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1.
Int Forum Allergy Rhinol ; 14(10): 1607-1617, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39212072

RESUMO

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve pulmonary outcomes in cystic fibrosis (CF) by stabilizing the CFTR protein on respiratory epithelial surfaces. To determine the efficacy of CFTR modulators on sinonasal outcomes in patients with CF, we performed a meta-analysis of clinical trials to date that include functional and radiographic evidence of sinus disease. METHODS: English full-text articles were searched in PubMed, Embase, and Scopus databases. Two reviewers screened articles and a third reviewer resolved disagreements. Articles were included if they reported functional or radiological sinonasal outcomes in patients with CF before and after CFTR modulator therapies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed, and the risk of bias in non-randomized studies of interventions tool was used for quality assessment. The generic inverse variance method with random effects model was used for meta-analysis. Standardized mean difference (SMD) and mean difference (MD) were used as effect measurements. RESULTS: Seven prospective and two retrospective studies representing 248 patients were included in this analysis. There was a significant improvement in sinonasal outcome test-22 scores on elexacaftor‒tezacaftor‒ivacaftor (MD = 12.80, [95% confidence interval, CI: 10.46‒15.13], p < 0.001, n = 222), with no heterogeneity detected (I2 = 0%, p = 0.820). There was also a significant improvement in Lund‒Mackay scores (SMD = 1.25, [95% CI: 0.58‒1.91], p < 0.001, n = 88), with heterogeneity detected (I2 = 67%, p = 0.030). CONCLUSIONS: CFTR modulators improve functional and radiologic sinonasal outcomes. Given the utility of CFTR modulators, the treatment paradigm for CF-related chronic rhinosinusitis promises to evolve.


Assuntos
Aminofenóis , Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Quinolonas , Rinossinusite , Humanos , Aminofenóis/uso terapêutico , Benzodioxóis/uso terapêutico , Fibrose Cística/complicações , Fibrose Cística/diagnóstico por imagem , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Seios Paranasais/diagnóstico por imagem , Quinolonas/uso terapêutico , Resultado do Tratamento , Rinossinusite/diagnóstico por imagem , Rinossinusite/tratamento farmacológico , Rinossinusite/etiologia
2.
Expert Opin Pharmacother ; 25(10): 1281-1290, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39058326

RESUMO

INTRODUCTION: Chronic idiopathic constipation (CIC) is characterized by infrequent bowel movements and hard stools lasting for at least three months or longer. This disease affects 8-12% of the US population and 10-17% of the world population. Treatment and management involve identifying the primary cause, changing dietary habits, and adequate physical activity. Linaclotide is a guanylate cyclase-agonist acting locally in the luminal surface of the intestinal enterocyte leading to a signal transduction cascade, activation of the cystic fibrosis transmembrane conductance regulator (CFTR), thus increasing secretion of chloride and bicarbonate into the intestinal lumen with eventual increased intestinal fluid and faster transit time. AREAS COVERED: We reviewed multiple studies and did a thorough literature review on CIC including its pathophysiology. Through this literature review, we were able to discuss and give the context and rationale for drug regimens indicated for CIC. EXPERT OPINION: The era we live in right now is akin to nutrient-rich and fertilized soil as knowledge and resources are abundant. The opportunities and potential are endless. Constipation being more extensively studied, our understanding of medications and diseases broadens, leading to novel medications being discovered. Linaclotide is a pioneer in this aspect and can pave the way for future generations.


Assuntos
Constipação Intestinal , Agonistas da Guanilil Ciclase C , Peptídeos , Humanos , Constipação Intestinal/tratamento farmacológico , Doença Crônica , Peptídeos/uso terapêutico , Agonistas da Guanilil Ciclase C/uso terapêutico , Animais , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Fármacos Gastrointestinais/uso terapêutico , Fármacos Gastrointestinais/farmacologia
3.
J Heart Lung Transplant ; 40(12): 1498-1501, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34538541

RESUMO

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapy has previously been contraindicated in solid organ transplant recipients. This was due to lack of data and concern for interactions with immunosuppressive drug regimens. However, in post-lung transplant recipients, CFTR modulators may improve extrapulmonary manifestations of cystic fibrosis without impacting graft function or immunosuppressive drug levels. Herein, we present our single center experience with the use of elexacaftor/tezacaftor/ivacaftor, Trikafta, in adult post-lung transplant recipients.


