Inhaled phage therapy: a promising and challenging approach to treat bacterial respiratory infections.

PubMed

Bodier-Montagutelli, Elsa; Morello, Eric; L'Hostis, Guillaume; Guillon, Antoine; Dalloneau, Emilie; Respaud, Renaud; Pallaoro, Nikita; Blois, Hélène; Vecellio, Laurent; Gabard, Jérôme; Heuzé-Vourc'h, Nathalie

2017-08-01

Bacterial respiratory tract infections (RTIs) are increasingly difficult to treat due to evolving antibiotic resistance. In this context, bacteriophages (or phages) are part of the foreseen alternatives or combination therapies. Delivering phages through the airways seems more relevant to accumulate these natural antibacterial viruses in proximity to their bacterial host, within the infectious site. Areas covered: This review addresses the potential of phage therapy to treat RTIs and discusses preclinical and clinical results of phages administration in this context. Recent phage formulation and aerosolization attempts are also reviewed, raising technical challenges to achieve efficient pulmonary deposition via inhalation. Expert opinion: Overall, the inhalation of phages as antibacterial treatment seems both clinically relevant and technically feasible. Several crucial points still need to be investigated, such as phage product pharmacokinetics and immunogenicity. Furthermore, given phage-specific features, appropriate regulatory and manufacturing guidelines will need to be defined. Finally, randomized controlled clinical trials should be carried out to establish phage therapy's clinical positioning in the antimicrobial arsenal against RTIs.

Inhalation delivery of protein therapeutics.

PubMed

Kane, Colleen; O'Neil, Karyn; Conk, Michelle; Picha, Kristen

2013-04-01

Inhaled therapeutics are used routinely to treat a variety of pulmonary diseases including asthma, COPD and cystic fibrosis. In addition, biological therapies represent the fastest growing segment of approved pharmaceuticals. However, despite the increased availability of biological therapies, nearly all inhaled therapeutics are small molecule drugs with only a single inhaled protein therapeutic approved. There remains a significant unmet need for therapeutics in pulmonary diseases, and biological therapies with potential to alter disease progression represent a significant opportunity to treat these challenging diseases. This review provides a background into efforts to develop inhaled biological therapies and highlights some of the associated challenges. In addition, we speculate on the ideal properties of a biologic therapy for inhaled delivery.

[Occupational allergic "march". Rapid evolution of contact dermatitis to ammonium persulfate into airborne contact dermatitis with rhinitis and asthma in a hairdresser].

PubMed

Poltronieri, Anna; Patrini, L; Pigatto, P; Riboldi, L; Marsili, Chiara; Previdi, M; Margonari, M; Marraccini, P

2010-01-01

Hairdressers are exposed to irritants and allergenic compounds that may cause contact dermatitis, rhinitis and asthma. In this paper we describe the case of a female, age 33 years, who developed contact dermatitis after 10 years of exposure to ammonium persulfate. After 7 months of progressively extensive and persistent skin lesions, respiratory symptoms appeared that were related to the occupational exposure (on-off test). SIDAPA and specific occupational patch test for hairdressers and occupational challenge with ammonium persulfate were performed. Clinical parameters of inflammation, ECP (eosinophil cationic protein) and exhaled nitric oxide (FeNO) were detected before and after the specific bronchial challenge. The patch test was positive to ammonium persulfate (++), and bronchial challenge for ammonium persulfate showed a significant late response (FEV1 decrease--33%). Both FeNO and ECP showed a significant increase after 24 hours. Dermatitis, urticaria and angioedema occurred on the uncovered skin due to airborne contact. Topic steroids and anti-histaminic drugs resolved the clinical symptoms. Bronchial challenge is, in fact, considered to be the gold standard for the diagnosis of occupational asthma, although new inflammatory parameters can contribute to the diagnosis and can be useful for monitoring after a specific inhalation test with occupational agents. The described case summarizes the evolution from contact dermatitis to inhalation allergy, suggesting the occurrence of an allergic "march" for occupational allergy.

Direct-reading inhalable dust monitoring--an assessment of current measurement methods.

PubMed

Thorpe, Andrew; Walsh, Peter T

2013-08-01

Direct-reading dust monitors designed specifically to measure the inhalable fraction of airborne dust are not widely available. Current practice therefore often involves comparing the response of photometer-type dust monitors with the concentration measured with a reference gravimetric inhalable sampler, which is used to adjust the dust monitor measurement. However, changes in airborne particle size can result in significant errors in the estimation of inhalable concentration by this method. The main aim of this study was to assess how these dust monitors behave when challenged with airborne dust containing particles in the inhalable size range and also to investigate alternative dust monitors whose response might not be as prone to variations in particle size or that could be adapted to measure inhalable dust concentration. Several photometer-type dust monitors and a Respicon TM, tapered element oscillating microbalance (TEOM) personal dust monitor (PDM) 3600, TEOM 1400, and Dustrak DRX were assessed for the measurement of airborne inhalable dust during laboratory and field trials. The PDM was modified to allow it to sample and measure larger particles in the inhalable size range. During the laboratory tests, the dust monitors and reference gravimetric samplers were challenged inside a large dust tunnel with aerosols of industrial dusts known to present an inhalable hazard and aluminium oxide powders with a range of discrete particle sizes. A constant concentration of each dust type was generated and peak concentrations of larger particles were periodically introduced to investigate the effects of sudden changes in particle size on monitor calibration. The PDM, Respicon, and DataRam photometer were also assessed during field trials at a bakery, joinery, and a grain mill. