dos Testes
9.
Sci Total Environ ; 795: 148806, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34243001

RESUMO

Previous studies have demonstrated the presence of precursors and coupling agents in wastewater from hair dyeing processes. The complex reaction involved in the oxidation of these compounds can generate extremely hazardous sub-products, leading to an increase in the mutagenicity and toxicity of wastewater. Without proper treatment, this highly toxic wastewater may find its way into the drinking water treatment plant. The present work aimed to investigate the main products generated after the oxidation reaction involving p-toluenediamine (PTD) and p-aminophenol (PAP) - precursors that widely used in the composition of commercial permanent hair dyes, under experimental conditions close to the routine hair dyeing process (in the presence and absence of hydrogen peroxide in ammoniacal medium), using spectroscopic techniques. The study also investigated the mutagenicity and toxicity of the products formed in the hairdressing wash water and conducted detection analysis to determine the presence of the precursors and Bandrowski's Base Derivative (BBD) in samples of wastewater, surface and drinking water using HPLC-DAD and linear voltammetry techniques. Based on this investigation, we identified several PTD and PAP self-oxidation products and eleven sub-products derived from the reaction between PTD and PAP. Assays conducted using Salmonella typhimurium YG1041, with and without activation-induced rat liver metabolism (S9), indicated mutagenicity of the reaction products in concentrations above 10.0 µg µL-1. The concentrations of PTD, PAP, and several reactions and oxidation products of these precursors were detected in wastewater and water samples.


Assuntos
Tinturas para Cabelo , Aminofenóis , Animais , Tinturas para Cabelo/toxicidade , Testes de Mutagenicidade , Mutagênicos/toxicidade , Estresse Oxidativo , Fenilenodiaminas , Ratos
12.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067708

RESUMO

Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta®/Kaftrio®) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60-70% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Pirrolidinas/farmacologia , Aminofenóis/farmacologia , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Combinação de Medicamentos , Células Epiteliais/metabolismo , Humanos , Indóis/farmacologia , Dobramento de Proteína/efeitos dos fármacos , Pirazóis/metabolismo , Piridinas/metabolismo , Pirrolidinas/metabolismo , Quinolinas/farmacologia
13.
J Clin Invest ; 131(16)2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34166230

RESUMO

Without cystic fibrosis transmembrane conductance regulator-mediated (CFTR-mediated) HCO3- secretion, airway epithelia of newborns with cystic fibrosis (CF) produce an abnormally acidic airway surface liquid (ASL), and the decreased pH impairs respiratory host defenses. However, within a few months of birth, ASL pH increases to match that in non-CF airways. Although the physiological basis for the increase is unknown, this time course matches the development of inflammation in CF airways. To learn whether inflammation alters CF ASL pH, we treated CF epithelia with TNF-α and IL-17 (TNF-α+IL-17), 2 inflammatory cytokines that are elevated in CF airways. TNF-α+IL-17 markedly increased ASL pH by upregulating pendrin, an apical Cl-/HCO3- exchanger. Moreover, when CF epithelia were exposed to TNF-α+IL-17, clinically approved CFTR modulators further alkalinized ASL pH. As predicted by these results, in vivo data revealed a positive correlation between airway inflammation and CFTR modulator-induced improvement in lung function. These findings suggest that inflammation is a key regulator of HCO3- secretion in CF airways. Thus, they explain earlier observations that ASL pH increases after birth and indicate that, for similar levels of inflammation, the pH of CF ASL is abnormally acidic. These results also suggest that a non-cell-autonomous mechanism, airway inflammation, is an important determinant of the response to CFTR modulators.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Interleucina-17/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Aminofenóis/administração & dosagem , Benzodioxóis/administração & dosagem , Bicarbonatos/metabolismo , Células Cultivadas , Fibrose Cística/tratamento farmacológico , Fibrose Cística/imunologia , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Combinação de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Indóis/administração & dosagem , Lactente , Recém-Nascido , Interleucina-17/administração & dosagem , Transporte de Íons , Mutação , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Quinolinas/administração & dosagem , Mucosa Respiratória/efeitos dos fármacos , Transportadores de Sulfato/genética , Transportadores de Sulfato/metabolismo , Fator de Necrose Tumoral alfa/administração & dosagem
14.
Colloids Surf B Biointerfaces ; 205: 111835, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33992822

