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1.
Br J Pharmacol ; 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38770951

RESUMO

BACKGROUND AND PURPOSE: Cystic fibrosis (CF) patients are living longer and healthier due to improved treatments, e.g. cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI), with treatment possibly occurring in pregnancy. The risk of ETI to foetuses remain unknown. Thus the effect of maternally administered ETI on foetal genetic and structural development was investigated. EXPERIMENTAL APPROACH: Pregnant Sprague Dawley rats were orally treated with ETI (6.7 mg·kg-1·day-1 elexacaftor + 3.5 mg·kg-1·day-1 tezacaftor + 25 mg·kg-1·day-1 ivacaftor) for 7 days from E12 to E19. Tissue samples collected at E19 were analysed using histology and RNA sequencing. Histological changes and differentially expressed genes (DEG) were assessed. KEY RESULTS: No overt structural abnormalities were found in foetal pancreas, liver, lung and small intestine after 7-day ETI exposure. Very few non-functionally associated DEG in foetal liver, lung and small intestine were identified using RNA-seq. 29 DEG were identified in thymus (27 up-regulated and two down-regulated) and most were functionally linked to each other. Gene ontology enrichment analysis revealed that multiple muscle-related terms were significantly enriched. Many more DEG were identified in cortex (44 up-regulated and four down-regulated) and a group of these were involved in central nervous system and brain development. CONCLUSION AND IMPLICATION: Sub-chronic ETI treatment in late pregnancy does not appear to pose a significant risk to the genetic and structural development of many foetal tissues. However, significant gene changes in foetal thymic myoid cells and cortical neuronal development requires future follow-up studies to assess the risk to these organs.

2.
ACS Pharmacol Transl Sci ; 7(4): 933-950, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38633590

RESUMO

Cystic fibrosis (CF) is a genetic disorder arising from variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to multiple organ system defects. CFTR tool compounds are molecules that can modify the activity of the CFTR channel. Especially, patients that are currently not able to benefit from approved CFTR modulators, such as patients with rare CFTR variants, benefit from further research in discovering novel tools to modulate CFTR. This Review explores the development and classification of CFTR tool compounds, including CFTR blockers (CFTRinh-172, GlyH-101), potentiators (VRT-532, Genistein), correctors (VRT-325, Corr-4a), and other approved and unapproved modulators, with detailed descriptions and discussions for each compound. The challenges and future directions in targeting rare variants and optimizing drug delivery, and the potential synergistic effects in combination therapies are outlined. CFTR modulation holds promise not only for CF treatment but also for generating CF models that contribute to CF research and potentially treating other diseases such as secretory diarrhea. Therefore, continued research on CFTR tool compounds is critical.

3.
Biomed Pharmacother ; 171: 116155, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38232663

RESUMO

BACKGROUND: The potential effects of the very effective cystic fibrosis triple combination drug, Elexacaftor/Tezacaftor/Ivacaftor (ETI) in pregnancy on prenatal development of offspring remain largely unknown. RESEARCH QUESTION: We aimed to investigate the fetal tissue distribution pattern of maternally administered ETI by placental transfer in the rat fetuses. STUDY DESIGN AND METHODS: Sprague Dawley pregnant rats were administered ETI (6.7 mg/kg/d elexacaftor + 3.5 mg/kg/d tezacaftor + 25 mg/kg/d ivacaftor) traced with [3 H]-ivacaftor in single dose acute experiments (intraperitoneal injection) or treated orally with ETI (the same dose) for 7 days in sub-chronic experiments. Fetal tissue samples were collected at embryonic day (E) 19 and analyzed using liquid scintillation counting for acute experiments or liquid chromatography-mass spectrometry for sub-chronic experiments. RESULTS: On day E19, after acute exposure, the entry of ivacaftor into fetal brain (brain/plasma concentration ratios <50%) was significantly lower than to other tissues (>100%). However, after sub-chronic exposure, the entry of all 3 components into the developing brain was comparably extensive as into other tissues (tissue/plasma ratios, 260 - 1000%). Each component of ETI accumulated in different fetal tissues to approximately equal extent. Inter-litter differences on fetal drug distribution were found in cortex for ivacaftor, muscle for tezacaftor and cortex and mid/hindbrain for elexacaftor. Fetal plasma concentrations of ETI (ng/mL) were variable between litters. The entry of ivacaftor and tezacaftor into adult brain appeared to be restricted (<100%). INTERPRETATION: Fetal rats are exposed to maternally ingested ETI after sub-chronic exposure, potentially impacting fetal development. The brain entry data highlights the need for attention be paid to any long-term potential effects ETI exposure could have on normal brain development.


