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1.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652850

RESUMO

Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named "correctors". So far, at least three different classes of correctors have been identified based on the additive/synergistic effects that are obtained when compounds of different classes are combined together. The development of class 2 correctors has lagged behind that of compounds belonging to the other classes. It was shown that the efficacy of the prototypical class 2 corrector, the bithiazole corr-4a, could be improved by generating conformationally-locked bithiazoles. In the present study, we investigated the effect of tricyclic pyrrolothiazoles as analogues of constrained bithiazoles. Thirty-five compounds were tested using the functional assay based on the halide-sensitive yellow fluorescent protein (HS-YFP) that measured CFTR activity. One compound, having a six atom carbocyle central ring in the tricyclic pyrrolothiazole system and bearing a pivalamide group at the thiazole moiety and a 5-chloro-2-methoxyphenyl carboxamide at the pyrrole ring, significantly increased F508del-CFTR activity. This compound could lead to the synthesis of a novel class of CFTR correctors.


Assuntos
Benzodioxóis/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Proteínas Mutantes/genética , Aminoimidazol Carboxamida/química , Benzodioxóis/química , Fibrose Cística/genética , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Humanos , Mutação/efeitos dos fármacos , Mutação/genética , Dobramento de Proteína/efeitos dos fármacos , Tiazóis/química
2.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669352

RESUMO

Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.


Assuntos
Anti-Inflamatórios/uso terapêutico , Fibrose Cística/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Inflamatórios/farmacologia , Azitromicina/farmacologia , Azitromicina/uso terapêutico , /tratamento farmacológico , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Fibrose Cística/complicações , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Eicosanoides/metabolismo , Humanos , Inflamação/complicações , Inflamação/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Roscovitina/farmacologia , Roscovitina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Timalfasina/farmacologia , Timalfasina/uso terapêutico
5.
Med Hypotheses ; 147: 110481, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33421691

RESUMO

Coronavirus disease 2019 (COVID-19) caused more than 52.775.271 million confirmed cases, 1.293.106 deaths, globally, and afflicted 208 countries, areas, or territories; and almost three months have passed since the World Health Organisation (WHO) declared COVID-19 as a pandemic. Despite the dramatic and global impact of the Coronavirus, the knowledge about the SARS-CoV-2 infection has been improved remarkably. Herein, we provided the rationale for SARS-CoV-2 infection as endothelial dysfunction rather than respiratory disease. Accordingly, we strongly invited the researchers to look beyond pulmonary injury and shift their attention from respiratory disease to endothelial disorder. This strategy could be particularly relevant to identifying therapeutic weapons stabilizing the endothelium rather than the lungs.


Assuntos
/complicações , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Pneumopatias/complicações , Pneumopatias/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Estado Terminal , Endotélio Vascular/metabolismo , Humanos , Inflamação , Pulmão , Pandemias
6.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429882

RESUMO

Persistent infections, such as those provoked by the Gram-negative bacterium Pseudomonas aeruginosa in the lungs of cystic fibrosis (CF) patients, can induce inflammation with lung tissue damage and progressive alteration of respiratory function. Therefore, compounds having both antimicrobial and immunomodulatory activities are certainly of great advantage in fighting infectious diseases and chronic inflammation. We recently demonstrated the potent antipseudomonal efficacy of the antimicrobial peptide (AMP) Esc(1-21) and its diastereomer Esc(1-21)-1c, namely Esc peptides. Here, we confirmed this antimicrobial activity by reporting on the peptides' ability to kill P. aeruginosa once internalized into alveolar epithelial cells. Furthermore, by means of enzyme-linked immunosorbent assay and Western blot analyses, we investigated the peptides' ability to detoxify the bacterial lipopolysaccharide (LPS) by studying their effects on the secretion of the pro-inflammatory cytokine IL-6 as well as on the expression of cyclooxygenase-2 from macrophages activated by P. aeruginosa LPS. In addition, by a modified scratch assay we showed that both AMPs are able to stimulate the closure of a gap produced in alveolar epithelial cells when cell migration is inhibited by concentrations of Pseudomonas LPS that mimic lung infection conditions, suggesting a peptide-induced airway wound repair. Overall, these results have highlighted the two Esc peptides as valuable candidates for the development of new multifunctional therapeutics for treatment of chronic infectious disease and inflammation, as found in CF patients.