RESUMO

Alkaline phosphatase (ALP) is an enzyme that catalyzes the dephosphorylation of proteins, nucleic acids, and biomolecules. It is a potential biomarker for diverse diseases such as breast cancer, osteopenia, and hepatobiliary. Herein, we developed a colorimetric sensor for the ALP assay based on its enzymatic activity to dephosphorylate the p-aminophenol phosphate (pAPP) into pAP. In a solution containing silver nanoparticles (AgNPs) and Ag+ ions prepared using a low concentration of NaBH4, pAP mediates the growth of AgNPs by reducing the concentration of Ag+ ions to enhance the intensity of localized surface plasmon resonance as the pAPP cannot induce a reduction of the remaining Ag+ due to the masking of the hydroxyl with phosphate. The quantitative assay of the ALP was demonstrated via the colorimetric detection of the pAP-mediated growth of AgNPs in the presence of an ALP. The highly sensitive enzymatic growth of AgNPs provided a wider dynamic linear range of 0.5-225 U/L with a lower limit of detection of 0.24 U/L than that previously reported. The use of pAP resulted in excellent selectivity of the sensor for the ALP assay in human serum, yielding a high recovery rate and a high precision of 99.2 ± 1.5 % for the standard addition method.


Assuntos
Técnicas Biossensoriais , Nanopartículas Metálicas , Fosfatase Alcalina , Aminofenóis , Colorimetria , Humanos , Limite de Detecção , Prata
15.
J Org Chem ; 86(10): 7119-7130, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33960192

RESUMO

A heterobimetallic zinc/strontium catalyst has been developed for the asymmetric Michael addition of 3-acetoxy-2-oxindoles to ß-ester enones in high yields with excellent enantioselectivities and high diastereoselectivities. This process represents that 3-acetoxy-2-oxindoles can be used as a stable air- and base-tolerant precursor for chiral 3-substituted 3-hydroxy-2-oxindoles.


Assuntos
Aminofenóis , Zinco , Catálise , Ésteres , Indóis , Metais Alcalinoterrosos , Oxindóis , Estereoisomerismo , Sulfonamidas
16.
Ecotoxicol Environ Saf ; 220: 112373, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34058675

RESUMO

The electronic conductivity of the metal oxides is generally increased by hybridization of highly conductive carbon supportive materials. In this present work, we have demonstrated a novel one-pot preparation of cerium niobate (CeNbO4) nanoparticles embedded with graphene oxide (GO/CeNbO4) composite, for ultrasensitive detection of the photographic developing agent, metol (MTL). The as-prepared GO/CeNbO4 was analyzed by various characterization techniques. The intensive characterization techniques were used to affirm the detailed structural moiety, size, morphology, and surface area of GO/CeNbO4. The GO/CeNbO4 modified glassy carbon electrode (GCE) affords a superior electrocatalytic activity toward MTL. The obtained amperometric response on the GO/CeNbO4/GCE holding an extremely low level detection of 10 nM and superior sensitivity of 10.97 µA µM-1 cm-2 toward MTL detection. Besides, the GO/CeNbO4/GCE also gives excellent selectivity, stability, repeatability, and reproducibility. We achieved excellent recovery results in real photographic solution and river water samples analysis with great accuracy. This work offers a novel insight into the growth of the carbon-based niobate family with electrochemical sensor applications.


Assuntos
Aminofenóis/análise , Técnicas Eletroquímicas/métodos , Monitoramento Ambiental/métodos , Poluentes Ambientais/análise , Nanocompostos/química , Rios/química , Sulfatos/análise , Carbono/química , Catálise , Cério/química , Eletricidade , Eletrodos , Grafite/química , Indústrias , Nanopartículas/química , Nióbio/química , Óxidos/química , Compostos de Oxigênio/química , Fotografação , Reprodutibilidade dos Testes , Soluções , Água/química
17.
Lancet Respir Med ; 9(9): 977-988, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33965000