Assuntos
Aminofenóis/uso terapêutico , Benzodioxóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Fibrose Cística/tratamento farmacológico , Fibrose Cística/cirurgia , Indóis/uso terapêutico , Transplante de Pulmão , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Quinolinas/uso terapêutico , Adulto , Glicemia , Índice de Massa Corporal , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
4.
Am J Respir Cell Mol Biol ; 64(5): 604-616, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33616476

RESUMO

Premature-termination codons (PTCs) in CFTR (cystic fibrosis [CF] transmembrane conductance regulator) result in nonfunctional CFTR protein and are the proximate cause of ∼11% of CF-causing alleles, for which no treatments exist. The CFTR corrector lumacaftor and the potentiator ivacaftor improve CFTR function with terminal PTC mutations and enhance the effect of readthrough agents. Novel correctors GLPG2222 (corrector 1 [C1]), GLPG3221 (corrector 2 [C2]), and potentiator GLPG1837 compare favorably with lumacaftor and ivacaftor in vitro. Here, we evaluated the effect of correctors C1a and C2a (derivatives of C1 and C2) and GLPG1837 alone or in combination with the readthrough compound G418 on CFTR function using heterologous Fischer rat thyroid (FRT) cells, the genetically engineered human bronchial epithelial (HBE) 16HBE14o- cell lines, and primary human cells with PTC mutations. In FRT lines pretreated with G418, GLPG1837 elicited dose-dependent increases in CFTR activity that exceeded those from ivacaftor in FRT-W1282X and FRT-R1162X cells. A three-mechanism strategy consisting of G418, GLPG1837, and two correctors (C1a + C2a) yielded the greatest functional improvements in FRT and 16HBE14o- PTC variants, noting that correction and potentiation without readthrough was sufficient to stimulate CFTR activity for W1282X cells. GLPG1837 + C1a + C2a restored substantial function in G542X/F508del HBE cells and restored even more function for W1282X/F508del cells, largely because of the corrector/potentiator effect, with no additional benefit from G418. In G542X/R553X or R1162X/R1162X organoids, enhanced forskolin-induced swelling was observed with G418 + GLPG1837 + C1a + C2a, although GLPG1837 + C1a + C2a alone was sufficient to improve forskolin-induced swelling in W1282X/W1282X organoids. Combination of CFTR correctors, potentiators, and readthrough compounds augments the functional repair of CFTR nonsense mutations, indicating the potential for novel correctors and potentiators to restore function to truncated W1282X CFTR.


Assuntos
Benzoatos/farmacologia , Benzopiranos/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Células Epiteliais/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Piranos/farmacologia , Pirazóis/farmacologia , Aminofenóis/farmacologia , Aminopiridinas/farmacologia , Animais , Benzodioxóis/farmacologia , Linhagem Celular , Cloretos/metabolismo , Códon sem Sentido , Fibrose Cística/tratamento farmacológico , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Regulador de Condutância Transmembrana em Fibrose Cística/deficiência , Células Epiteliais/metabolismo , Humanos , Transporte de Íons/efeitos dos fármacos , Quinolonas/farmacologia , Ratos , Recuperação de Função Fisiológica , Células Epiteliais da Tireoide/efeitos dos fármacos , Células Epiteliais da Tireoide/metabolismo
5.
J Diabetes Complications ; 35(6): 107845, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33558149

RESUMO

BACKGROUND: Half of adults with cystic fibrosis (CF) develop CF-related diabetes (CFRD). CFRD contributes to worsened pulmonary function and malnutrition. We undertook this study to determine the effect of cystic fibrosis transmembrane regulator (CFTR) modulators on CRFD. METHODS: We reviewed the medical records of adults with CF who followed in the CF clinic at Oklahoma University Medical Center. We collected data for age at diagnosis of CF and CFRD, CF mutations present, first date of ivacaftor therapy either alone or in combination, insulin use, pulmonary function, body mass index data, and home glucose monitoring results. Clinical resolution of CFRD was taken as discontinuation of routine insulin and resolution of high interstitial home glucose values. RESULTS: We identified 69 adult CF patients, of whom 31 had CFRD. Among these 14 CFRD patients taking ivacaftor alone or in combination, four patients completely stopped using insulin. Another patient went from three times a day pre-prandial insulin to using insulin once a week. Home blood glucose and hemoglobin A1c values supported resolution of CFRD. Three patients continued to have hypoglycemia despite stopping insulin. No CFRD patient not taking CFTR modulators markedly changed the insulin regimen. Pulmonary function was preserved in those patients with resolved CFRD (FEV1 +6.75% ±7.6), whereas it worsened in CFRD patients who either were not taking CFTR modulators (FEV1 -2.09% ±3.9) or who had no response of CFRD status (FEV1 -4.9% ±7.6). CONCLUSIONS: About one-third of patients on CFTR modulator therapy had resolution or near resolution of CFRD.


Assuntos
Aminofenóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística , Diabetes Mellitus , Quinolonas/uso terapêutico , Adulto , Glicemia , Automonitorização da Glicemia , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Diabetes Mellitus/tratamento farmacológico , Humanos , Insulina/uso terapêutico
6.
J Manag Care Spec Pharm ; 27(2): 281-284, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33506726

RESUMO

DISCLOSURES: No funding contributed to the writing of this commentary. Both authors are employed by the Cystic Fibrosis Foundation. The Cystic Fibrosis Foundation has entered into therapeutic development award agreements and licensing agreements to assist with the development of CFTR modulators that may result in intellectual property rights, royalties, and other forms of consideration provided to CFF. Some of these agreements are subject to confidentiality restrictions and, thus, CFF cannot comment on them.


Assuntos
Agonistas dos Canais de Cloreto/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Fibrose Cística/tratamento farmacológico , Custos de Medicamentos , Aminofenóis/economia , Aminofenóis/uso terapêutico , Benzodioxóis/economia , Benzodioxóis/uso terapêutico , Agonistas dos Canais de Cloreto/economia , Fibrose Cística/economia , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Aprovação de Drogas/economia , Combinação de Medicamentos , Humanos , Indóis/economia , Indóis/uso terapêutico , Assistência Médica , Mutação , Pirazóis/economia , Pirazóis/uso terapêutico , Piridinas/economia , Piridinas/uso terapêutico , Quinolinas/economia , Quinolinas/uso terapêutico , Quinolonas/economia , Quinolonas/uso terapêutico , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
7.
J Manag Care Spec Pharm ; 27(2): 276-280, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33506736

RESUMO

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Seidner, Rind, and Pearson are employed by ICER. Tice reports contracts to his institution, University of California, San Francisco, from ICER during the conduct of this study. Wherry has nothing to disclose.


Assuntos
Agonistas dos Canais de Cloreto/uso terapêutico , Análise Custo-Benefício , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Fibrose Cística/tratamento farmacológico , Modelos Econômicos , Adolescente , Aminofenóis/economia , Aminofenóis/uso terapêutico , Aminopiridinas/economia , Aminopiridinas/uso terapêutico , Benzodioxóis/economia , Benzodioxóis/uso terapêutico , Criança , Agonistas dos Canais de Cloreto/economia , Fibrose Cística/economia , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Aprovação de Drogas/economia , Combinação de Medicamentos , Custos de Medicamentos , Política de Saúde/economia , Humanos , Indóis/economia , Indóis/uso terapêutico , Mutação , Pirazóis/economia , Pirazóis/uso terapêutico , Piridinas/economia , Piridinas/uso terapêutico , Quinolinas/economia , Quinolinas/uso terapêutico , Quinolonas/economia , Quinolonas/uso terapêutico , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
8.
Eur J Med Chem ; 209: 112888, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33092904

RESUMO

We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6'-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC50 ∼600 nM representing an ∼17-fold improvement over the original compound identified in a small molecule screen.


Assuntos
Agonistas dos Canais de Cloreto/química , Agonistas dos Canais de Cloreto/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Indóis/química , Indóis/farmacologia , Aminofenóis/farmacologia , Animais , Linhagem Celular , Agonistas dos Canais de Cloreto/síntese química , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Indóis/síntese química , Modelos Moleculares , Mutação , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Quinolonas/farmacologia , Ratos , Relação Estrutura-Atividade
9.
Pediatr Pulmonol ; 55(12): 3364-3370, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32897653

RESUMO

BACKGROUND: Several studies have assessed safety and efficacy outcomes for lumacaftor/ivacaftor therapy. We report on lumacaftor/ivacaftor's impact on lung function, physical performance, and health-related quality of life (HRQOL) in a subpopulation of Danish people with Cystic Fibrosis (CF; PWCF) with advanced pulmonary disease who would not fulfill inclusion criteria for these studies. METHODS: This follow-up study examined lumacaftor/ivacaftor's effect in a highly selected CF population. Inclusion criteria included low percent predicted forced expiratory volume in one second (ppFEV1 ), fast deteriorating ppFEV1 , low body mass index (BMI), and difficult-to-treat infections. Primary endpoints included change in ppFEV1 slope, cardiopulmonary exercise testing (CPET), and all domains of the Cystic Fibrosis Questionnaire-Revised (CFQ-R). Secondary outcomes included change in ppFEV1 , BMI Z-score, and sweat chloride concentration. RESULTS: A total of 21 patients homozygous for the F508del mutation and a median ppFEV1 of 38.7 were included. We found significant improvements in ppFEV1 (+4.2 p < .01, +5.8 p < .01, +4.8 p < .01 and +3.8 p = .03 ppFEV1 after 3, 6, 9, and 12 months of treatment compared to baseline), ppFEV1 slope (+6.84 ppFEV1 /year between the year before and the year after treatment initiation; p = .02), and saturation at CPET initiation (+1.4%, p < .02) and termination (+2.6%, p < .01) after 6 months of treatment. Finally, HRQOL improved significantly in all CFQ-R domains except Emotion and Treat. CONCLUSIONS: Our findings suggest that lumacaftor/ivacaftor reduces lung function decline, improves lung function, physical performance, and HRQOL to a greater extent in PWCF with severe lung disease than previously recognized.


Assuntos
Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/tratamento farmacológico , Quinolonas/uso terapêutico , Adolescente , Adulto , Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Adulto Jovem
10.
Pediatr Pulmonol ; 55(12): 3381-3383, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32910556

RESUMO

Exocrine pancreatic insufficiency (EPI), which leads to malabsorption and poor weight gain, is seen in 85% of patients with cystic fibrosis (CF). EPI is treated with pancreatic enzyme replacement therapy taken with each meal. The highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator, ivacaftor, restores CFTR function in patients with responsive mutations. It is a widely held view that EPI in CF is irreversible due to the complete destruction of pancreatic ducts and acinar cells. We describe three pediatric CF patients with EPI who were started on ivacaftor, and subsequently showed evidence of restored exocrine pancreatic function with clinical and biochemical parameters.


Assuntos
Aminofenóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/tratamento farmacológico , Insuficiência Pancreática Exócrina/tratamento farmacológico , Quinolonas/uso terapêutico , Criança , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Humanos , Masculino , Mutação , Pâncreas/efeitos dos fármacos
11.
Int J Mol Sci ; 21(16)2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32824306

RESUMO

Over the last years CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown the ability to improve relevant clinical outcomes in patients with cystic fibrosis (CF). This review aims at a systematic research of the current evidence on efficacy and tolerability of CFTR modulators for different genetic subsets of patients with CF. Two investigators independently performed the search on PubMed and included phase 2 and 3 clinical trials published in the study period 1 January 2005-31 January 2020. A final pool of 23 papers was included in the systematic review for a total of 4219 patients. For each paper data of interest were extracted and reported in table. In terms of lung function, patients who had the most beneficial effects from CFTR modulation were those patients with one gating mutation receiving IVA (ivacaftor) and patients with p.Phe508del mutation, both homozygous and heterozygous, receiving ELX/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor) had the most relevant beneficial effects in term of lung function, pulmonary exacerbation decrease, and symptom improvement. CFTR modulators showed an overall favorable safety profile. Next steps should aim to systematize our comprehension of scientific data of efficacy and safety coming from real life observational studies.