Assuntos
Doenças Transmissíveis/tratamento farmacológico , Fibrose Cística/tratamento farmacológico , Inflamação/tratamento farmacológico , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Linhagem Celular , Doença Crônica/prevenção & controle , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/patologia , Ciclo-Oxigenase 2/genética , Fibrose Cística/microbiologia , Fibrose Cística/patologia , Defensinas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fatores Imunológicos/farmacologia , Inflamação/microbiologia , Inflamação/patologia , Interleucina-6/genética , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/química , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Proteínas Citotóxicas Formadoras de Poros/química , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Estereoisomerismo , Cicatrização/efeitos dos fármacos , Cicatrização/genética
7.
J Med Chem ; 64(1): 343-353, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33399458

RESUMO

Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small molecules can partially restore the CFTR function. Correctors are small molecules that enhance the amount of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel. Herein, we describe the discovery and optimization of a novel potentiator series. Scaffold hopping, focusing on retaining the different intramolecular contacts, was crucial in the whole discovery process to identify a novel series devoid of genotoxic liabilities. From this series, the clinical candidate GLPG2451 was selected based on its pharmacokinetic properties, allowing QD dosing and based on its low CYP induction potential.


Assuntos
Fibrose Cística/tratamento farmacológico , Descoberta de Drogas , Piridinas/farmacologia , Piridinas/uso terapêutico , Animais , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Piridinas/química , Piridinas/farmacocinética , Ratos
8.
J Med Chem ; 63(24): 15773-15784, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33314931

RESUMO

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, encoding for a chloride ion channel. Membrane expression of CFTR is negatively regulated by CFTR-associated ligand (CAL). We previously showed that inhibition of the CFTR/CAL interaction with a cell-permeable peptide improves the function of rescued F508del-CFTR. In this study, optimization of the peptidyl inhibitor yielded PGD97, which exhibits a KD value of 6 nM for the CAL PDZ domain, ≥ 130-fold selectivity over closely related PDZ domains, and a serum t1/2 of >24 h. In patient-derived F508del homozygous cells, PGD97 (100 nM) increased short-circuit currents by ∼3-fold and further potentiated the therapeutic effects of small-molecule correctors (e.g., VX-661) by ∼2-fold (with an EC50 of ∼10 nM). Our results suggest that PGD97 may be used as a novel treatment for CF, either as a single agent or in combination with small-molecule correctors/potentiators.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/antagonistas & inibidores , Peptídeos Cíclicos/química , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Estabilidade de Medicamentos , Humanos , Cinética , Ligantes , Simulação de Acoplamento Molecular , Mutação , Domínios PDZ , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacologia , Permeabilidade/efeitos dos fármacos , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Trocadores de Sódio-Hidrogênio/química , Trocadores de Sódio-Hidrogênio/metabolismo
9.
Cochrane Database Syst Rev ; 12: CD010966, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33331662