Assuntos
Aminofenóis , Regulador de Condutância Transmembrana em Fibrose Cística , Indóis , Placenta , Pirazóis , Piridinas , Pirrolidinas , Quinolonas , Feminino , Gravidez , Ratos , Animais , Ratos Sprague-Dawley , Feto , Benzodioxóis , Mutação
4.
Front Pharmacol ; 14: 1265138, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37795027

RESUMO

Highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapies (HEMT), including elexacaftor-tezacaftor-ivacaftor, correct the underlying molecular defect causing CF. HEMT decreases general symptom burden by improving clinical metrics and quality of life for most people with CF (PwCF) with eligible CFTR variants. This has resulted in more pregnancies in women living with CF. All HEMT are known to be able pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of HEMT in young rats demonstrated infant cataracts, and case reports have reported the presence of congenital cataracts in early life exposure to HEMT. This article reviews the evidence for how HEMT influences the dynamic and interdependent processes of healthy and abnormal lens development in the context of HEMT exposure during pregnancy and breastfeeding, and raises questions that remain unanswered.

5.
Am J Respir Crit Care Med ; 207(11): e77-e96, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37260227

RESUMO

Background: Patients with mild asthma are believed to represent the majority of patients with asthma. Disease-associated risks such as exacerbations, lung function decline, and death have been understudied in this patient population. There have been no prior efforts from major societies to describe research needs in mild asthma. Methods: A multidisciplinary, diverse group of 24 international experts reviewed the literature, identified knowledge gaps, and provided research recommendations relating to mild asthma definition, pathophysiology, and management across all age groups. Research needs were also investigated from a patient perspective, generated in conjunction with patients with asthma, caregivers, and stakeholders. Of note, this project is not a systematic review of the evidence and is not a clinical practice guideline. Results: There are multiple unmet needs in research on mild asthma driven by large knowledge gaps in all areas. Specifically, there is an immediate need for a robust mild asthma definition and an improved understanding of its pathophysiology and management strategies across all age groups. Future research must factor in patient perspectives. Conclusions: Despite significant advances in severe asthma, there remain innumerable research areas requiring urgent attention in mild asthma. An important first step is to determine a better definition that will accurately reflect the heterogeneity and risks noted in this group. This research statement highlights the topics of research that are of the highest priority. Furthermore, it firmly advocates the need for engagement with patient groups and for more support for research in this field.


Assuntos
Asma , Humanos , Estados Unidos , Asma/diagnóstico , Asma/terapia , Sociedades Médicas , Cuidadores
6.
Pharmaceutics ; 15(5)2023 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-37242730

RESUMO

Pulmonary drug delivery has long been used for local and systemic administration of different medications used in acute and chronic respiratory diseases. Certain lung diseases, such as cystic fibrosis, rely heavily on chronic treatments, including targeted lung delivery. Pulmonary drug delivery possesses various physiological advantages compared to other delivery methods and is also convenient for the patient to use. However, the formulation of dry powder for pulmonary delivery proves challenging due to aerodynamic restrictions and the lower tolerance of the lung. The aim of this review is to provide an overview of the respiratory tract structure in patients with cystic fibrosis, including during acute and chronic lung infections and exacerbations. Furthermore, this review discusses the advantages of targeted lung delivery, including the physicochemical properties of dry powder and factors affecting clinical efficacy. Current inhalable drug treatments and drugs currently under development will also be discussed.

7.
Antibiotics (Basel) ; 12(3)2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-36978351

RESUMO

Characterized by impaired mucus transport and subsequent enhanced colonization of bacteria, pulmonary infection causes major morbidity and mortality in patients with cystic fibrosis (CF). Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) are the two most common types of bacteria detected in CF lungs, which undergo multiple adaptational mechanisms such as biofilm formation resulting in chronic pulmonary infections. With the advantages of greater airway concentration and minimized systemic toxicity, inhaled antibiotics are introduced to treat chronic pulmonary infection in CF. Inhaled tobramycin, aztreonam, levofloxacin, and colistin are the four most common discussed inhaled antibiotics targeting P. aeruginosa. Additionally, inhaled liposomal amikacin and murepavadin are also in development. This review will discuss the virulence factors and adaptational mechanisms of P. aeruginosa and S. aureus in CF. The mechanism of action, efficacy and safety, current status, and indications of corresponding inhaled antibiotics will be summarized. Combination therapy and the strategies to select an optimal inhaled antibiotic protocol will also be discussed.

8.
ACS Pharmacol Transl Sci ; 6(3): 355-360, 2023 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-36926454

RESUMO

In cystic fibrosis (CF) the ability of the CF transmembrane conductance regulator (CFTR) protein to mediate chloride and water transport is disrupted. While much progress has been made in CF research leading to effective treatments to improve CFTR function, including small molecule modulators, patients present with varying disease manifestations and responses to therapy. For many CF-affected organs, disease onset is known to occur during in utero development before treatments can be administered and progresses over time leading to irreversible damage to these organs. Thus, the role of functional CFTR protein, in particular, during early development needs to be further elucidated. Studies have detected CFTR proteins at very early gestational stages and revealed temporally and spatially variable CFTR expression patterns in fetuses, suggesting a potential role of CFTR in fetal development. However, the actual mechanisms of how defective CFTR in CF results in fetal morphogenetic abnormalities are yet to be established. This review aims to summarize fetal CFTR expression patterns specifically in the lung, pancreas, and gastrointestinal tract (GIT), as compared to adult patterns. Case studies of structural abnormalities in CF fetuses and newborns and the role of CFTR in fetal development will also be discussed.

9.
Inflamm Res ; 72(1): 57-74, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36322182

RESUMO

BACKGROUND: Respiratory inflammation is the body's response to lung infection, trauma or hypersensitivity and is often accompanied by comorbidities, including gastrointestinal (GI) symptoms. Why respiratory inflammation is accompanied by GI dysfunction remains unclear. Here, we investigate the effect of lipopolysaccharide (LPS)-induced lung inflammation on intestinal barrier integrity, tight-junctions, enteric neurons and inflammatory marker expression. METHODS: Female C57bl/6 mice (6-8 weeks) were intratracheally administered LPS (5 µg) or sterile saline, and assessed after either 24 or 72 h. Total and differential cell counts in bronchoalveolar lavage fluid (BALF) were used to evaluate lung inflammation. Intestinal barrier integrity was assessed via cross sectional immunohistochemistry of tight junction markers claudin-1, claudin-4 and EpCAM. Changes in the enteric nervous system (ENS) and inflammation in the intestine were quantified immunohistochemically using neuronal markers Hu + and nNOS, glial markers GFAP and S100ß and pan leukocyte marker CD45. RESULTS: Intratracheal LPS significantly increased the number of neutrophils in BALF at 24 and 72 h. These changes were associated with an increase in CD45 + cells in the ileal mucosa at 24 and 72 h, increased goblet cell expression at 24 h, and increased expression of EpCAM at 72 h. LPS had no effect on the expression of GFAP, S100ß, nor the number of Hu + neurons or proportion of nNOS neurons in the myenteric plexus. CONCLUSIONS: Intratracheal LPS administration induces inflammation in the ileum that is associated with enhanced expression of EpCAM, decreased claudin-4 expression and increased goblet cell density, these changes may contribute to systemic inflammation that is known to accompany many inflammatory diseases of the lung.


