RESUMO
BACKGROUND: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of inhaled corticosteroids (budesonide, beclomethasone, or fluticasone propionate) in preventing bronchopulmonary dysplasia (BPD) for premature infants. METHOD: Electronic databases, including PubMed, EMBASE, Web of science, Scopus, and Cochrane library, were searched from databases inception to January 2022 for eligible randomized controlled trials. Clinical outcomes such as BPD, mortality, BPD or death, adverse events, and neurodevelopmental outcomes were assessed. RESULTS: Overall, budesonide was significantly associated with a reduction in BPD at 36 weeks' postmenstrual age (RR 0.48; 95 % CI [0.38, 0.62]) and patent ductus arteriosus (PDA) (RR 0.75; 95 % CI [0.63, 0.89]) compared with control treatments. Early longer duration inhalation of budesonide alone was associated with a lower risk of BPD at 36 weeks' postmenstrual age and PDA compared with controls. Early shorter duration intratracheal instillation of budesonide with surfactant as vehicle was associated with a lower risk of BPD at 36 weeks' postmenstrual age and all-cause mortality compared with surfactant. There was no statistically significant difference between budesonide and control groups regarding neurodevelopmental impairment. Beclomethasone and fluticasone propionate did not show any superior or inferior effect on clinical outcomes compared to control treatments. CONCLUSION: These findings suggest that budesonide, especially intratracheal instillation of budesonide using surfactant as a vehicle, is a safe and effective option in preventing BPD for preterm infants. More well-design large-scale trials with long-term follow-ups are necessary to verify the present findings.
Assuntos
Beclometasona , Displasia Broncopulmonar , Budesonida , Fluticasona , Recém-Nascido Prematuro , Humanos , Displasia Broncopulmonar/prevenção & controle , Displasia Broncopulmonar/epidemiologia , Administração por Inalação , Recém-Nascido , Budesonida/administração & dosagem , Budesonida/uso terapêutico , Beclometasona/administração & dosagem , Fluticasona/administração & dosagem , Fluticasona/uso terapêutico , Resultado do Tratamento , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Permeabilidade do Canal Arterial/tratamento farmacológico , Permeabilidade do Canal Arterial/prevenção & controle , Feminino , Masculino , Surfactantes Pulmonares/administração & dosagemRESUMO
BACKGROUND: The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined. OBJECTIVES: To delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS responsiveness. METHODS: Randomized open-label bronchoscopy study of high-dose ICS therapy in 30 healthy adult volunteers randomized 2:1 to (i) fluticasone propionate 500 mcg bd daily or (ii) no treatment, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics. RESULTS: ICS induced small between-group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV1, microbiome or DNA methylation. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B-cell immunity (CD20, immunoglobulin heavy and light chains) and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS. CONCLUSIONS: In healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS.
Assuntos
Corticosteroides , Voluntários Saudáveis , Humanos , Adulto , Masculino , Administração por Inalação , Feminino , Corticosteroides/administração & dosagem , Adulto Jovem , Pessoa de Meia-Idade , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/efeitos dos fármacos , Fluticasona/administração & dosagem , Fluticasona/farmacologiaRESUMO
Advair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development. This work developed the PK models for inhaled FP and SX that could represent potential batch variability. Two batches each of the reference and the test product (R1, R2, T1, T2) of Advair Diskus (100 µg FP/50 µg SX inhalation) were administered to 60 healthy subjects in a 4-period, 4-sequence crossover study. The failure of the bioequivalence (BE) between R1 and R2 confirmed the high between-batch variability of the RLD. Non-linear mixed effect modeling was used to estimate the population mean PK parameters for each batch. For FP, a 2-compartment model with a sequential dual zero-order absorption best described the PK profile. For SX, a 2-compartment model with a first-order absorption model best fit the data. Both models were able to capture the plasma concentration, the maximum concentration, and the total exposure (AUCinf) adequately for each batch, which could be used to simulate the BE study in the future. In vitro properties were also measured for each batch, and the batch with a higher fraction of the fine particle (diameter < 1 µm, < 2 µm) had a higher AUCinf. This positive correlation for both FP and SX could potentially assist the batch selection for the PK BE study.
Assuntos
Broncodilatadores , Estudos Cross-Over , Inaladores de Pó Seco , Combinação Fluticasona-Salmeterol , Modelos Biológicos , Equivalência Terapêutica , Humanos , Administração por Inalação , Masculino , Adulto , Combinação Fluticasona-Salmeterol/farmacocinética , Combinação Fluticasona-Salmeterol/administração & dosagem , Adulto Jovem , Broncodilatadores/farmacocinética , Broncodilatadores/administração & dosagem , Broncodilatadores/sangue , Feminino , Pessoa de Meia-Idade , Fluticasona/farmacocinética , Fluticasona/administração & dosagem , Xinafoato de Salmeterol/farmacocinética , Xinafoato de Salmeterol/administração & dosagem , Voluntários SaudáveisRESUMO
Fixed dose combinations (FDCs) incorporating two or three medicines in a single inhaler have been created to enhance patient compliance and hence clinical outcomes. However, the development of dry powder inhalers (DPIs), particularly for FDCs, faces challenges pertinent to formulation uniformity and reproducibility. Therefore, this project aimed to employ nanotechnology to develop a FDC of DPIs for market-leading medicines-fluticasone propionate (FP) and salmeterol xinafoate (SAL)-for asthma management. Nanoaggregates were prepared using a novel biocompatible and biodegradable poly(ester amide) based on the amino acid tyrosine, utilising a one-step interfacial polymerisation process. The produced tyrosine poly (ester amide) drug-loaded nanoparticles were evaluated for content uniformity, PSA, FTIR, TEM, DSC, XRD and aerodynamic performance (in vitro and in vivo). The optimised formulation demonstrated high entrapment efficiency- > 90%. The aerodynamic performance in terms of the emitted dose, fine particle fraction and respirable dose was superior to the carrier-based marketed product. In-vivo studies showed that FP (above the marketed formulation) and SAL reached the lungs of mice in a reproducible manner. These results highlight the superiority of novel FDC FP/SAL nanoparticles prepared via a one-step process, which can be used as a cost-effective and efficient method to alleviate the burden of asthma.