RESUMO

BACKGROUND: Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del (found in up to 90% of people with CF (pwCF)) is the commonest CF-causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators. OBJECTIVES: To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. Most recent search: 14 October 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and evidence quality (GRADE); we contacted investigators for additional data. MAIN RESULTS: We included 19 RCTs (2959 participants), lasting between 1 day and 24 weeks; an extension of two lumacaftor-ivacaftor studies provided additional 96-week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), six dual-therapy RCTs (1840 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and five triple-therapy RCTs (775 participants) (elexacaftor-tezacaftor-ivacaftor or VX-659-tezacaftor-ivacaftor); below we report only the data from elexacaftor-tezacaftor-ivacaftor combination which proceeded to Phase 3 trials. In 14 RCTs participants had F508del/F508del genotypes, in three RCTs F508del/minimal function (MF) genotypes and in two RCTs both genotypes. Risk of bias judgements varied across different comparisons. Results from 11 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non-standard design (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinically-relevant improvements in quality of life (QoL). There was insufficient evidence to determine any important effects on lung function. No placebo-controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess with their variety and small number of participants (all F508del/F508del). Dual therapy Investigators reported no deaths (moderate- to high-quality evidence). QoL scores (respiratory domain) favoured both lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all time points. At six months lumacaftor 600 mg or 400 mg (both once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores slightly compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high-quality evidence). A similar effect was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg), but with low-quality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice-daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate-quality evidence). At six months, the relative change in forced expiratory volume in one second (FEV1) % predicted improved with combination therapies compared to placebo by: 5.21% with once-daily lumacaftor-ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high-quality evidence); 2.40% with twice-daily lumacaftor-ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low-quality evidence); and 6.80% with tezacaftor-ivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence). More pwCF reported early transient breathlessness with lumacaftor-ivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality evidence). Over 120 weeks (initial study period and follow-up) systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice-daily 400 mg lumacaftor-ivacaftor (80 participants; high-quality evidence). The tezacaftor-ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate-quality evidence). Triple therapy Three RCTs of elexacaftor to tezacaftor-ivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (high-quality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (MD 20.2 points (95% CI 16.2 to 24.2)) and absolute change in FEV1 (MD 14.3% predicted (95% CI 12.7 to 15.8)) compared to placebo at 24 weeks. At four weeks in 107 F508del/F508del participants, elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (17.4 points (95% CI 11.9 to 22.9)) and absolute change in FEV1 (MD 10.0% predicted (95% CI 7.5 to 12.5)) compared to tezacaftor-ivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftor-tezacaftor-ivacaftor and placebo or control (moderate-quality evidence). In 403 F508del/F508del participants, there was a longer time to protocol-defined pulmonary exacerbation with elexacaftor-tezacaftor-ivacaftor over 24 weeks (moderate-quality evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer-term adult data when considering lumacaftor-ivacaftor. There is high-quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor-tezacaftor-ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Mutação , Adulto , Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Viés , Criança , Combinação de Medicamentos , Humanos , Indóis/uso terapêutico , Fenilbutiratos/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Qualidade de Vida , Quinolinas/uso terapêutico , Quinolonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
PLoS One ; 15(12): e0242945, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33370348

RESUMO

BACKGROUND: Emerging data suggests a possible role for cysteamine as an adjunct treatment for pulmonary exacerbations of cystic fibrosis (CF) that continue to be a major clinical challenge. There are no studies investigating the use of cysteamine in pulmonary exacerbations of CF. This exploratory randomized clinical trial was conducted to answer the question: In future pivotal trials of cysteamine as an adjunct treatment in pulmonary exacerbations of CF, which candidate cysteamine dosing regimens should be tested and which are the most appropriate, clinically meaningful outcome measures to employ as endpoints? METHODS AND FINDINGS: Multicentre double-blind randomized clinical trial. Adults experiencing a pulmonary exacerbation of CF being treated with standard care that included aminoglycoside therapy were randomized equally to a concomitant 14-day course of placebo, or one of 5 dosing regimens of cysteamine. Outcomes were recorded on days 0, 7, 14 and 21 and included sputum bacterial load and the patient reported outcome measures (PROMs): Chronic Respiratory Infection Symptom Score (CRISS), the Cystic Fibrosis Questionnaire-Revised (CFQ-R); FEV1, blood leukocyte count, and inflammatory markers. Eighty nine participants in fifteen US and EU centres were randomized, 78 completed the 14-day treatment period. Cysteamine had no significant effect on sputum bacterial load, however technical difficulties limited interpretation. The most consistent findings were for cysteamine 450mg twice daily that had effects additional to that observed with placebo, with improved symptoms, CRISS additional 9.85 points (95% CI 0.02, 19.7) p = 0.05, reduced blood leukocyte count by 2.46x109 /l (95% CI 0.11, 4.80), p = 0.041 and reduced CRP by geometric mean 2.57 nmol/l (95% CI 0.15, 0.99), p = 0.049. CONCLUSION: In this exploratory study cysteamine appeared to be safe and well-tolerated. Future pivotal trials investigating the utility of cysteamine in pulmonary exacerbations of CF need to include the cysteamine 450mg doses and CRISS and blood leukocyte count as outcome measures. CLINICAL TRIAL REGISTRATION: NCT03000348; www.clinicaltrials.gov.