Assuntos
Aminofenóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Ensaios Clínicos como Assunto , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Fibrose Cística/tratamento farmacológico , Quinolonas/uso terapêutico , Aminofenóis/administração & dosagem , Aminofenóis/efeitos adversos , Criança , Agonistas dos Canais de Cloreto/administração & dosagem , Agonistas dos Canais de Cloreto/efeitos adversos , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Combinação de Medicamentos , Humanos , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos
13.
Int J Pharm ; 582: 119304, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32272167

RESUMO

In this paper the innovative approach of nano into micro dry powders (NiM) was applied to incorporate into mannitol or mannitol/cysteamine micromatrices ivacaftor-loaded nanoparticles for pulmonary delivery in CF. Nanoparticles composed by a mixture of two polyhydrohydroxyethtylaspartamide copolymers containing loaded with ivacaftor at 15.5% w/w were produced. The nanoparticles were incorporated into microparticles to obtain NiM that were fully characterized in terms of size, morphology, interactions with artificial Cf mucus (CF-AM) as well as for aerodynamic behaviour. Finally the activity of ivacaftor-containing NiM was evaluated by in vitro preliminary experiments. NiM at matrix composed by a mixture of mannitol:cysteamine showed greater ability to reduce CF-AM viscosity whereas that based on just mannitol showed better aerodynamic properties with a FPF of about 25%. All produced NiM showed very good cytocompatibility and the released ivacaftor was able to restore the chroride transport in vitro.


Assuntos
Aminofenóis/administração & dosagem , Agonistas dos Canais de Cloreto/administração & dosagem , Cisteamina/administração & dosagem , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Fibrose Cística/tratamento farmacológico , Expectorantes/administração & dosagem , Manitol/administração & dosagem , Nanopartículas , Peptídeos/química , Quinolonas/administração & dosagem , Administração por Inalação , Aminofenóis/química , Animais , Células Cultivadas , Agonistas dos Canais de Cloreto/química , Cisteamina/química , Fibrose Cística/genética , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Composição de Medicamentos , Liberação Controlada de Fármacos , Expectorantes/química , Manitol/química , Mutação , Pós , Quinolonas/química , Ratos Endogâmicos F344
14.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L908-L920, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32159371

RESUMO

Over 2,000 mutations have been reported in the cystic fibrosis transmembrane conductance regulator (cftr) gene, many of which cause disease but are rare and have no effective treatment. Thus, there is an unmet need for new, mutation-agnostic therapies for cystic fibrosis (CF). Phosphodiesterase (PDE) inhibitors are one such class of therapeutics that have been shown to elevate intracellular cAMP levels and stimulate CFTR-dependent anion secretion in human airway epithelia; however, the number of people with CF that could be helped by PDE inhibitors remains to be determined. Here we used Fisher rat thyroid (FRT) cells stably transduced with rare human CFTR mutants and studied their responsiveness to the dual phosphodiesterase 3/4 inhibitor RPL554 (Verona Pharma). Through its inhibitory effect on PDE4D, we find that RPL554 can elevate intracellular cAMP leading to a potentiation of forskolin-stimulated current mediated by R334W, T338I, G551D, and S549R mutants of CFTR when used alone or in combination with CFTR modulators. We also were able to reproduce these effects of RPL554 on G551D-CFTR when it was expressed in primary human bronchial epithelial cells, indicating that RPL554 would have stimulatory effects on rare CFTR mutants in human airways and validating FRT cells as a model for PDE inhibitor studies. Furthermore, we provide biochemical evidence that VX-809 causes surprisingly robust correction of several class III and IV CFTR mutants. Together, our findings further support the therapeutic potential of RPL554 for patients with CF with class III/IV mutations and emphasize the potential of PDEs as potential drug targets that could benefit patients with CF.