RESUMO

BACKGROUND: A previous phase 3 study showed that lumacaftor-ivacaftor was generally safe and well tolerated over 24 weeks of treatment in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation. In this study, we aimed to assess the long-term safety of lumacaftor-ivacaftor in a rollover study of children who participated in this previous phase 3 study. METHODS: In this multicentre, phase 3, open-label, extension study (study 116; VX16-809-116), we assessed safety of lumacaftor-ivacaftor in children included in a previous multicentre, phase 3, open-label study (study 115; VX15-809-115). The study was done at 20 cystic fibrosis care centres in the USA and Canada. Children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation who completed 24 weeks of lumacaftor-ivacaftor treatment in study 115 received weight-based and age-based doses of oral lumacaftor-ivacaftor: children weighing less than 14 kg and aged younger than 6 years at study 116 screening received lumacaftor 100 mg-ivacaftor 125 mg every 12 h; children weighing 14 kg or more and aged younger than 6 years at screening received lumacaftor 150 mg-ivacaftor 188 mg every 12 h; and children aged 6 years or older received lumacaftor 200 mg-ivacaftor 250 mg every 12 h. Children received treatment for up to 96 weeks, equivalent to up to 120 weeks of treatment in total from the start of study 115 to completion of study 116. The primary endpoint was the safety and tolerability of the study drug in all participants who had received lumacaftor-ivacaftor for 24 weeks in study 115 and had received at least one dose in study 116. Secondary endpoints included change from baseline in study 115 at week 96 of study 116 in sweat chloride concentration, growth parameters, markers of pancreatic function, and lung clearance index (LCI) parameters in all children who received at least one dose of lumacaftor-ivacaftor in study 116. This study is registered with ClinicalTrials.gov, NCT03125395. FINDINGS: This extension study ran from May 12, 2017, to July 17, 2019. Of 60 participants enrolled and who received lumacaftor-ivacaftor in study 115, 57 (95%) were included in study 116 and continued to receive the study drug. A total of 47 (82%) of 57 participants completed 96 weeks of treatment. Most participants (56 [98%] of 57) had at least one adverse event during study 116, most of which were mild (19 [33%] participants) or moderate (29 [51%] participants) in severity. The most common adverse events were cough (47 [82%] participants), nasal congestion (25 [44%] participants), pyrexia (23 [40%] participants), rhinorrhoea (18 [32%] participants), and vomiting (17 [30%] participants). A total of 15 (26%) participants had at least one serious adverse event; most were consistent with underlying cystic fibrosis or common childhood illnesses. Respiratory adverse events occurred in five (9%) participants, none of which were serious or led to treatment discontinuation. Elevated aminotransferase concentrations, most of which were mild or moderate in severity, occurred in ten (18%) participants. Three (5%) participants discontinued treatment due to adverse events (two due to increased aminotransferase concentrations [one of whom had concurrent pancreatitis], considered as possibly related to study drug; and one due to gastritis and metabolic acidosis, considered unlikely to be related to study drug). No clinically significant abnormalities or changes were seen in electrocardiograms, vital signs, pulse oximetry, ophthalmological examinations, or spirometry assessments. Improvements in secondary endpoints observed in study 115 were generally maintained up to week 96 of study 116, including improvements in sweat chloride concentration (mean absolute change from study 115 baseline at week 96 of study 116 -29·6 mmol/L [95% CI -33·7 to -25·5]), an increase in growth parameters and pancreatic function, and stable lung function relative to baseline, as measured by the LCI. INTERPRETATION: Lumacaftor-ivacaftor was generally safe and well tolerated, and treatment effects were generally maintained for the duration of the extension study. These findings support the use of lumacaftor-ivacaftor for up to 120 weeks in young children with cystic fibrosis aged 2 years and older homozygous for the F508del-CFTR mutation. FUNDING: Vertex Pharmaceuticals Incorporated.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Aminofenóis/efeitos adversos , Aminopiridinas/efeitos adversos , Benzodioxóis/efeitos adversos , Criança , Pré-Escolar , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Mutação , Quinolonas
20.
Am J Physiol Gastrointest Liver Physiol ; 320(6): G1123-G1130, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33949881

RESUMO

Cystic fibrosis is a deadly multiorgan disorder caused by loss of function mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) chloride/bicarbonate ion channel. More than 1,700 CFTR genetic variants exist that can cause CF, and majority of these are extremely rare. Because of genetic and environmental influences, CF patients exhibit large phenotypic variation. These factors make clinical trials difficult and largely impractical due to limited and heterogeneous patient pools. Also, the benefit of approved small-molecule CF modulators in a large number of rare mutation patients remains unknown. The goal of this study is to perform a comprehensive bench-side study using in vitro patient enteroids and in vivo mice implanted human intestinal organoids (HIOs) to test CF modulator-Ivacaftor response for a rare CF mutation patient. Based on the positive Ivacaftor response in the enteroids, the patient was enrolled in a (N = 1) clinical trial and showed improved clinical outcomes upon Ivacaftor treatment. HIO implantation model allowed in vivo modulator dosing and provided an elegant human organ-based demonstration of bench-to-bedside testing of modulator effects. Additionally, using the CF HIO model the role of CFTR function in the maturation of human intestine was reported for the first time. In all, we demonstrate that these models effectively serve to translate data from the lab to the clinic and back so that patient-specific therapies could be easily identified and disease-relevant developmental abnormalities in CF organs could be studied and addressed.NEW & NOTEWORTHY In this study, we report an example of laboratory models informing clinical care for rare CF mutation patient, with subsequent recapitulation of clinical benefit in a unique and disease relevant, human-derived in vivo model, effectively translating data from the lab to the clinic and back. This extensive work outlines a potential platform to identify patient-specific therapies and to understand relevant developmental abnormalities associated with CF disease.


Assuntos
Aminofenóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Mutação , Quinolonas/uso terapêutico , Aminofenóis/farmacologia , Animais , Criança , Agonistas dos Canais de Cloreto/farmacologia , Fibrose Cística/genética , Humanos , Camundongos , Organoides/efeitos dos fármacos , Medicina de Precisão , Quinolonas/farmacologia
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