Assuntos
Cisteamina/administração & dosagem , Cisteamina/uso terapêutico , Fibrose Cística/tratamento farmacológico , Pulmão/efeitos dos fármacos , Administração Oral , Adulto , Cisteamina/efeitos adversos , Feminino , Humanos , Masculino , Adesão à Medicação , Segurança
11.
Brasília; CONITEC; nov. 2020.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1141406

RESUMO

CONTEXTO: A fibrose cística (FC) é uma doença de herança autossômica recessiva que se manifesta principalmente na infância, sendo considerada uma das doenças genéticas letais mais comuns na população caucasiana, com prevalência de 1/3.000 nascidos vivos. No Brasil, a incidência ainda não foi estabelecida, contudo sugere-se uma incidência variável em torno de 1:7.000. A FC é causada por uma mutação no gene CFTR. O funcionamento deficiente ou ausente do CFTR ocasiona maior fluxo de sódio e água para dentro das células e consequente desidratação e aumento da viscosidade das secreções mucosas, favorecendo a obstrução das vias respiratórias, ductos intrapancreáticos, ductos seminíferos e vias biliares. O sintoma respiratório mais frequente é a tosse persistente, inicialmente seca e aos poucos produtiva, com expectoração de escarro mucoso ou francamente purulento. As exacerbações da doença pulmonar caracterizam-se pelo aumento da frequência ou intensidade da tosse, presença de taquipneia, dispneia, mal estar, anorexia, febre e perda de peso. De acordo com o Protocolo Clínico e Diretrizes Terapêuticas (PCDT) do Ministério da Saúde, os medicamentos disponíveis no SUS são as enzimas pancreáticas, a alfadornase e a tobramicina. TECNOLOGIA: Lumacaftor/Ivacaftor (Orkambi®). PERGUNTA: Lumacaftor/ivacaftor (Orkambi®) é eficaz, seguro e econômico no tratamento de pacientes de idade ≥ 6 anos com FC e homozigotos para a mutação F508del quando comparado ao tratamento vigente? EVIDÊNCIAS CIENTÍFICAS: Busca sistemática na literatura identificou seis estudos relevantes, sendo ensaios clínicos considerados como de moderada qualidade de evidência. Os desfechos avaliados foram variação na concentração de cloreto no suor; variação absoluta no índice de massa corporal (IMC); função pulmonar (ppFEV1); eventos adversos e Cystic Fibrosis Questionnaire (CFQ). Lumacaftor/ivacaftor comparado a placebo apresentou melhora significativa na concentração de cloreto de sódio no suor em relação a linha de base (-24,8 mmol/L [IC 95%: -29,1 a -20,5]; p < 0,0001)4 . Foi evidenciado aumento no IMC em relação à linha de base em ambos os grupos (lumacaftor/ivacaftor versus placebo) até a semana 24 de tratamento, porém a diferença entre os tratamentos não foi significativa: 0,1 (IC 95%: -0,1 a 0,3); p = 0,25225. Para ppFEV1, o grupo lumacaftor/ivacaftor uma vez ao dia apresentou melhora significativa (diferença em comparação com o grupo placebo: +5,6%, p = 0,013)1 . No estudo de Wainwright et al (2015) a diferença entre lumacaftor/ivacaftor versus placebo em relação à mudança relativa média para este desfecho foi considerada significativa e variou de 4,3 a 6,7% (P < 0,001). Houve uma redução de 42% na taxa anual de declínio da função pulmonar (grupo lumacaftor/ivacaftor redução de -1,33% pontos percentuais de ppVEF1 ao ano [IC 95%: -1,80 a -0,85] e grupo placebo redução de -2,29% pontos percentuais de ppVEF1 ao ano [IC 95%: -2,56 a -2,03]; p < 0.001). Lumacaftor/ivacaftor apresentou menor taxa de eventos adversos quando comparado ao placebo (17,3 a 22,8% versus 28,6%) e razão de taxa de exacerbação pulmonar que variou de 0,57 a 0,72 (p < 0,001 a p = 0,05). A qualidade da evidência dos desfechos avaliados seguiu a metodologia GRADE, sendo considerada moderada devido ao risco de viés. A adição de lumacaftor/ivacaftor foi associada a um aumento nos anos de vida. AVALIAÇÃO ECONÔMICA: Para a análise de custo-efetividade de lumacaftor/ivacaftor versus tratamento padrão utilizou-se um modelo de microssimulação. Como resultado, o demandante encontrou uma razão de custo efetividade incremental (RCEI) de R$ 2.258.270/QALY. Nas análises de sensibilidade para diferentes cenários em termos de desfechos e custos, o lumacaftor/ivacaftor tem probabilidade maior que 50% de ter uma boa relação custo-benefício em limites de disposição a pagar acima de aproximadamente R$ 2.233.000,00. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário incremental (IO) acumulado em 5 anos foi de R$ 1.609.445.240. Para avaliar a variabilidade em outros cenários, foram avaliados dois outros cenários de disseminação tecnológica, tanto com a variação no valor inicial quanto com a velocidade da disseminação tecnológica tendo como resultado um IO incremental em 5 anos de R$ 2.551.884.271,00 (cenário otimista ­ velocidade de disseminação muito rápida) e R$ 917.952.683,00 (cenário pessimista ­ velocidade de disseminação lenta). Foram consideradas como limitações a incerteza de como ocorrerá a substituição terapêutica no sistema e a velocidade dessa substituição, além do fato de que a análise de sensibilidade se restringiu à velocidade de disseminação tecnológica. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Os ensaios clínicos analisados mostram que a perspectiva para o tratamento dessa população de pacientes é o advento de uma nova geração de moduladores de CFTR, moduladores "next generation", a serem combinados em esquemas triplete. Nesse tipo de esquema, três moduladores de CFTR seriam utilizados em combinação, sendo que a hipótese de que resultariam em maior eficácia no tratamento da doença tem sido testada. DISCUSSÃO: A evidência disponível sobre eficácia e segurança do lumacaftor/Ivacaftor para o tratamento de pacientes com fibrose cística homozigótica para a mutação F508del é baseada em estudos clínicos randomizados com moderada qualidade da evidência. Não há dados em relação à melhora de sobrevida ou taxa de hospitalizações. Mesmo os dados de qualidade de vida são muito escassos, e o que foi apresentado foi considerado pouco relevante. Os desfechos analisados pelos estudos são desfechos principais e intermediários. Lumacaftor/Ivacaftor tem sido associado a melhorias modestas nos níveis de cloreto no suor, na função pulmonar e na prevenção significativa de exacerbações respiratórias. A análise de custo-efetividade (ACE) realizada foi adequada e criteriosamente desenvolvida, utilizando o modelo de microssimulação, com adequadas análises de sensibilidade univariada e probabilística. A RCEI apresentada foi, entretanto, extremamente alta, de R$ 2.258.270/QALY. A tecnologia apresentaria 50% de probabilidade de ser considerada custoefetiva apenas em um cenário de limiar de disposição a pagar de R$ 2.233.000,00. O impacto orçamentário incremental acumulado em 5 anos foi de R$ 1.609.445.240,00. Para avaliar a variabilidade em outros cenários, foram avaliados dois outros cenários de disseminação tecnológica, tanto com a variação no valor inicial quanto com a velocidade da disseminação tecnológica, tendo como resultado um impacto orçamentário incremental em 5 anos de R$ 2.551.884.271,00 (cenário otimista) e R$ 917.952.683,00 (cenário pessimista). Foram consideradas como limitações a incerteza sobre como ocorrerá a substituição terapêutica no sistema e a velocidade dessa substituição, e a realização de uma análise de sensibilidade restrita apenas à velocidade de disseminação tecnológica. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do plenário consideraram as seguintes questões: avaliação de resultados intermediários; pouco tempo de seguimento, gerando incertezas sobre a manutenção do efeito em longo prazo; ausência de critérios de interrupção do medicamento; custo elevado, acarretando uma razão de custo-efetividade extremamente alta; e a necessidade de um exame de genotipagem específico. Diante do exposto, no dia 09 de julho de 2020, em sua 88ª reunião de plenário, os membros da Conitec recomendaram preliminarmente, por unanimidade, a não incorporação do lumacaftor/ivacaftor para tratamento da fibrose cística em pacientes com idade ≥ 6 anos que são homozigotos para a mutação F508del no gene CFTR. CONSULTA PÚBLICA: O relatório de recomendação inicial da CONITEC, foi disponibilizado para contribuições por meio da consulta pública nº 37/2020 entre os dias 12/08/2020 e 31/08/2020. Foram recebidas 12.304 contribuições, sendo 388 contribuições de cunho técnico-científico e 11.916 contribuições de experiência pessoal ou opinião, destas 94,79% discordavam da recomendação preliminar da Conitec. RECOMENDAÇÃO FINAL: O plenário da Conitec ponderou a respeito dos resultados modestos de eficácia do lumacaftor/ivacaftor, assim como da razão de custo-efetividade incremental e do impacto orçamentário que foram considerados elevados. Sendo assim, os membros da CONITEC presentes na 92ª reunião ordinária, no dia 05/11/2020, deliberaram, por unanimidade, recomendar a não incorporação do Lumacaftor/Ivacaftor para o tratamento da fibrose cística em pacientes com idade ≥ 6 anos que são homozigotos para a mutação F508del no gene CFTR. Foi assinado o registro de deliberação nº 575/2020. DECISÃO: Não incorporar o Lumacaftor/Ivacaftor para tratamento de fibrose cística (FC) em pacientes com 6 anos de idade ou mais e que são homozigotos para a mutação F508del no gene regulador de condutância transmembrana da fibrose cística (CFTR), no âmbito do Sistema Único de Saúde - SUS, conforme Portaria nº 61, publicada no Diário Oficial da União nº 231, seção 1, página 124, em 03 de dezembro de 2020.