Assuntos
Nanopartículas , Tirosina , Animais , Nanopartículas/química , Tirosina/química , Tirosina/análogos & derivados , Administração por Inalação , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Camundongos , Asma/tratamento farmacológico , Poliésteres/química , Poliésteres/síntese química , Inaladores de Pó Seco , Fluticasona/química , Fluticasona/administração & dosagem , Sistemas de Liberação de Medicamentos , Xinafoato de Salmeterol/química , Xinafoato de Salmeterol/administração & dosagem , Tamanho da Partícula , Portadores de Fármacos/químicaRESUMO
Inhalation of pharmaceutical aerosol formulations is widely used to treat respiratory diseases. Spatially resolved thermal characterization offers promise for better understanding drug release rates from particles; however, this has been an analytical challenge due to the small particle size (from a few micrometers down to nanometers) and the complex composition of the formulations. Here, we employ nano-thermal analysis (nanoTA) to probe the nanothermal domain of a pharmaceutical aerosol formulation containing a mixture of fluticasone propionate (FP), salmeterol xinafoate (SX), and excipient lactose, which is widely used to treat asthma and chronic obstructive pulmonary disease (COPD). Furthermore, atomic force microscopy-infrared spectroscopy (AFM-IR) and AFM force measurements are performed to provide nanochemical and nanomechanical information to complement the nanothermal data. The colocalized thermal and chemical mapping clearly reveals the surface heterogeneity of the drugs in the aerosol particles and demonstrates the contribution of the surface chemical composition to the variation in the thermal properties of the particles. We present a powerful analytical approach for in-depth characterization of thermal/chemical/morphological properties of dry powder inhaler particles at micro- and nanometer scales. This approach can be used to facilitate the comparison between generics and reference inhalation products and further the development of high-performance pharmaceutical formulations.
Assuntos
Aerossóis , Inaladores de Pó Seco , Fluticasona , Lactose , Microscopia de Força Atômica , Tamanho da Partícula , Pós , Xinafoato de Salmeterol , Fluticasona/química , Fluticasona/administração & dosagem , Xinafoato de Salmeterol/química , Xinafoato de Salmeterol/administração & dosagem , Lactose/química , Microscopia de Força Atômica/métodos , Excipientes/química , Administração por Inalação , Broncodilatadores/administração & dosagem , Broncodilatadores/química , Espectrofotometria Infravermelho/métodos , Química Farmacêutica/métodos , Propriedades de SuperfícieRESUMO
INTRODUCTION: Asthma treatment guidelines classify inhaled corticosteroid (ICS) regimens as low, medium, or high dose. However, efficacy and safety are not independently assessed accordingly. Moreover, differences in ICS duration of action are not considered when a dose regimen is selected. We investigated the efficacy and safety implications of these limitations for available ICS molecules. METHODS: Published pharmacodynamic and pharmacokinetic parameters were used, alongside physiological and pharmacological principles, to estimate the efficacy and safety of available ICS molecules. Extent and duration of glucocorticoid receptor (GR) occupancy in the lung (efficacy) and cortisol suppression (systemic exposure and safety) were estimated. RESULTS: Some ICS regimens (e.g., fluticasone furoate, fluticasone propionate, and ciclesonide) rank high for efficacy but low for systemic exposure, contrary to how ICS dose equivalence is currently viewed. Differences in dose-response relationships for efficacy and systemic exposure were unique for each ICS regimen and reflected in their therapeutic indices. Notably, even low doses of most ICSs can generate high GR occupancy (≥ 90%) across the entire dose interval at steady state, which may explain previously reported difficulties in obtaining dose responses within the clinical dose range and observations that most clinical benefit typically occurs at low doses. The estimated post dose duration of lung GR occupancy for ICS molecules was categorized as 4-6 h (short), 14-16 h (medium), 25-40 h (long), or > 80 h (ultra-long), suggesting potentially large differences in anti-inflammatory duration of action. CONCLUSION: In a real-world clinical setting where there may be poor adherence to prescribed therapy, our findings suggest a significant therapeutic advantage for longer-acting ICS molecules in patients with asthma.