Assuntos
AMP Cíclico/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Isoquinolinas/farmacologia , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Pirimidinonas/farmacologia , Células Epiteliais da Tireoide/efeitos dos fármacos , Aminopiridinas/farmacologia , Animais , Benzodioxóis/farmacologia , Brônquios/citologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Linhagem Celular , Colforsina/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Regulador de Condutância Transmembrana em Fibrose Cística/classificação , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Mutação , Cultura Primária de Células , Ratos , Ratos Endogâmicos F344 , Células Epiteliais da Tireoide/citologia , Células Epiteliais da Tireoide/metabolismo , Transgenes
16.
J Ocul Pharmacol Ther ; 36(3): 147-153, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31934802

RESUMO

Purpose: Dry eye disorders are a major health care burden. We previously reported the identification of N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine [cystic fibrosis transmembrane conductance regulator (CFTR)act-K267], which activated human wild-type CFTR chloride conductance with EC50 ∼ 30 nM. Here, we report in vivo evidence for CFTRact-K267 efficacy in an experimental mouse model of dry eye using a human compatible ophthalmic vehicle. Methods: CFTR activation in mice in vivo was demonstrated by ocular surface potential difference (OSPD) measurements. Ocular surface pharmacodynamics was measured in tear fluid samples obtained at different times after topical administration of CFTRact-K267. Dry eye was produced by lacrimal duct cautery (LDC) and corneal epithelial injury and was assessed by Lissamine green (LG) staining. Results: OSPD measurements demonstrated a hyperpolarization of -8.6 ± 3 mV (standard error of the mean, 5 mice) in response to CFTRact-K267 exposure in low chloride solution that was reversed by a CFTR inhibitor. Following single-dose topical administration of 2 nmol CFTRact-K267, tear fluid CFTRact-K267 concentration was >500 nM for more than 6 h. Following LDC, corneal surface epithelial injury, as assessed by LG staining, was substantially reversed in 10 of 12 eyes receiving 2 nmol CFTRact-K267 3 times daily starting on day 2, when marked epithelial injury had already occurred. Improvement was seen in 3 of 12 vehicle-treated eyes. Conclusion: These studies provide in vivo evidence in mice for the efficacy of a topical, human use compatible CFTRact-K267 formulation in stimulating chloride secretion and reversing corneal epithelial injury in dry eye.


Assuntos
Lesões da Córnea/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Síndromes do Olho Seco/tratamento farmacológico , Triazinas/farmacologia , Administração Tópica , Animais , Benzoatos/administração & dosagem , Benzoatos/farmacologia , Cauterização/efeitos adversos , Canais de Cloreto/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Aparelho Lacrimal/fisiopatologia , Corantes Verde de Lissamina/química , Camundongos , Camundongos Endogâmicos BALB C , Nanotecnologia , Lágrimas/efeitos dos fármacos , Tiazolidinas/administração & dosagem , Tiazolidinas/farmacologia , Resultado do Tratamento , Triazinas/administração & dosagem , Triazinas/farmacocinética , Triazinas/uso terapêutico
17.
Drugs ; 79(18): 2001-2007, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31784874

RESUMO

A fixed-dose combination tablet of the cystic fibrosis transmembrane conductance regulator (CFTR) corrector tezacaftor and the CFTR potentiator ivacaftor with the next-generation CFTR corrector elexacaftor (hereafter referred to as elexacaftor/ivacaftor/tezacaftor) [Trikafta™] has been developed by Vertex Pharmaceuticals Inc. to treat patients with the most common cystic fibrosis mutation (F508del). Its use has been associated with statistically significant and/or clinically meaningful improvements in lung function and respiratory-related quality of life compared with comparator regimens (placebo or ivacaftor/tezacaftor) in multinational phase II and III studies, and in October 2019 elexacaftor/ivacaftor/tezacaftor was approved by the US FDA for the treatment of cystic fibrosis in patients aged ≥ 12 years who have ≥ 1 F508del mutation in the CFTR gene. A regulatory assessment for elexacaftor/ivacaftor/tezacaftor as a treatment for cystic fibrosis is underway in the EU. This article summarizes the milestones in the development of elexacaftor/ivacaftor/tezacaftor leading to this first approval for the treatment of cystic fibrosis in patients aged ≥ 12 years who have ≥ 1 F508del mutation in the CFTR gene.