Assuntos
Humanos , Recém-Nascido , Lactente , Pré-Escolar , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Fibrose Cística/tratamento farmacológico , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economia
12.
Lancet Respir Med ; 8(10): 975-986, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33007285

RESUMO

BACKGROUND: Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa. METHODS: We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin. Both were combined with 12 weeks inhaled colistimethate sodium. Randomisation lists were generated by a statistician, who had no involvement in the trial, using a computer-generated list. Randomisation was stratified by centre and because of the nature of the interventions, blinding was not possible. Our primary outcome was eradication of P aeruginosa at 3 months and remaining free of infection to 15 months. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who received at least one dose of study drug. TORPEDO-CF was registered on the ISRCTN register, ISRCTN02734162, and EudraCT, 2009-012575-10. FINDINGS: Between Oct 5, 2010, and Jan 27, 2017, 286 patients were randomly assigned to treatment: 137 to intravenous antibiotics and 149 to oral antibiotics. 55 (44%) of 125 participants in the intravenous group and 68 (52%) of 130 participants in the oral group achieved the primary outcome. Participants randomly assigned to the intravenous group were less likely to achieve the primary outcome, although the difference between groups was not statistically significant (relative risk 0·84, 95% CI 0·65-1·09; p=0·18). 11 serious adverse events occurred in ten (8%) of 126 participants in the intravenous antibiotics group and 17 serious adverse events in 12 (8%) of 146 participants in the oral antibiotics group. INTERPRETATION: Compared with oral therapy, intravenous antibiotics did not achieve sustained eradication of P aeruginosa in a greater proportion of patients with cystic fibrosis and was more expensive. Although there were fewer hospitalisations in the intravenous group than the oral group during follow-up, this confers no advantage over oral treatment because intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P aeruginosa in cystic fibrosis. FUNDING: National Institute for Health Research Health Technology Assessment Programme.


Assuntos
Antibacterianos/administração & dosagem , Ceftazidima/administração & dosagem , Fibrose Cística/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa , Tobramicina/administração & dosagem , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Criança , Pré-Escolar , Fibrose Cística/tratamento farmacológico , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Infecções por Pseudomonas/complicações , Resultado do Tratamento , Adulto Jovem
13.
Wiad Lek ; 73(8): 1790-1795, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33055353

RESUMO

OBJECTIVE: The aim: The clinical case was studied: comorbidity of mucoviscidosis and congenital dysfunction of adrenal glands cortex. PATIENTS AND METHODS: Materials and methods: The clinical case of combined orphan pathology - cystic fibrosis and congenital dysfunction of adrenal glands cortex (adrenogenital syndrome) has been described. RESULTS: Clinical case: A 2-month child has been diagnosed with mucoviscidosis, of a mixed form, which was genetically confirmed. The proband and the father were found to be heterozygotes for the F508del mutation of the CFTR gene (the father suffers from mucoviscidosis). Congenital dysfunction of the adrenal glands, a viral form, was diagnosed when he was three years old. The child is currently receiving: Creon 100 000 units per day with eating, Colomycin 1 vial per day, Pulmozyme 2.5 mg/2.5 ml daily in the morning for inhalations, Ursofalk 600 mg every day constantly, Hydrocortisone 50 mg/day. CONCLUSION: Conclusions: This clinical case can be attributed to rare, as most such pathological conditions are usually diagnosed in maternity homes along with the prescription of appropriate therapy. This is an example of late diagnosis of the viral form of congenital adrenal dysfunction against the background of cystic fibrosis, indicating the need for earlier detection and timely introduction of substitution therapy to improve favourable prognosis for a disease.