Assuntos
Íleo , Inflamação , Pneumonia , Animais , Feminino , Camundongos , Claudina-4/metabolismo , Estudos Transversais , Molécula de Adesão da Célula Epitelial/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos/metabolismo , Pulmão/metabolismo , Pneumonia/induzido quimicamente , Íleo/patologia
11.
12.
Respirology ; 27(9): 688-719, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35981737

RESUMO

The Thoracic Society of Australia and New Zealand (TSANZ) and the Australian and New Zealand Society of Respiratory Science (ANZSRS) commissioned a joint position paper on pulmonary function testing during coronavirus disease 2019 (COVID-19) in July 2021. A working group was formed via an expression of interest to members of both organizations and commenced work in September 2021. A rapid review of the literature was undertaken, with a 'best evidence synthesis' approach taken to answer the research questions formed. This allowed the working group to accept findings of prior relevant reviews or societal document where appropriate. The advice provided is for providers of pulmonary function tests across all settings. The advice is intended to supplement local infection prevention and state, territory or national directives. The working group's key messages reflect a precautionary approach to protect the safety of both healthcare workers (HCWs) and patients in a rapidly changing environment. The decision on strategies employed may vary depending on local transmission and practice environment. The advice is likely to require review as evidence grows and the COVID-19 pandemic evolves. While this position statement was contextualized specifically to the COVID-19 pandemic, the working group strongly advocates that any changes to clinical/laboratory practice, made in the interest of optimizing the safety and well-being of HCWs and patients involved in pulmonary function testing, are carefully considered in light of their potential for ongoing use to reduce transmission of other droplet and/or aerosol borne diseases.


Assuntos
COVID-19 , SARS-CoV-2 , Austrália/epidemiologia , COVID-19/diagnóstico , COVID-19/epidemiologia , Humanos , Nova Zelândia , Pandemias/prevenção & controle , Testes de Função Respiratória
13.
ACS Pharmacol Transl Sci ; 5(6): 419-428, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35711814

RESUMO

Background and purpose: Cystic fibrosis (CF) is associated with a myriad of respiratory complications including increased susceptibility to lung infections and inflammation. Progressive inflammatory insults lead to airway damage and remodeling, resulting in compromised lung function. Treatment with ivacaftor significantly improves respiratory function and reduces the incidence of pulmonary exacerbations; however, its effect on lung inflammation is yet to be fully elucidated. Experimental approach: This study investigates the effects of ivacaftor on lung inflammation in a lipopolysaccharide (LPS) exposure mouse model (C57BL/6). All groups received intratracheal (IT) administration of LPS (10 µg). Prophylactic treatment involved intraperitoneal injections of ivacaftor (40 mg/kg) once a day beginning 4 days prior to LPS challenge. The therapeutic group received a single intraperitoneal ivacaftor injection (40 mg/kg) directly after LPS. Mice were culled either 24 or 72 h after LPS challenge, and serum, bronchoalveolar lavage fluid (BALF), and lung tissue samples were collected. The degree of inflammation was assessed through cell infiltration, cytokine expression, and histological analysis. Key results: Ivacaftor did not decrease the total number of immune cells within the BALF; however, prophylactic treatment did significantly reduce macrophage and lymphocyte infiltration. Prophylactic treatment exhibited a significant negative correlation between the immune cell number and ivacaftor concentrations in BALF; however, no significant changes in the cytokine expression or histological parameters were determined. Conclusions and implications: Ivacaftor possesses some inherent immunomodulatory effects within the lungs following LPS inoculation; however, further analysis of larger sample sizes is required to confirm the results.