Patients with asthma often rely on inhaled corticosteroids to manage their symptoms by controlling lung inflammation. Inhaled corticosteroids can be used at low, medium, or high doses; however, the effectiveness, safety, and how long the effects last for a particular inhaled corticosteroid molecule are not considered when choosing them. This study investigated the safety and efficacy of different inhaled corticosteroid molecules. Leveraging published data on the mode of anti-inflammatory action and the rates these molecules are absorbed and eliminated from the body, we estimated their effectiveness and safety profiles, including duration of action in the lungs and systemic exposure levels. Some inhaled corticosteroid molecules such as fluticasone furoate, fluticasone propionate, and ciclesonide were found to exhibit high anti-inflammatory effectiveness in the lungs with minimal systemic exposure, contrasting the perceived similarities among currently used drug molecules. Anti-inflammatory duration of the unwanted systemic effect in the rest of the body was unique for each inhaled corticosteroid molecule. Notably, even the lowest doses of most inhaled corticosteroids were found to be effective in the lungs when taken as prescribed, supporting previous observations that clinical benefits are mostly realized at lower doses. Furthermore, estimated post dose durations of effectiveness for different inhaled corticosteroid molecules varied widely among different molecules, with some lasting a few hours and others lasting more than 80 h, suggesting significant differences in their duration of action. Overall, these findings demonstrate the potential advantage of using longer-acting inhaled corticosteroids, particularly for patients with asthma who may face challenges in adhering to prescribed regimens.
Assuntos
Corticosteroides , Asma , Relação Dose-Resposta a Droga , Humanos , Administração por Inalação , Asma/tratamento farmacológico , Corticosteroides/administração & dosagem , Corticosteroides/farmacocinética , Antiasmáticos/administração & dosagem , Antiasmáticos/farmacocinética , Receptores de Glucocorticoides/efeitos dos fármacos , Resultado do Tratamento , Fluticasona/administração & dosagemRESUMO
Importance: Allergic rhinitis affects an estimated 15% of the US population (approximately 50 million individuals) and is associated with the presence of asthma, eczema, chronic or recurrent sinusitis, cough, and both tension and migraine headaches. Observations: Allergic rhinitis occurs when disruption of the epithelial barrier allows allergens to penetrate the mucosal epithelium of nasal passages, inducing a T-helper type 2 inflammatory response and production of allergen-specific IgE. Allergic rhinitis typically presents with symptoms of nasal congestion, rhinorrhea, postnasal drainage, sneezing, and itching of the eyes, nose, and throat. In an international study, the most common symptoms of allergic rhinitis were rhinorrhea (90.38%) and nasal congestion (94.23%). Patients with nonallergic rhinitis present primarily with nasal congestion and postnasal drainage frequently associated with sinus pressure, ear plugging, muffled sounds and pain, and eustachian tube dysfunction that is less responsive to nasal corticosteroids. Patients with seasonal allergic rhinitis typically have physical examination findings of edematous and pale turbinates. Patients with perennial allergic rhinitis typically have erythematous and inflamed turbinates with serous secretions that appear similar to other forms of chronic rhinitis at physical examination. Patients with nonallergic rhinitis have negative test results for specific IgE aeroallergens. Intermittent allergic rhinitis is defined as symptoms occurring less than 4 consecutive days/week or less than 4 consecutive weeks/year. Persistent allergic rhinitis is defined as symptoms occurring more often than 4 consecutive days/week and for more than 4 consecutive weeks/year. Patients with allergic rhinitis should avoid inciting allergens. In addition, first-line treatment for mild intermittent or mild persistent allergic rhinitis may include a second-generation H1 antihistamine (eg, cetirizine, fexofenadine, desloratadine, loratadine) or an intranasal antihistamine (eg, azelastine, olopatadine), whereas patients with persistent moderate to severe allergic rhinitis should be treated initially with an intranasal corticosteroid (eg, fluticasone, triamcinolone, budesonide, mometasone) either alone or in combination with an intranasal antihistamine. In contrast, first-line therapy for patients with nonallergic rhinitis consists of an intranasal antihistamine as monotherapy or in combination with an intranasal corticosteroid. Conclusions and Relevance: Allergic rhinitis is associated with symptoms of nasal congestion, sneezing, and itching of the eyes, nose, and throat. Patients with allergic rhinitis should be instructed to avoid inciting allergens. Therapies include second-generation H1 antihistamines (eg, cetirizine, fexofenadine, desloratadine, loratadine), intranasal antihistamines (eg, azelastine, olopatadine), and intranasal corticosteroids (eg, fluticasone, triamcinolone, budesonide, mometasone) and should be selected based on the severity and frequency of symptoms and patient preference.
Assuntos
Glucocorticoides , Antagonistas dos Receptores Histamínicos , Rinite Alérgica , Humanos , Budesonida/administração & dosagem , Budesonida/uso terapêutico , Cetirizina/uso terapêutico , Fluticasona/administração & dosagem , Fluticasona/uso terapêutico , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Imunoglobulina E/imunologia , Furoato de Mometasona/administração & dosagem , Furoato de Mometasona/uso terapêutico , Cloridrato de Olopatadina/administração & dosagem , Cloridrato de Olopatadina/uso terapêutico , Prurido/etiologia , Rinite Alérgica/complicações , Rinite Alérgica/diagnóstico , Rinite Alérgica/imunologia , Rinite Alérgica/terapia , Rinorreia/etiologia , Espirro , Triancinolona/administração & dosagem , Triancinolona/uso terapêutico , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Rinite/tratamento farmacológico , Antagonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos/uso terapêutico , Administração IntranasalRESUMO
PURPOSE: The primary objective of this study was to optimize formulation variables and investigate the in vitro characteristics of fluticasone propionate (FP)-loaded mixed polymeric micelles, which were composed of depolymerized chitosan-stearic acid copolymer (DC-SA) in combination with either tocopheryl polyethylene glycol succinate or dipalmitoylphosphatidylcholine for pulmonary drug delivery. METHODS: A D-optimal design was employed for the optimization procedure, considering lipid/ polymer ratio, polymer concentration, drug/ polymer ratio, and lipid type as independent variables. Dependent variables included particle size, polydispersion index, zeta potential, drug encapsulation efficiency, and loading efficiency of the polymeric micelles. Additionally, the nebulization efficacy and cell viability of the optimal FP-loaded DC-SA micellar formulations were evaluated. RESULTS: The mixed polymeric micelles were successfully prepared with properties falling within the desired ranges, resulting in four optimized formulations. The release of FP from the optimal systems exhibited a sustained release profile over 72 hours, with 70% of the drug still retained within the core of the micelles. The nebulization efficiency of these optimal formulations reached up to 63%, and the fine particle fraction (FPF) ranged from 41% to 48%. Cellular viability assays demonstrated that FP-loaded DC-SA polymeric micelles exhibited lower cytotoxicity than the free drug but were slightly more cytotoxic than empty mixed micelles. CONCLUSION: In conclusion, this study suggests that DC-SA/ lipid mixed micelles have the potential to serve as effective carriers for nebulizing poorly soluble FP.
Assuntos
Sobrevivência Celular , Quitosana , Fluticasona , Micelas , Ácidos Esteáricos , Quitosana/química , Ácidos Esteáricos/química , Humanos , Fluticasona/administração & dosagem , Fluticasona/farmacologia , Fluticasona/química , Sobrevivência Celular/efeitos dos fármacos , Tamanho da Partícula , Administração por Inalação , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Nebulizadores e Vaporizadores , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacologia , Broncodilatadores/químicaRESUMO
OBJECTIVE: Despite limited safety and efficacy data, inhaled corticosteroids (ICS) are prescribed to premature infants in the neonatal intensive care unit (NICU). We examined contemporary use and risk factors for ICS use in the NICU. STUDY DESIGN: Infants <33 weeks gestational age and <1500 gm birth weight discharged from Pediatrix Medical Group NICUs between 2010 and 2020 were included. We evaluated the association between ICS prescription and clinical characteristics using univariable and multivariable logistic regression. RESULTS: Of 74,123 infants from 308 NICUs, 9253 (12.5%) were prescribed ICS: budesonide, fluticasone, or beclomethasone. Diagnosis of bronchopulmonary dysplasia (BPD), earlier gestational age, male sex, longer mechanical ventilation, oxygen support, and systemic steroids were independent risk factors for ICS prescription. CONCLUSIONS: Use of ICS is common in many NICUs and is associated with a diagnosis of BPD and healthcare utilization. Prospective trials are needed to establish the safety, efficacy, and optimal indication in this vulnerable population.
Assuntos
Displasia Broncopulmonar , Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Padrões de Prática Médica , Humanos , Recém-Nascido , Administração por Inalação , Masculino , Feminino , Displasia Broncopulmonar/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Idade Gestacional , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Estudos Retrospectivos , Beclometasona/administração & dosagem , Beclometasona/uso terapêutico , Budesonida/administração & dosagem , Budesonida/uso terapêutico , Modelos Logísticos , Fatores de Risco , Fluticasona/administração & dosagem , Fluticasona/uso terapêuticoRESUMO
BACKGROUND: Swallowed topical corticosteroids (tC) are common therapy for patients with eosinophilic esophagitis (EoE). Widely heterogeneous results have occurred due to their active ingredients, formulations and doses. OBJECTIVE: To assess the effectiveness of topical corticosteroid therapy for EoE in real-world practice. METHODS: Cross-sectional study analysis of the multicentre EoE CONNECT registry. Clinical remission was defined as a decrease of ≥50% in dysphagia symptom scores; histological remission was defined as a peak eosinophil count below 15 per high-power field. The effectiveness in achieving clinico-histological remission (CHR) was compared for the main tC formulations. RESULTS: Overall, data on 1456 prescriptions of tC in monotherapy used in 866 individual patients were assessed. Of those, 904 prescriptions with data on formulation were employed for the induction of remission; 234 reduced a previously effective dose for maintenance. Fluticasone propionate formulations dominated the first-line treatment, while budesonide was more common in later therapies. A swallowed nasal drop suspension was the most common formulation of fluticasone propionate. Doses ≥0.8 mg/day provided a 65% CHR rate and were superior to lower doses. Oral viscous solution prepared by a pharmacist was the most common prescription of budesonide; 4 mg/day provided no benefit over 2 mg/day (CHR rated being 72% and 80%, respectively). A multivariate analysis revealed budesonide orodispersible tablets as the most effective therapy (OR 18.9, p < 0.001); use of higher doses (OR 4.3, p = 0.03) and lower symptom scores (OR 0.9, p = 0.01) were also determinants of effectiveness. CONCLUSION: Reduced symptom severity, use of high doses, and use of budesonide orodispersible tablets particularly were all independent predictors of tC effectiveness.
Assuntos
Budesonida , Esofagite Eosinofílica , Fluticasona , Sistema de Registros , Humanos , Esofagite Eosinofílica/tratamento farmacológico , Esofagite Eosinofílica/diagnóstico , Estudos Transversais , Masculino , Feminino , Fluticasona/administração & dosagem , Fluticasona/uso terapêutico , Resultado do Tratamento , Budesonida/administração & dosagem , Budesonida/uso terapêutico , Adulto , Administração Tópica , Indução de Remissão/métodos , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Criança , Adolescente , Transtornos de Deglutição/tratamento farmacológico , Transtornos de Deglutição/etiologia , Pessoa de Meia-Idade , Adulto Jovem , Administração OralRESUMO
BACKGROUND: Optimising intranasal distribution and retention of topical therapy is essential for effectively managing patients with chronic rhinosinusitis, including those that have had functional endoscopic sinus surgery (FESS). This study presents a new technique for quantifying in vitro experiments of fluticasone propionate deposition within the sinuses of a 3D-printed model from a post-FESS patient. METHODS: Circular filter papers were placed on the sinus surfaces of the model. Deposition of fluticasone on the filter paper was quantified using high-performance liquid chromatography (HPLC) assay-based techniques. The deposition patterns of two nasal drug delivery devices, an aqueous nasal spray (Flixonase) and metered dose inhaler (Flixotide), were compared. The effects of airflow (0 L/min vs. 12 L/min) and administration angle (30° vs. and 45°) were evaluated. RESULTS: Inhaled airflow made little difference to sinus deposition for either device. A 45° administration angle improved frontal sinus deposition with the nasal spray and both ethmoidal and sphenoidal deposition with the inhaler. The inhaler provided significantly better deposition within the ethmoid sinuses (8.5x) and within the maxillary sinuses (3.9x) compared with the nasal spray under the same conditions. CONCLUSION: In the post-FESS model analysed, the inhaler produced better sinus deposition overall compared with the nasal spray. The techniques described can be used and adapted for in vitro performance testing of different drug formulations and intranasal devices under different experimental conditions. They can also help validate computational fluid dynamics modelling and in vivo studies.
Assuntos
Fluticasona/administração & dosagem , Glucocorticoides/administração & dosagem , Modelos Anatômicos , Seios Paranasais/metabolismo , Administração por Inalação , Composição de Medicamentos , Feminino , Fluticasona/química , Fluticasona/metabolismo , Glucocorticoides/química , Glucocorticoides/metabolismo , Humanos , Inaladores Dosimetrados , Pessoa de Meia-Idade , Sprays Nasais , Seios Paranasais/anatomia & histologia , Seios Paranasais/cirurgia , Impressão Tridimensional , Distribuição Tecidual , Cirurgia Endoscópica TransanalRESUMO
Steroid resistance in asthma has been associated with neutrophilic inflammation and severe manifestations of the disease. Macrolide add-on therapy can improve the quality of life and the exacerbation rate in refractory cases, possibly with greater effectiveness in neutrophilic phenotypes. The mechanisms leading to these beneficial effects are incompletely understood and whether macrolides potentiate the modulation of bronchial remodeling induced by inhaled corticosteroids (ICS) is unknown. The objective of this study was to determine if adding azithromycin to ICS leads to further improvement of lung function, airway inflammation and bronchial remodeling in severe asthma. The combination of azithromycin (10 mg/kg q48h PO) and inhaled fluticasone (2500 µg q12h) was compared to the sole administration of fluticasone for five months in a randomized blind trial where the lung function, airway inflammation and bronchial remodeling (histomorphometry of central and peripheral airways and endobronchial ultrasound) of horses with severe neutrophilic asthma were assessed. Although the proportional reduction of airway neutrophilia was significantly larger in the group receiving azithromycin, the lung function and the peripheral and central airway smooth muscle mass decreased similarly in both groups. Despite a better control of airway neutrophilia, azithromycin did not potentiate the other clinical effects of fluticasone.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Antibacterianos/uso terapêutico , Asma/veterinária , Azitromicina/uso terapêutico , Doenças dos Cavalos/tratamento farmacológico , Administração por Inalação , Animais , Antibacterianos/farmacologia , Asma/tratamento farmacológico , Asma/imunologia , Azitromicina/farmacologia , Broncodilatadores/administração & dosagem , Quimioterapia Combinada , Feminino , Fluticasona/administração & dosagem , Doenças dos Cavalos/imunologia , Cavalos , Masculino , NeutrófilosRESUMO
OBJECTIVE: Atopic dermatitis (AD) is a pruritic, chronic, relapsing inflammatory skin disease. The research aims to study the effects of Sarsasapogenin and its combination with Fluticasone in 2, 4-Dinitrofluorobenzene (DNFB) induced atopic dermatitis in BALB/c mice. MATERIAL AND METHODS: Thirty male Balb/c mice were divided into 5 groups: (i) Normal control (NC), (ii) Disease control (DNFB), (iii) Sarsasapogenin (SG) (50 µg/mice), (iv) Fluticasone (FC) (50 µg/mice), (v) Sarsasapogenin + Fluticasone (SG + FC) combination (25 µg/mice). Dermatitis was induced by repeated application of DNFB in Balb/c mice. On topical application of SG, FC, and SG + FC combination on the ear and skin lesions, body weight, ear weight, ear thickness, erythema score, spleen weight, cytokines, immunoglobulin E (IgE) levels, nitric oxide (NO) level, hematological parameters, and oxidative stress markers were evaluated. Histological analysis of the ear tissue was also done. RESULTS: The results stated that SG and SG + FC treatment to mice considerably decrease the ear weight, ear thickness, spleen weight, serum IgE, cytokines, NO levels, and restoration of antioxidant stress markers with elevation in the hematological parameters. The observations were further confirmed by histopathological analysis of ear tissue. CONCLUSION: These data specify that SG has been demonstrated as a probable therapy for the treatment of allergic skin diseases in combination with FC by decreasing its dose from 50 to 25 µg/mice to avoid the chronic side effects of FC. Hence, it can be concluded that SG and SG + FC combination significantly improved the AD-like symptoms in the DNFB sensitized mice through mitigating the production of proinflammatory mediators and restoration of oxidative stress markers.
Assuntos
Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/administração & dosagem , Dinitrofluorbenzeno/toxicidade , Medicamentos de Ervas Chinesas/administração & dosagem , Fluticasona/administração & dosagem , Espirostanos/administração & dosagem , Animais , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/metabolismo , Quimioterapia Combinada , Feminino , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Toxicidade Aguda/métodosRESUMO
BACKGROUND: There are significant drug-drug interactions between human immunodeficiency virus antiretroviral therapy and intranasal steroids, leading to high serum concentrations of iatrogenic steroids and subsequently Cushing's syndrome. METHOD: All articles in the literature on cases of intranasal steroid and antiretroviral therapy interactions were reviewed. Full-length manuscripts were analysed and the relevant data were extracted. RESULTS: A literature search and further cross-referencing yielded a total of seven reports on drug-drug interactions of intranasal corticosteroids and human immunodeficiency virus protease inhibitors, published between 1999 and 2019. CONCLUSION: The use of potent steroids metabolised via CYP3A4, such as fluticasone and budesonide, are not recommended for patients taking ritonavir or cobicistat. Mometasone should be used cautiously with ritonavir because of pharmacokinetic similarities to fluticasone. There was a delayed onset of symptoms in many cases, most likely due to the relatively lower systemic bioavailability of intranasal fluticasone.
Assuntos
Corticosteroides/efeitos adversos , Síndrome de Cushing/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , HIV , Administração Intranasal , Corticosteroides/administração & dosagem , Adulto , Cobicistat/administração & dosagem , Cobicistat/efeitos adversos , Interações Medicamentosas , Fluticasona/administração & dosagem , Fluticasona/efeitos adversos , Inibidores da Protease de HIV/administração & dosagem , Humanos , Masculino , Ritonavir/administração & dosagem , Ritonavir/efeitos adversosRESUMO
Allergic rhinitis (AR) is prevalent, and many patients present with moderate-to-severe symptomatic disease. The majority of patients are not satisfied with their AR treatment, despite the use of concurrent medications. These gaps underscore the need for treatment with more effective options for moderate-to-severe AR. The authors' objective was to review systematically the efficacy and safety of MP-AzeFlu for the treatment of AR. The primary outcomes studied were nasal, ocular, and total symptoms. Other outcomes included time to onset and of AR control, quality of life, and safety. Searches of PubMed and Cochrane databases were conducted on May 14, 2020, with no date restrictions, to identify publications reporting data on MP-AzeFlu. Clinical studies of any phase were included. Studies were excluded if they were not in English, were review articles, did not discuss the safety and efficacy of MP-AzeFlu for AR symptoms. Treatment of AR with MP-AzeFlu results in effective, sustained relief of nasal and ocular symptoms, and faster onset and time to control compared with intranasal azelastine or fluticasone propionate. Long-term use of MP-AzeFlu was safe, with benefits in children, adults, and adults aged ≥65 years. Other treatment options, including fluticasone propionate and azelastine alone or the combination of intranasal corticosteroids and oral antihistamine, do not provide the same level of efficacy as MP-AzeFlu in terms of rapid and sustained relief of the entire AR symptom complex. Furthermore, MP-AzeFlu significantly improves patient quality of life. MP-AzeFlu is a currently available combination that may satisfy all these patient needs and expectations.
Assuntos
Corticosteroides/administração & dosagem , Antialérgicos/administração & dosagem , Fluticasona/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Ftalazinas/administração & dosagem , Rinite Alérgica/tratamento farmacológico , Corticosteroides/efeitos adversos , Antialérgicos/efeitos adversos , Combinação de Medicamentos , Fluticasona/efeitos adversos , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Humanos , Ftalazinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Although it is known that oral antihistamine-pseudoephedrine combination tablets have a faster onset than intranasal corticosteroid sprays in the treatment of allergic rhinitis after the first dose, the magnitude of change has not been measured in a comparative manner. Furthermore, the sensation of sprayed liquid in the nose may lead patients to mistakenly believe that intranasal steroid sprays work instantly. OBJECTIVE: To evaluate, numerically, nasal airflow changes provided by a single dose of loratadine-pseudoephedrine tablet (LP) and fluticasone propionate nasal spray (FP) in participants experiencing allergic rhinitis symptoms, including nasal congestion. METHODS: This single-center, double-blinded, placebo-controlled, crossover study evaluated objective nasal airflow changes in patients with a documented sensitivity to ragweed pollen. Participants were randomized to receive 1 of 4 treatment sequences, and their peak nasal inspiratory flow (PNIF) was measured in a span of 4 hours after pollen exposure in an environmental exposure unit. RESULTS: Average change in PNIF was 31% with LP in the course of the study, significantly greater than with placebo and FP (12% and 15%, respectively; P < .001). Nevertheless, FP did not produce a significant change compared with its placebo. At hour one post-dose, LP had a clinically significant 31% increase in PNIF, whereas FP only yielded an 8.6% increase (P < .001). Measurable nasal airflow improvements are associated with the opening of nasal passages, allowing congested patients to breathe more freely. CONCLUSION: A single dose of LP quickly and significantly (P < .001) improved nasal airflow after ragweed pollen challenge in an environmental exposure unit. Comparatively, FP did not display this same benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03443843.
Assuntos
Antialérgicos/administração & dosagem , Fluticasona/administração & dosagem , Loratadina/administração & dosagem , Descongestionantes Nasais/administração & dosagem , Pseudoefedrina/administração & dosagem , Rinite Alérgica/tratamento farmacológico , Administração Intranasal , Adulto , Antialérgicos/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Fluticasona/efeitos adversos , Humanos , Loratadina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Cavidade Nasal/fisiologia , Descongestionantes Nasais/efeitos adversos , Sprays Nasais , Pseudoefedrina/efeitos adversos , Fenômenos Fisiológicos Respiratórios , Rinite Alérgica/fisiopatologia , Comprimidos , Adulto JovemRESUMO
Middle ear barotrauma (MEB) is a common complication of hyperbaric oxygen (HBO2) therapy. It has been reported in more than 40% of HBO2 treatments and can interrupt the sequence of HBO2. MEB may lead to pain, tympanic membrane rupture, and even hearing loss. The aim of this study was to determine if pretreatment with intranasal fluticasone and oxymetazoline affected the incidence of MEB. We conducted a retrospective chart review of subjects undergoing HBO2 at our institution between February 1, 2014, and May 31, 2019. Subjects in the fluticasone/oxymetazoline (FOT) treatment group used intranasal fluticasone 50 mcg two times per day and oxymetazoline 0.05% one spray two times per day beginning 48 hours prior to initial HBO2. Oxymetazoline was discontinued after four days. Fluticasone was continued for the duration of HBO2 therapy. A total of 154 unique subjects underwent 5,683 HBO2 treatments: 39 unique subjects in the FOT group underwent 1,501 HBO2; 115 unique subjects in the nFOT (no oxymetazoline or fluticasone treatment) group underwent 4,182 HBO2 treatments. The incidence of MEB was 15.4% in the FOT group and 16.2% in the nFOT group. This was not a statistically significant difference (OR = 0.77; p = 0.636). Treatment pressure, age over 65 years, male sex, and BMI were not associated with a difference in MEB incidence. In summary, pretreatment with intranasal oxymetazoline and fluticasone in patients undergoing HBO2 did not significantly reduce MEB. More investigation with larger numbers of participants and prospective studies could further clarify this issue.
Assuntos
Anti-Inflamatórios/uso terapêutico , Barotrauma/prevenção & controle , Orelha Média/lesões , Fluticasona/uso terapêutico , Oxigenoterapia Hiperbárica/efeitos adversos , Descongestionantes Nasais/uso terapêutico , Oximetazolina/uso terapêutico , Administração Intranasal , Idoso , Anti-Inflamatórios/administração & dosagem , Barotrauma/epidemiologia , Barotrauma/etiologia , Esquema de Medicação , Feminino , Fluticasona/administração & dosagem , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Descongestionantes Nasais/administração & dosagem , Sprays Nasais , Oximetazolina/administração & dosagem , Estudos RetrospectivosRESUMO
BACKGROUND: Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness, and cough. Treatment with inhaled steroids and bronchodilators can result in good control of symptoms, prevention of further morbidity, and improved quality of life. However, an increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta2-agonists) compared with placebo for chronic asthma has been demonstrated in previous Cochrane Reviews. This increase was statistically significant in trials that did not randomise participants to an inhaled corticosteroid, but not when formoterol or salmeterol was combined with an inhaled corticosteroid. The confidence intervals were found to be too wide to ensure that the addition of an inhaled corticosteroid renders regular long-acting beta2-agonists completely safe; few participants and insufficient serious adverse events in these trials precluded a definitive decision about the safety of combination treatments. OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events in trials that have randomised patients with chronic asthma to regular formoterol and an inhaled corticosteroid versus regular salmeterol and an inhaled corticosteroid. SEARCH METHODS: We searched the Cochrane Airways Register of Trials, CENTRAL, MEDLINE, Embase, and two trial registries to identify reports of randomised trials for inclusion. We checked manufacturers' websites and clinical trial registers for unpublished trial data, as well as Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was 24 February 2021. SELECTION CRITERIA: We included controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma, if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid) and were of at least 12 weeks' duration. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion in the review, extracted outcome data from published papers and trial registries, and applied GRADE rating for the results. We sought unpublished data on mortality and serious adverse events from study sponsors and authors. The primary outcomes were all cause mortality and non-fatal serious adverse events. We chose not to calculate an average result from all the formulations of formoterol and inhaled steroid, as the doses and delivery devices are too diverse to assume a single class effect. MAIN RESULTS: Twenty-one studies in 11,572 adults and adolescents and two studies in 723 children met the eligibility criteria of the review. No data were available for two studies; therefore these were not included in the analysis. Among adult and adolescent studies, seven compared formoterol and budesonide to salmeterol and fluticasone (N = 7764), six compared formoterol and beclomethasone to salmeterol and fluticasone (N = 1923), two compared formoterol and mometasone to salmeterol and fluticasone (N = 1126), two compared formoterol and fluticasone to salmeterol and fluticasone (N = 790), and one compared formoterol and budesonide to salmeterol and budesonide (N = 229). In total, five deaths were reported among adults, none of which was thought to be related to asthma. The certainty of evidence for all-cause mortality was low, as there were not enough deaths to permit any precise conclusions regarding the risk of mortality on combination formoterol versus combination salmeterol. In all, 201 adults reported non-fatal serious adverse events. In studies comparing formoterol and budesonide to salmeterol and fluticasone, there were 77 in the formoterol arm and 68 in the salmeterol arm (Peto odds ratio (OR) 1.14, 95% confidence interval (CI) 0.82 to 1.59; 5935 participants, 7 studies; moderate-certainty evidence). In the formoterol and beclomethasone studies, there were 12 adults in the formoterol arm and 13 in the salmeterol arm with events (Peto OR 0.94, 95% CI 0.43 to 2.08; 1941 participants, 6 studies; moderate-certainty evidence). In the formoterol and mometasone studies, there were 18 in the formoterol arm and 11 in the salmeterol arm (Peto OR 1.02, 95% CI 0.47 to 2.20; 1126 participants, 2 studies; moderate-certainty evidence). One adult in the formoterol and fluticasone studies in the salmeterol arm experienced an event (Peto OR 0.05, 95% CI 0.00 to 3.10; 293 participants, 2 studies; low-certainty evidence). Another adult in the formoterol and budesonide compared to salmeterol and budesonide study in the formoterol arm had an event (Peto OR 7.45, 95% CI 0.15 to 375.68; 229 participants, 1 study; low-certainty evidence). Only 46 adults were reported to have experienced asthma-related serious adverse events. The certainty of the evidence was low to very low due to the small number of events and the absence of independent assessment of causation. The two studies in children compared formoterol and fluticasone to salmeterol and fluticasone. No deaths and no asthma-related serious adverse events were reported in these studies. Four all-cause serious adverse events were reported: three in the formoterol arm, and one in the salmeterol arm (Peto OR 2.72, 95% CI 0.38 to 19.46; 548 participants, 2 studies; low-certainty evidence). AUTHORS' CONCLUSIONS: Overall, for both adults and children, evidence is insufficient to show whether regular formoterol in combination with budesonide, beclomethasone, fluticasone, or mometasone has a different safety profile from salmeterol in combination with fluticasone or budesonide. Five deaths of any cause were reported across all studies and no deaths from asthma; this information is insufficient to permit any firm conclusions about the relative risks of mortality on combination formoterol in comparison to combination salmeterol inhalers. Evidence on all-cause non-fatal serious adverse events indicates that there is probably little to no difference between formoterol/budesonide and salmeterol/fluticasone inhalers. However events for the other formoterol combination inhalers were too few to allow conclusions. Only 46 non-fatal serious adverse events were thought to be asthma related; this small number in addition to the absence of independent outcome assessment means that we have very low confidence for this outcome. We found no evidence of safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy by adults and children with asthma.
Assuntos
Antiasmáticos/efeitos adversos , Asma/tratamento farmacológico , Fumarato de Formoterol/administração & dosagem , Glucocorticoides/efeitos adversos , Xinafoato de Salmeterol/administração & dosagem , Administração por Inalação , Adolescente , Adulto , Antiasmáticos/administração & dosagem , Asma/mortalidade , Beclometasona/administração & dosagem , Beclometasona/efeitos adversos , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Budesonida/administração & dosagem , Budesonida/efeitos adversos , Criança , Doença Crônica , Quimioterapia Combinada/efeitos adversos , Fluticasona/administração & dosagem , Fluticasona/efeitos adversos , Fumarato de Formoterol/efeitos adversos , Glucocorticoides/administração & dosagem , Humanos , Furoato de Mometasona/administração & dosagem , Furoato de Mometasona/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Xinafoato de Salmeterol/efeitos adversosRESUMO
In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 µm (A-4.5), 3.8 µm (B-3.8), and 3.7 µm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 µg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0-Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0-Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).
Assuntos
Broncodilatadores/farmacocinética , Medicamentos Genéricos/farmacocinética , Fluticasona/farmacocinética , Administração por Inalação , Adolescente , Adulto , Aerossóis , Área Sob a Curva , Broncodilatadores/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Liberação Controlada de Fármacos , Medicamentos Genéricos/administração & dosagem , Inaladores de Pó Seco , Feminino , Fluticasona/administração & dosagem , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pós , Equivalência Terapêutica , Adulto JovemRESUMO
This work aimed to elaborate an optimised fluticasone propionate (FP)-loaded solid lipid nanoparticles (SLNs) to enhance FP effectiveness for topical inflammatory remediation. The influences of drug amount, lipid, and surfactant ratios, on drug release pattern and stability were investigated utilising Box-Behnken design. Elaboration, characterisation, and pharmacodynamic evaluation in comparison with the marketed formulation (Cutivate® cream, 0.05%w/w FP), were conducted for the optimised SLNs. The optimised SLNs with a size of 248.3 ± 1.89 nm (PDI = 0.275) and -32.4 ± 2.85 mV zeta potential were evidenced good stability physiognomies. The optimised SLNs pre-treated rats exhibited non-significant difference in paw volume from that of the control group and showed a significant reduction in both PGE2 and TNF-α levels by 51.5 and 61%, respectively, in comparison with the Carrageenan group. The optimised FP-loaded SLNs maximised the efficacy of FP towards inflammation alleviation that increase its potential as efficient implement in inflammatory skin diseases remediation.