Assuntos
Hiperplasia Suprarrenal Congênita , Fibrose Cística , Glândulas Suprarrenais , Córtex Cerebral , Criança , Pré-Escolar , Comorbidade , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Humanos , Masculino , Gravidez
14.
Curr Opin Pulm Med ; 26(6): 696-701, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32941351

RESUMO

PURPOSE OF REVIEW: The current review provides an overview of key psychological issues and challenges for the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator era of care. It discusses research from diagnosis and beyond, to patient-team communication with a particular focus on medical trials, adherence and living with CFTR modulators. RECENT FINDINGS: The impact of the diagnosis on parents is immense and the complexity of treatment now and in the future, are a challenge for both parents and teams. Communicating digitally is starting to become daily practice for many in CF care, with coronavirus disease 2019 accelerating this process. Participating in trials has a psychological impact, but most of all the (delayed) access and timing of accessing CFTR modulators is an important theme. Adherence remains of significance, both to 'old' and 'new' treatments. Living with CF in the era of CFTR modulators is beginning to impact on patients' quality of life, including new possibilities, opportunities and challenges. SUMMARY: Psychological care needs to engage and keep pace with the rapid medical changes. Some care priorities remain the same, including psychological screening and assessment, as well as psychoeducation, communication training and psychotherapy. The presence of CF psychologist in the CF clinic remains as important as ever.


Assuntos
Comunicação , Infecções por Coronavirus , Fibrose Cística/tratamento farmacológico , Fibrose Cística/psicologia , Adesão à Medicação , Pandemias , Pneumonia Viral , Betacoronavirus , Ensaios Clínicos como Assunto/psicologia , Fibrose Cística/diagnóstico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Qualidade de Vida
16.
APMIS ; 128(12): 647-653, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32794206

RESUMO

IL-2 is a pro-inflammatory and a Th1 inducing cytokine, which is important for activation of the cell-mediated immunity. IL-2 in serum and sputum has been observed to be reduced in cystic fibrosis (CF) patients. The present IL-2 treatment study of Pseudomonas aeruginosa (PA) lung infected mice was performed in order to evaluate the effect of IL-2 supplement. One hundred-and-twenty female BALB/c mice were divided into three groups: 1) IL-2 treatment/infection (TIG), 2) non-treatment/infection (NTIG), and 3) IL-2 treatment/non-infection (TNIG). The mice were challenged intra-tracheally with PA (PAO579) embedded in seaweed alginate to resemble the biofilm mode of growth. At day 0 and 1, the treatment groups received IL-2 s.c. Mice were killed on day 1 or 2, and cytokine production, lung pathology, and quantitative lung bacteriology were estimated. IL-2 treatment of infected mice reduced the number of mice with signs of macroscopic lung pathology at day 2 (p < 0.05). The reduced macroscopic pathology was paralleled by a reduced IL-1ß and TNF-α. In contrast, an increased PMN response at day 2 was observed in the IL-2 treated mice (p < 0.01). This was preceded by a significantly higher degree of microscopic inflammation at day 1 (p < 0.02). The IL-12 levels decreased in both groups of infected mice at day 2 (p < 0.01), however, significantly more in the IL-2 treated mice (p < 0.02). In accordance, but surprisingly, IFN-γ was significantly reduced in the IL-2 treated PA infected group at day 2 (p < 0.05). The present results indicate that early IL-2 treatment prolongs the PMN response but also reduces pro-inflammatory IL-1ß and TNF-α and macroscopic signs of pathology.


Assuntos
Interleucina-2/administração & dosagem , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/fisiologia , Animais , Fibrose Cística/tratamento farmacológico , Fibrose Cística/imunologia , Fibrose Cística/microbiologia , Fibrose Cística/patologia , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/genética
17.
PLoS One ; 15(7): e0235638, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687499

RESUMO

IMPORTANCE: Sinonasal symptoms in patients suffering from cystic fibrosis can negatively influence the quality of life and sinuses can be a niche for pathogens causing infection and inflammation leading to a decrease of lung function. Ivacaftor, a potentiator of the Cystic Fibrosis Transmembrane Conductance Regulator protein, has shown improvement in pulmonary function in cystic fibrosis patients with different forms of class III gating mutations. However, the effects of ivacaftor on sinonasal pathology have hardly been studied. OBJECTIVE: To determine the impact of ivacaftor therapy on sinonasal pathology in patients with cystic fibrosis with an S1251N mutation. DESIGN: Prospective observational mono-center cohort study, between June 2015 and December 2016. SETTING: A tertiary referral center in Utrecht, The Netherlands. PARTICIPANTS: Eight patients with cystic fibrosis with an S1251N mutation, treated with the potentiator ivacaftor were investigated. EXPOSURES: Ivacaftor (Kalydeco, VX-770) therapy. Computed tomography imaging of paranasal sinuses. Nasal nitric oxide concentration measurements and nasal endoscopy. MAIN OUTCOMES AND MEASURES: Primary outcome is opacification of paranasal sinuses examined with computed tomography scan analysis and scaled by the modified Lund-Mackay score before and one year after treatment. Secondary outcomes are nasal nitric oxide concentration levels, sinonasal symptoms and nasal endoscopic findings before and approximately two months and in some cases one year after treatment. RESULTS: Computed tomography scan analysis showed a significant decrease in opacification of the majority of paranasal sinuses comparing the opacification score per paranasal sinus before and after one year of treatment with ivacaftor. Median nasal nitric oxide levels significantly improved from 220.00 (IQR:136.00-341.18) to 462.84 (IQR:233.17-636.25) (p = 0.017) parts per billion. Likewise, the majority of sinonasal symptoms and nasal endoscopic pathology decreased or resolved at two months after the use of ivacaftor. CONCLUSION AND RELEVANCE: Ivacaftor appears to improve sinonasal outcome parameters and thereby sinonasal health in patients with cystic fibrosis with an S1251N mutation.


Assuntos
Aminofenóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Seios Paranasais/patologia , Quinolonas/uso terapêutico , Adolescente , Adulto , Estudos de Coortes , Fibrose Cística/genética , Fibrose Cística/patologia , Feminino , Genótipo , Humanos , Masculino , Óxido Nítrico/metabolismo , Seios Paranasais/diagnóstico por imagem , Seios Paranasais/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Centros de Atenção Terciária , Tomografia Computadorizada por Raios X , Adulto Jovem
18.
Genes Immun ; 21(4): 260-262, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32606316

RESUMO

Cystic fibrosis (CF) is one of the most common autosomal recessive life-limiting conditions affecting Caucasians. The resulting defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) results in defective chloride and bicarbonate secretion, as well as dysregulation of epithelial sodium channels (ENaC). These changes bring about defective mucociliary clearance, reduced airway surface liquid and an exaggerated proinflammatory response driven, in part, by infection. In this short article we explore the overlap in the pathophysiology of CF and COVID-19 infection and discuss how understanding the interaction between both diseases may shed light on future treatments.


Assuntos
Infecções por Coronavirus/metabolismo , Fibrose Cística/metabolismo , Pneumonia Viral/metabolismo , Animais , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Citocinas/metabolismo , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia
20.
Am J Respir Crit Care Med ; 202(9): 1271-1282, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32584141

RESUMO

Rationale: Animal models have been highly informative for understanding the characteristics, onset, and progression of cystic fibrosis (CF) lung disease. In particular, the CFTR-/- rat has revealed insights into the airway mucus defect characteristic of CF but does not replicate a human-relevant CFTR (cystic fibrosis transmembrane conductance regulator) variant.Objectives: We hypothesized that a rat expressing a humanized version of CFTR and harboring the ivacaftor-sensitive variant G551D could be used to test the impact of CFTR modulators on pathophysiologic development and correction.Methods: In this study, we describe a humanized-CFTR rat expressing the G551D variant obtained by zinc finger nuclease editing of a human complementary DNA superexon, spanning exon 2-27, with a 5' insertion site into the rat gene just beyond intron 1. This targeted insertion takes advantage of the endogenous rat promoter, resulting in appropriate expression compared with wild-type animals.Measurements and Main Results: The bioelectric phenotype of the epithelia recapitulates the expected absence of CFTR activity, which was restored with ivacaftor. Large airway defects, including depleted airway surface liquid and periciliary layers, delayed mucus transport rates, and increased mucus viscosity, were normalized after the administration of ivacaftor.Conclusions: This model is useful to understand the mechanisms of disease and the extent of pathology reversal with CFTR modulators.


Assuntos
Aminofenóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Muco/efeitos dos fármacos , Quinolonas/uso terapêutico , Animais , Humanos , Modelos Animais , Ratos
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