14.
J Cyst Fibros ; 21(2): 212-219, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34454846

RESUMO

BACKGROUND: The effects of lumacaftor-ivacaftor on cystic fibrosis transmembrane conductance regulator (CFTR)-associated liver disease remain unclear. The objective of the study was to describe the effect of this treatment on features of liver involvement in a cystic fibrosis (CF) adolescent population homozygous for F508del. METHODS: Clinical characteristics, liver blood tests, abdominal ultrasonography (US), and pancreas and liver proton density fat fraction (PDFF) by magnetic resonance imaging, were obtained at treatment initiation and at 12 months for all patients. Biomarkers of CFTR activity (sweat chloride test, nasal potential difference, and intestinal current measurement) were assessed at initiation and at 6 months therapy. RESULTS: Of the 37 patients who started ivacaftor/lumacaftor treatment, 28 were eligible for analysis. In this group, before treatment initiation, 4 patients were diagnosed with multinodular liver and portal hypertension, 19 with other forms of CF liver involvement, and 5 with no signs of liver involvement. During treatment, no hepatic adverse reactions were documented, and no patient developed liver failure. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyl transferase (GGT) decreased significantly following initiation of lumacaftor-ivacaftor, and remained so after 12 months treatment. This was not correlated with changes in clinical status, liver and pancreas US and PDFF, fecal elastase, or lumacaftor-ivacaftor serum levels. The most "responsive" patients demonstrated a significant increase in biomarkers of CFTR activity. CONCLUSIONS: These results may suggest a potential beneficial effect of CFTR modulators on CF liver disease and warrant further investigation in larger, prospective studies.


Assuntos
Fibrose Cística , Adolescente , Aminofenóis/efeitos adversos , Aminopiridinas , Benzodioxóis/efeitos adversos , Biomarcadores , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Combinação de Medicamentos , Humanos , Fígado/diagnóstico por imagem , Mutação , Estudos Prospectivos , Quinolonas
15.
Am J Respir Crit Care Med ; 204(10): e97-e109, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34779751

RESUMO

Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma. Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered. Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidence-based answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations. Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice. Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence.


Assuntos
Corticosteroides/normas , Corticosteroides/uso terapêutico , Antiasmáticos/normas , Antiasmáticos/uso terapêutico , Asma/diagnóstico , Asma/tratamento farmacológico , Óxido Nítrico/análise , Guias de Prática Clínica como Assunto , Humanos , Estados Unidos
16.
Pharmaceutics ; 13(8)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34452117

RESUMO

Nanomaterials provide enormous opportunities to overcome the limitations of conventional ocular delivery systems, such as low therapeutic efficacy, side effects due to the systemic exposure, or invasive surgery. Apart from the more common ocular disorders, there are some genetic diseases, such as cystic fibrosis, that develop ocular disorders as secondary effects as long as the disease progresses. These patients are more difficult to be pharmacologically treated using conventional drug routes (topically, systemic), since specific pharmacological formulations can be incompatible, display increased toxicity, or their therapeutic efficacy decreases with the administration of different kind of chemical molecules. Magnetic nanoparticles can be used as potent drug carriers and magnetic hyperthermia agents due to their response to an external magnetic field. Drugs can be concentrated in the target point, limiting the damage to other tissues. The other advantage of these magnetic nanoparticles is that they can act as magnetic resonance imaging agents, allowing the detection of the exact location of the disease. However, there are some drawbacks related to their use in drug delivery, such as the limitation to maintain efficacy in the target organ once the magnetic field is removed from outside. Another disadvantage is the difficulty in maintaining the therapeutic action in three dimensions inside the human body. This review summarizes all the application possibilities related to magnetic nanoparticles in ocular diseases.

17.
Front Pharmacol ; 12: 577263, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408649

RESUMO

Background: The advent of cystic fibrosis transmembrane conductance regulator protein (CFTR) modulators like ivacaftor have revolutionised the treatment of cystic fibrosis (CF). However, due to the plethora of variances in disease manifestations in CF, there are inherent challenges in unified responses under CFTR modulator treatment arising from variability in patient outcomes. The pharmacokinetic (PK) data available for ivacaftor-lumacaftor cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drug combination is limited. Methods: Secondary objectives were to identify (1) patient characteristics and (2) the interactions between ivacaftor-lumacaftor responsible for interindividual variability (IIV). Results: Peak plasma concentrations (Cmax) of ivacaftor - lumacaftor were >10 fold lower than expected compared to label information. The one-way ANOVA indicated that the patient site had an effect on Cmax values of ivacaftor metabolites ivacaftor-M1, ivacaftor-M6, and lumacaftor (p < 0.001, p < 0.001, and p < 0.001, respectively). The Spearman's rho test indicated that patient weight and age have an effect on the Cmax of lumacaftor (p = 0.003 and p < 0.001, respectively) and ivacaftor metabolite M1 (p = 0.020 and p < 0.001, respectively). Age (p < 0.001) was found to effect on Cmax of ivacaftor M6 and on Tmax of ivacaftor M1 (p = 0.026). A large impact of patient characteristics on the IIV of PK parameters Cmax and Tmax, was observed among the CF patients. Conclusion: Understanding the many sources of variability can help reduce this individual patient variability and ensure consistent patient outcomes.

18.
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
19.
J Cyst Fibros ; 20(5): 857-864, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34193363

RESUMO

BACKGROUND: The potential effects of ivacaftor during pregnancy and breastfeeding on the offspring are still unknown. This study aimed to investigate pre-/postnatal age-related entry into the brain and lungs and transfer of maternally administered drug by the placental and via the milk. METHODS: In acute experiments Sprague Dawley rats at embryonic day (E) 19, postnatal days (P) 4, 9, 16, and adult were administered an intraperitoneal injection of ivacaftor (40 mg/kg) traced with [3H] ivacaftor. To determine tissue entry, plasma, cerebrospinal fluid (CSF), lungs and brains were collected, and radioactivity measured using liquid scintillation counting. For long term experiments pregnant dams were orally treated at 25 mg/kg/day for 7 days and pups collected at E19. For postnatal pups, dams received treatment for 7 or 14 days and pups were collected at P6, 9, 13 and 16. To estimate placental and milk transfer concentration of ivacaftor in pup & maternal plasma was determined by liquid chromatography-mass spectrometry. RESULTS: At all ages, entry of ivacaftor into lungs, following either acute or prolonged exposure, was much higher than into brain & CSF. Brain entry appeared higher at earlier ages. Transfer across the placenta and breast milk. was estimated to be around ~40% of maternal plasma. CONCLUSIONS: Fetal and postnatal rats were exposed to maternally administered ivacaftor via placental and milk transfer. Preferential entry in the lungs at all ages suggests the possibility that exposing CF babies to maternally administered ivacaftor could be beneficial for limiting progression of CF pathology in early development.


Assuntos
Aminofenóis/farmacocinética , Encéfalo/metabolismo , Fibrose Cística/tratamento farmacológico , Pulmão/metabolismo , Quinolonas/farmacocinética , Animais , Regulador de Condutância Transmembrana em Fibrose Cística , Feminino , Leite/química , Placenta/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley
20.
Intern Med J ; 51(10): 1567-1579, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34105222

RESUMO

Ambient (outdoor) air pollution is a key risk factor for health for which effective policy plays an important preventative role. Australian federal and related state air quality standards have historically relied on international evidence for guidance, which may not accurately reflect the Australian context. However, there has been a large increase in Australian epidemiological studies over recent years. The aim of this study is to provide an updated systematic literature review of peer-reviewed epidemiological studies that examined the health impacts of outdoor air pollution in Australia, including short- and long-term exposure. Following PRISMA guidelines, we conducted a systematic literature review. Broad search terms were applied to two databases (PubMed and Web of Science) and Google Scholar. Quality assessment and risk of bias were assessed using standard metrics. Included studies were summarised by tabulating key study characteristics, grouped by health outcomes. In total, 72 studies were included in the review. Sixty-four (89%) studies used daily or hourly pollutant concentrations to examine short-term exposure impacts, of which 59 (92%) revealed significant associations with one or more health outcomes, including cardio-respiratory, all-cause mortality or morbidity and birth outcomes. Eight (11%) studies used annual average pollutant concentrations to investigate the long-term exposure finding significant associations with asthma, reduced lung function, atopy and cardio-respiratory mortality across five studies. The remaining three studies found no significant association with asthma, mortality and a range of self-reported diseases, respectively. Ambient air pollution has substantial health impacts in Australia. The body of domestic evidence has increased markedly since national air quality standards were first set in the 1990s, which could be drawn on by policy-makers when revising the existing standards, or considering new standards.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Austrália/epidemiologia , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Estudos Epidemiológicos , Humanos , Fatores de Risco
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