Assuntos
Aminofenóis/farmacologia , Benzodioxóis/farmacologia , Agonistas dos Canais de Cloreto/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Fibrose Cística/tratamento farmacológico , Aprovação de Drogas , Indóis/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Pirrolidinas/farmacologia , Quinolonas/farmacologia , Fibrose Cística/genética , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Mutação , Estados Unidos , United States Food and Drug Administration
18.
Pancreatology ; 19(8): 1023-1026, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31611131

RESUMO

BACKGROUND: Approximately 1 in 5 patients with pancreas sufficient cystic fibrosis (PS-CF) will develop acute pancreatitis (AP). It is not known whether ivacaftor alone or in combination with other CFTR (cystic transmembrane regulator) modulators (tezacaftor or lumacaftor) can reduce the risk of AP in patients with PS-CF and AP history. METHODS: We retrospectively queried the CF registry at our institution for adult patients with PS-CF, a documented history of AP and initiation of CFTR modulators for pulmonary indications. Patient characteristics including demographics, CFTR genotype, pancreatitis risk factors, pancreatic exocrine function and other relevant laboratory, imaging parameters were obtained from the time of the sentinel AP episode through the follow-up period. RESULTS: A total of 15 adult CF patients were identified with mean age of 44.1 years (SD ±â€¯13.8). In the 24 months preceding CFTR modulator initiation, six of these patients had at least 1 episode of AP with median of 2 episodes [1.75, 2.5]. None of the patients had evidence of pancreatic calcifications or exocrine pancreas insufficiency at the time of CFTR modulator initiation. The mean duration of follow-up after CFTR modulator initiation was 36.7 months (SD ±â€¯21.5). None of the patients who remained on CFTR modulators developed an episode of AP or required hospitalization for AP related abdominal pain during follow-up. CONCLUSIONS: CFTR modulators, alone or in combination, substantially reduce the risk of recurrent AP over a mean follow-up period of 3 years in adult patients with PS-CF and a history of prior AP. These data suggest that any augmentation of CFTR function can reduce the risk of pancreatitis.


Assuntos
Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Fibrose Cística/complicações , Insuficiência Pancreática Exócrina/prevenção & controle , Indóis/uso terapêutico , Quinolonas/uso terapêutico , Adulto , Idoso , Aminofenóis/administração & dosagem , Aminopiridinas/administração & dosagem , Benzodioxóis/administração & dosagem , Insuficiência Pancreática Exócrina/etiologia , Feminino , Humanos , Indóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Quinolonas/administração & dosagem , Estudos Retrospectivos
19.
Sci Rep ; 8(1): 16233, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389955

RESUMO

To determine if ivacaftor (Kalydeco) influences non-CF human CFTR function in vivo, we measured CFTR-dependent (C-sweat) and CFTR-independent (M-sweat) rates from multiple identified sweat glands in 8 non-CF adults. The two types of sweating were stimulated sequentially with intradermal injections of appropriate reagents; each gland served as its own control via alternating off-on drug tests on both arms, given at weekly intervals with 3 off and 3 on tests per subject. We compared drug effects on C-sweating stimulated by either high or low concentrations of ß-adrenergic cocktail, and on methacholine-stimulated M-sweating. For each subject we measured ~700 sweat volumes from ~75 glands per arm (maximum 12 readings per gland), and sweat volumes were log-transformed for statistical analysis. T-tests derived from linear mixed models (LMMs) were more conservative than the familiar paired sample t-tests, and show that ivacaftor significantly increased C-sweating stimulated by both levels of agonist, with a larger effect in the low cocktail condition; ivacaftor did not increase M-sweat. Concurrent sweat chloride tests detected no effect of ivacaftor. We conclude that ivacaftor in vivo increases the open channel probability (PO) of WT CFTR, provided it is not already maximally stimulated.


Assuntos
Aminofenóis/administração & dosagem , Agonistas dos Canais de Cloreto/administração & dosagem , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Quinolonas/administração & dosagem , Glândulas Sudoríparas/efeitos dos fármacos , Sudorese/efeitos dos fármacos , Adulto , Cloretos/análise , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Suor/química , Glândulas Sudoríparas/metabolismo
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