Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29.296
Filtrar
2.
Medicine (Baltimore) ; 98(41): e17139, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593077

RESUMO

BACKGROUND: The molecular studies showed that Nitric oxide (NO) is an essential factor which regulates pulmonary artery tension. However, the conclusions of existing clinical studies were inconsistent. OBJECTIVE: This meta-analysis is aimed to determine whether the inhalation of NO could improve oxygenation and reduce rate of death and use of extracorporeal membrane oxygenation (ECMO). METHODS: The strategies used to search PubMed, The Cochrane Central Register of Controlled trials in the Cochrane Library, Embase, Web of science, Clinical Trials Registry, and China Biology Medicine disc, from inception to February, 2018. The primary outcomes were death or use of ECMO, death before hospital discharge, use of ECMO before hospital discharge, change in PaO2 after treatment. We assess the risk of bias in each included study by Cochrane Handbook, and calculated typical estimates of RR, each with its 95% CI, and for continuous outcomes, WMD or a summary estimate for SMD, each with its 95% CI. RESULTS: Nine randomized controlled trials (RCTs) with a total of 856 participants were included in this meta-analysis. This meta-analysis revealed that the experimental group had significantly lower death or use of ECMO (RR 0.66, 95% CI 0.57-0.77, I = 0%, P < .00001) and lower use of ECMO before hospital discharge (RR 0.89, 95% CI 0.50-0.71, I = 0%, P < .00001) compared to control group. And in the infants without diaphragmatic hernia, experimental group had significantly higher change in PaO2 after treatment (MD 50.40, 95% CI 32.14-68.66, P < .00001). The meta-analysis also showing a tendency to improve in the death before hospital discharge (RR 0.89, 95% CI 0.60-1.31, I = 0%, P = .55) and the change in PaO2 after treatment of the infants with diaphragmatic hernia (MD 6.70, 95% CI -2.32 to 15.72, P < .00001, P = .15), but no difference between experimental group and control group. CONCLUSION: We found that NO inhalation can improve oxygenation and reduce rate of death and use of ECMO in this meta-analysis. Therefore, we recommend the use of NO inhalation for infants born at or near term with respiratory failure.


Assuntos
Broncodilatadores/administração & dosagem , Oxigenação por Membrana Extracorpórea/estatística & dados numéricos , Óxido Nítrico/administração & dosagem , Insuficiência Respiratória/terapia , Administração por Inalação , Oxigenação por Membrana Extracorpórea/métodos , Feminino , Idade Gestacional , Hérnias Diafragmáticas Congênitas/complicações , Hérnias Diafragmáticas Congênitas/mortalidade , Hérnias Diafragmáticas Congênitas/terapia , Humanos , Recém-Nascido , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/mortalidade , Nascimento a Termo , Resultado do Tratamento
4.
N Engl J Med ; 381(10): 923-932, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31483963

RESUMO

BACKGROUND: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear. METHODS: We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 µg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25. RESULTS: The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group. CONCLUSIONS: In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).


Assuntos
Doenças Autoimunes/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Proteinose Alveolar Pulmonar/tratamento farmacológico , Administração por Inalação , Adulto , Idoso , Autoanticorpos/sangue , Doenças Autoimunes/diagnóstico por imagem , Método Duplo-Cego , Esquema de Medicação , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Proteinose Alveolar Pulmonar/diagnóstico por imagem , Proteinose Alveolar Pulmonar/imunologia , Capacidade de Difusão Pulmonar , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Fumar/efeitos adversos , Tomografia Computadorizada por Raios X , Teste de Caminhada
5.
Toxicol Lett ; 316: 127-135, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539569

RESUMO

Carfentanil (CRF) is an extremely potent opioid capable of inducing fatal respiratory depression. Naloxone (NX) and naltrexone (NTX) are opioid antagonists for which the efficacy against CRF remains largely unexplored. In this study, the effects of aerosolized CRF on respiratory function were investigated using adult male CD-1 mice. Mice were exposed to 0.4 mg/m3 of CRF for 15 min using custom whole-body plethysmograph units. Minute volume (MV), respiratory frequency (f), duty cycle (DC), and tidal volume (TV) were monitored and compared to control animals exposed to aerosolized H2O. CRF exposure induced respiratory depression, characterized by a marked decrease in MV, which was sustained throughout 24 h post-exposure. Prophylactic and therapeutic treatment with intramuscular (i.m.) NX marginally improved MV, with slight dose-dependent effects. Analogous treatment with i.m. NTX returned MV to baseline levels, with all doses and intervention times performing similarly. Despite improvements in MV, treatment administration did not reverse changes in DC, a measure of respiratory timing. Overall, NX and NTX administration alleviated volumetric aspects of opioid-induced respiratory toxicity, while changes in respiratory timing remained unresolved throughout post-exposure observation. These sustained changes and differences in recovery between two aspects of respiratory dynamics may provide insights for further exploration into the underlying mechanism of action of opioids and opioid antagonists.


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/toxicidade , Fentanila/análogos & derivados , Pulmão/efeitos dos fármacos , Naloxona/administração & dosagem , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Respiração/efeitos dos fármacos , Insuficiência Respiratória/prevenção & controle , Administração por Inalação , Aerossóis , Analgésicos Opioides/farmacocinética , Animais , Simulação por Computador , Relação Dose-Resposta a Droga , Fentanila/administração & dosagem , Fentanila/farmacocinética , Fentanila/toxicidade , Humanos , Pulmão/fisiopatologia , Masculino , Camundongos , Modelos Biológicos , Pletismografia Total , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/fisiopatologia , Medição de Risco
7.
Cochrane Database Syst Rev ; 9: CD006924, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31553802

RESUMO

BACKGROUND: Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. There has been much debate about whether regular (daily) long-acting beta2-agonists (LABA) are safe when used in combination with inhaled corticosteroids (ICS). This updated Cochrane Review includes results from two large trials that recruited 23,422 adolescents and adults mandated by the US Food and Drug Administration (FDA). OBJECTIVES: To assess the risk of mortality and non-fatal serious adverse events (SAEs) in trials that randomly assign participants with chronic asthma to regular formoterol and inhaled corticosteroids versus the same dose of inhaled corticosteroid alone. SEARCH METHODS: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data as well as FDA submissions in relation to formoterol. The date of the most recent search was February 2019. SELECTION CRITERIA: We included randomised clinical trials (RCTs) with a parallel design involving adults, children, or both with asthma of any severity who received regular formoterol and ICS (separate or combined) treatment versus the same dose of ICS for at least 12 weeks. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors of the studies. We assessed our confidence in the evidence using GRADE recommendations. The primary outcomes were all-cause mortality and all-cause non-fatal serious adverse events. MAIN RESULTS: We found 42 studies eligible for inclusion and included 39 studies in the analyses: 29 studies included 35,751 adults, and 10 studies included 4035 children and adolescents. Inhaled corticosteroids included beclomethasone (daily metered dosage 200 to 800 µg), budesonide (200 to 1600 µg), fluticasone (200 to 250 µg), and mometasone (200 to 800 µg). Formoterol metered dosage ranged from 12 to 48 µg daily. Fixed combination ICS was used in most of the studies. We judged the risk of selection bias, performance bias, and attrition bias as low, however most studies did not report independent assessment of causation of SAEs.DeathsSeventeen of 18,645 adults taking formoterol and ICS and 13 of 17,106 adults taking regular ICS died of any cause. The pooled Peto odds ratio (OR) was 1.25 (95% confidence interval (CI) 0.61 to 2.56, moderate-certainty evidence), which equated to one death occurring for every 1000 adults treated with ICS alone for 26 weeks; the corresponding risk amongst adults taking formoterol and ICS was also one death (95% CI 0 to 2 deaths). No deaths were reported in the trials on children and adolescents (4035 participants) (low-certainty evidence).In terms of asthma-related deaths, no children and adolescents died from asthma, but three of 12,777 adults in the formoterol and ICS treatment group died of asthma (both low-certainty evidence).Non-fatal serious adverse eventsA total of 401 adults experienced a non-fatal SAE of any cause on formoterol with ICS, compared to 369 adults who received regular ICS. The pooled Peto OR was 1.00 (95% CI 0.87 to 1.16, high-certainty evidence, 29 studies, 35,751 adults). For every 1000 adults treated with ICS alone for 26 weeks, 22 adults had an SAE; the corresponding risk for those on formoterol and ICS was also 22 adults (95% CI 19 to 25).Thirty of 2491 children and adolescents experienced an SAE of any cause when receiving formoterol with ICS, compared to 13 of 1544 children and adolescents receiving ICS alone. The pooled Peto OR was 1.33 (95% CI 0.71 to 2.49, moderate-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 8 had an non-fatal SAE; the corresponding risk amongst those on formoterol and ICS was 11 children and adolescents (95% CI 6 to 21).Asthma-related serious adverse eventsNinety adults experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 102 with ICS alone. The pooled Peto OR was 0.86 (95% CI 0.64 to 1.14, moderate-certainty evidence, 28 studies, 35,158 adults). For every 1000 adults treated with ICS alone for 26 weeks, 6 adults had an asthma-related non-fatal SAE; the corresponding risk for those on formoterol and ICS was 5 adults (95% CI 4 to 7).Amongst children and adolescents, 9 experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 5 on ICS alone. The pooled Peto OR was 1.18 (95% CI 0.40 to 3.51, very low-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 3 had an asthma-related non-fatal SAE; the corresponding risk on formoterol and ICS was 4 (95% CI 1 to 11). AUTHORS' CONCLUSIONS: We did not find a difference in the risk of death (all-cause or asthma-related) in adults taking combined formoterol and ICS versus ICS alone (moderate- to low-certainty evidence). No deaths were reported in children and adolescents. The risk of dying when taking either treatment was very low, but we cannot be certain if there is a difference in mortality when taking additional formoterol to ICS (low-certainty evidence).We did not find a difference in the risk of non-fatal SAEs of any cause in adults (high-certainty evidence). A previous version of the review had shown a lower risk of asthma-related SAEs in adults taking combined formoterol and ICS; however, inclusion of new studies no longer shows a difference between treatments (moderate-certainty evidence).The reported number of children and adolescents with SAEs was small, so uncertainty remains in this age group.We included results from large studies mandated by the FDA. Clinical decisions and information provided to patients regarding regular use of formoterol and ICS need to take into account the balance between known symptomatic benefits of formoterol and ICS versus the remaining degree of uncertainty associated with its potential harmful effects.


Assuntos
Corticosteroides/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Antiasmáticos/efeitos adversos , Asma/tratamento farmacológico , Fumarato de Formoterol/efeitos adversos , Administração por Inalação , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Antiasmáticos/administração & dosagem , Antiasmáticos/uso terapêutico , Quimioterapia Combinada , Fumarato de Formoterol/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
N Engl J Med ; 381(13): 1227-1239, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31553835

RESUMO

BACKGROUND: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. METHODS: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. RESULTS: When quintupling the dose of fluticasone (to 250 µg twice a day) was compared with adding salmeterol (50 µg twice a day) and doubling the fluticasone (to 100 µg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age. CONCLUSIONS: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Afro-Americanos , Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Fluticasona/administração & dosagem , Glucocorticoides/administração & dosagem , Xinafoato de Salmeterol/administração & dosagem , Administração por Inalação , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Masculino , Estudos Prospectivos
11.
Vasc Health Risk Manag ; 15: 159-174, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417268

RESUMO

While tobacco cigarette (TC) smoking has continued to drop to all-time lows, the use of electronic cigarettes (ECs), introduced in the US in 2007, has been rising dramatically, especially among youth. In EC emissions, nicotine is the major biologically active element, while levels of carcinogens and harmful combustion products that typify TC smoke are very low or even undetectable. TCs cause cardiovascular harm by activation of inflammatory pathways and oxidative damage, leading to atherogenesis and thrombosis, as well as through sympathetic activation triggering ischemia and arrhythmia. While ECs are generally believed to be safer than TCs, there remain many uncertainties regarding the overall cardiovascular health effects of EC usage. In this review, we discuss the various components of EC smoke and review the potential mechanisms of cardiovascular injury caused by EC use. We also discuss the controversy regarding the increasing epidemic of youth EC use weighed against the use of ECs as a smoking-cessation aid.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Sistemas Eletrônicos de Liberação de Nicotina , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Abandono do Hábito de Fumar/métodos , Fumar/efeitos adversos , Vaping , Administração por Inalação , Fatores Etários , Animais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Humanos , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Medição de Risco , Fatores de Risco , Fumar/epidemiologia , Resultado do Tratamento , Vaping/efeitos adversos
12.
AAPS PharmSciTech ; 20(7): 271, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363868

RESUMO

Dry powder inhalers have attracted more interest over the years in every aspect related to them. Interestingly, when focusing on the effects of particle morphology of the active or carrier (excipient), it is generally regarded particle size and shape to influence drug availability of aerosolized particles. However, to date, few studies have examined the effect of texture, i.e., roughness, on this relationship. The main objective of the present work is to gain a closer understanding of the influence of carrier morphology on the aerosolization performance of dry powder inhaler formulations. Image analysis and microscopy were used to visualize the aerosolization process. It is considered that the scale of morphological features on the surface of the carrier particles is responsible for the dispersion of the powder formulation, separation of the drug/carrier, and entrainment from a dry powder inhaler. Thus, for this study, the carrier particles of different surface roughness were mixed with micronized salbutamol sulphate. Aerosolization in vitro testing was used to evaluate the performance. The results indicate a connection between the qualitative surface roughness of coarse carriers and aerosolization performance during powder dispersibility. This investigation demonstrated that indeed, powder dispersion, a dynamic process, is influenced by the scale of the carrier morphology.


Assuntos
Albuterol/química , Albuterol/farmacocinética , Broncodilatadores/química , Broncodilatadores/farmacocinética , Química Farmacêutica/métodos , Inaladores de Pó Seco/métodos , Administração por Inalação , Aerossóis/química , Aerossóis/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Inaladores de Pó Seco/instrumentação , Excipientes/química , Excipientes/farmacocinética , Tamanho da Partícula , Pós , Propriedades de Superfície
13.
Pharm Res ; 36(10): 142, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31376020

RESUMO

BACKGROUND: With the recent approval of the first small interfering RNA (siRNA) therapeutic formulated as nanoparticles, there is increased incentive for establishing the factors of importance for the design of stable solid dosage forms of such complex nanomedicines. METHODS: The aims of this study were: (i) to identify factors of importance for the design of spray-dried siRNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles (LPNs), and (ii) to evaluate their influence on the resulting powders by using a quality-by-design approach. Critical formulation and process parameters were linked to critical quality attributes (CQAs) using design of experiments, and an optimal operating space (OOS) was identified. RESULTS: A series of CQAs were identified based on the quality target product profile. The loading (ratio of LPNs to the total solid content) and the feedstock concentration were determined as critical parameters, which were optimized systematically. Mannitol was chosen as stabilizing excipient due to the low water content of the resulting powders. The loading negatively affected the colloidal stability of the LPNs, whereas feedstock concentration correlated positively with the powder particle size. The optimal mannitol-based solid formulation, defined from the OOS, displayed a loading of 5% (w/w), mass median aerodynamic diameter of 3.3 ± 0.2 µm, yield of 60.6 ± 6.6%, and a size ratio of 1.15 ± 0.03. Dispersed micro-embedded LPNs had preserved physicochemical characteristics as well as in vitro siRNA release profile and gene silencing, as compared to non-spray-dried LPNs. CONCLUSION: The optimal solid dosage forms represent robust formulations suitable for higher scale-up manufacturing.


Assuntos
Dessecação/métodos , Lipídeos/química , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , RNA Interferente Pequeno/química , Administração por Inalação , Animais , Composição de Medicamentos , Excipientes/química , Inativação Gênica , Técnicas de Transferência de Genes , Manitol/química , Camundongos , Nanomedicina , Tamanho da Partícula , Pós , Células RAW 264.7 , RNA Interferente Pequeno/administração & dosagem , Solubilidade , Solventes/química
14.
Pharm Res ; 36(9): 136, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31321552

RESUMO

PURPOSE: Human tuberculosis (TB) is a global health problem that causes nearly 2 million deaths per year. Anti-TB therapy exists, but it needs to be administered as a cocktail of antibiotics for six months. This lengthy therapy results in low patient compliance and is the main reason attributable to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. METHODS: One alternative approach is to combine anti-TB multidrug therapy with inhalational TB therapy. The aim of this work was to develop and characterize dry powder formulations of spectinamide 1599 and ensure in vitro and in vivo delivered dose reproducibility using custom dosators. RESULTS: Amorphous dry powders of spectinamide 1599 were successfully spray dried with mass median aerodynamic diameter (MMAD) = 2.32 ± 0.05 µm. The addition of L-leucine resulted in minor changes to the MMAD (1.69 ± 0.35 µm) but significantly improved the inhalable portion of spectinamide 1599 while maintaining amorphous qualities. Additionally, we were able to demonstrate reproducibility of dry powder administration in vitro and in vivo in mice. CONCLUSIONS: The corresponding systemic drug exposure data indicates dose-dependent exposure in vivo in mice after dry powder intrapulmonary aerosol delivery in the dose range 15.4 - 32.8 mg/kg.


Assuntos
Antituberculosos/farmacocinética , Inaladores de Pó Seco/métodos , Espectinomicina/análogos & derivados , Administração por Inalação , Aerossóis , Animais , Antituberculosos/administração & dosagem , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Farmacorresistência Bacteriana Múltipla , Feminino , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/efeitos dos fármacos , Tamanho da Partícula , Pós , Reprodutibilidade dos Testes , Espectinomicina/administração & dosagem , Espectinomicina/farmacocinética
15.
Cochrane Database Syst Rev ; 7: CD001915, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31271656

RESUMO

BACKGROUND: The reduction of lung inflammation is one of the goals of cystic fibrosis therapy. Inhaled corticosteroids are often used in this respect to treat children and adults with cystic fibrosis. The rationale for this is their potential to reduce lung damage arising from inflammation, as well as their effect on symptomatic wheezing. It is important to establish the current level of evidence for the risks and benefits of inhaled corticosteroids, especially in the light of their known adverse effects on growth. This is an update of a previously published review; however, due to the lack of research in this area, we do not envisage undertaking any further updates. OBJECTIVES: To assess the effectiveness of taking regular inhaled corticosteroids compared to not taking them in children and adults with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We requested information from pharmaceutical companies manufacturing inhaled corticosteroids and authors of identified trials.Date of most recent search of the Group's Trials Register: 19 November 2018. SELECTION CRITERIA: Randomised or quasi-randomised trials, published and unpublished, comparing inhaled corticosteroids to placebo or standard treatment in individuals with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two independent authors assessed methodological quality and risk of bias in trials using established criteria and extracted data using standard pro formas. The quality of the evidence was assessed using the GRADE criteria. MAIN RESULTS: The searches identified 35 citations, of which 27 (representing 13 trials) were eligible for inclusion. These 13 trials reported the use of inhaled corticosteroids in 525 people with cystic fibrosis aged between 6 and 55 years. One was a withdrawal trial in 171 individuals who were already taking inhaled corticosteroids. Methodological quality and risk of bias were difficult to assess from published information.Objective measures of airway function were reported in most trials but were often incomplete and reported at different time points. We found no difference in forced expiratory volume in one second (FEV1) or forced vital capacity (FVC) % predicted in any of the trials, although the quality of the evidence was low due to risks of bias within the included trials and low participant numbers. We are uncertain whether inhaled corticosteroids result in an improvement in exercise tolerance, bronchial hyperreactivity or exacerbations as the quality of the evidence was very low. Data from one trial suggested that inhaled corticosteroids may make little or no difference to quality of life (low-quality evidence).Three trials reported adverse effects, but the quality of the evidence is low and so we are uncertain whether inhaled corticosteroids increase the risk of adverse effects. However, one study did show that growth was adversely affected by high doses of inhaled corticosteroids. AUTHORS' CONCLUSIONS: Evidence from these trials is of low to very low quality and insufficient to establish whether inhaled corticosteroids are beneficial in cystic fibrosis, but withdrawal in those already taking them has been shown to be safe. There is some evidence they may cause harm in terms of growth. It has not been established whether long-term use is beneficial in reducing lung inflammation, which should improve survival, but it is unlikely this will be proven conclusively in a randomised controlled trial.


Assuntos
Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Fibrose Cística/tratamento farmacológico , Administração por Inalação , Adolescente , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Criança , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Capacidade Vital , Adulto Jovem
17.
Arkh Patol ; 81(3): 19-26, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31317927

RESUMO

OBJECTIVE: To determine the structural changes in the cerebral cortex tissues, which are characteristic of the severe course of chronic obstructive pulmonary disease (COPD) and ischemic cerebral stroke (ICS). MATERIAL AND METHODS: The autopsy material of the microcirculatory bed of the cerebral cortex from 18 people aged 48-64 years who had died from COPD, ICS, and a concurrence of these conditions underwent histological examination and morphometric analysis. RESULTS: The state of the brain from the persons who died from ICS was characterized by a decline in the total number of neurons and glial elements, by structural and regional blood flow changes with obvious venous hyperemia, stasis, and red blood cell aggregation in the vessels. There was pericellular and perivascular edema in the perifocal area of the brain from people who died from COPD, as well as morphological signs of cerebral hemodynamic disorders. The brain structural features in ICS concurrent with COPD included a double decrease in the numerical density of capillaries, their hyperemia, perivascular edema, and venous plethora, a substantial change in the diameter of non-muscular venules, parenchymal atrophy, and stromal sclerosis, indicating the presence of a chronic process. CONCLUSION: Patients with ICS in the presence of COPD versus those who died from the isolated variants of these conditions were recorded to have an obvious decrease in the numerical density of capillaries, their hyperemia, and a pronounced change in the structure of the cerebral vein wall, which is a consequence of multisystem processes associated with COPD.


Assuntos
Isquemia Encefálica , Córtex Cerebral , Doença Pulmonar Obstrutiva Crônica , Acidente Vascular Cerebral , Administração por Inalação , Corticosteroides , Idoso , Isquemia Encefálica/complicações , Córtex Cerebral/patologia , Humanos , Microcirculação , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Acidente Vascular Cerebral/complicações
18.
Life Sci ; 232: 116650, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302196

RESUMO

BACKGROUND: Inhalation of NO2 leads to a progressive airflow limitation and the development of emphysema-like lesions. We report on the efficacy of hydrogen sulfide (NaHS) for alleviating NO2-induced pulmonary impairment. METHODS: Sprague Dawley rats were exposed to 20 ppm NO2 for 6 h over six consecutive days for 75 days. At day 75, rats who had developed NO2-induced emphysema were then divided into sodium hydrosulfide (NaHS) administrated group, placebo (NaCl) group and spontaneous recovery group for about one month (days 76-105); Pulmonary function (PF) and hematological and biochemical indices were measured at days 14, 45, 75, and 105. RESULTS: NO2 exposure for 75 days was associated with a significant decrease in FEV100/FVC%, an increased in functional residual capacity (FRC), and histologic evidence of emphysema, moreover; NO2 exposure led to elevated triglyceride (TG), red blood cell (RBC), hemoglobin (HGB), and hematocrit (HCT) levels. Impaired rats treated with NaHS showed no further deterioration in PF compared to rats exposed to ambient air and elevated WBC, granulocyte and lymphocyte counts and HDL-C levels to rats given NaCl. CONCLUSIONS: NO2 exposure causes emphysema and a decline in PF in rats. NaHS could alleviate the PF decline as possible indicated by an elevation of HDL-C levels and leukocyte. NaHS has therapeutic potential for emphysema caused by air pollutant NO2.


Assuntos
Testes Hematológicos , Pulmão/efeitos dos fármacos , Dióxido de Nitrogênio/toxicidade , Sulfetos/administração & dosagem , Sulfetos/farmacologia , Administração por Inalação , Animais , Pulmão/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Testes de Função Respiratória
19.
AAPS PharmSciTech ; 20(6): 249, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286316

RESUMO

The performances of three statistical approaches for assessing in vitro equivalence was evaluated with a set of 55 scenarios of realistic test (T) and reference (R) cascade impactor (CI) profiles (originally employed by the Product Quality Research Institute to evaluate the chi-square ratio statistic: CSRS) by comparing the outcomes against experts' opinion (surrogate for the truth). The three methods were (A) a stepwise aerodynamic particle size distribution (APSD) equivalence test integrating population bioequivalence (PBE) testing of impactor-sized mass (ISM) with the CSRS (PBE-CSRS approach), previously suggested by the USFDA; (B) the combination of PBE testing of single actuation content and ISM with the newly suggested modified CSRS (PBE-mCSRS approach), a method employing reference variance scaling; and (C) EMA's average bioequivalence (ABE approach). Based on Monte-Carlo simulations, both PBE-CSRS and ABE approaches resulted in high misclassification rates, the former with highest false-pass rate and the latter with highest false-fail rate at both ≥ 50% and ≥ 80% classification threshold values (the % of simulations or experts necessary to judge a given scenario as equivalent). Based on DeLong's tests, the PBE-mCSRS approach showed significantly better overall agreement with experts' opinion compared to the other approaches. Comparison of CSRS with mCSRS (both without PBE) suggested that the more discriminatory characteristics of the mCSRS method is based on the integration of variance scaling into the mCSRS method. Contrary to the ABE approach, the application of PBE-mCSRS approach for assessing APSD profiles of three dry powder inhaler (DPI) formulations supported the pharmacokinetic bioequivalence assessment of these formulations.


Assuntos
Inaladores de Pó Seco , Equivalência Terapêutica , Administração por Inalação , Distribuição de Qui-Quadrado , Humanos , Método de Monte Carlo , Tamanho da Partícula , Estados Unidos
20.
AAPS PharmSciTech ; 20(6): 242, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31264190

RESUMO

The utilization of ferrets as a non-clinical model for disease is rapidly increasing within drug development. Many of these models include respiratory diseases that involve targeted drug delivery via nose-only inhalation. While the deposition patterns within other non-clinical models (mice, rats, canines, and non-human primates) have been well studied, the local and regional deposition of aerosols in ferrets has not been well characterized. Therefore, inhalation aerosols were developed, radiolabeled and the radiolabeling methods validated to support SPECT-CT imaging and quantification of regional deposition within ferrets. The studies were conducted with one liquid formulation and one dry powder formulation (two concentrations of dry powder). Additionally, both aerosols were polydisperse and therefore reflect the majority of pharmaceutical aerosols. Overall, the studies showed lung deposition fractions between 5 and 10% with median aerodynamic particle sizes of 2.5 and 2.8 µm. The lung deposition fraction of the liquid aerosol was ~ 9%, nearly double observed in rats with a similarly sized aerosol. Analysis of respiratory tract (oropharynx, laryngopharynx, trachea, bifurcation area, and lung) deposition indicates increased deposition of the liquid aerosol compared to the dry powder aerosol, however, when this analysis was refined to the pulmonary region (trachea, bifurcation, and lung) the deposition was similar between formulations. These data provide the first description of the regional deposition of inhalation aerosols in ferrets with standard nose-only inhalation procedures. These data can be used for calculations of both total and regional doses within ferret inhalation drug delivery.


Assuntos
Aerossóis/farmacocinética , Sistemas de Liberação de Medicamentos , Pulmão/metabolismo , Pós , Administração por Inalação , Animais , Furões , Humanos , Camundongos , Nebulizadores e Vaporizadores , Tamanho da Partícula , Ratos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA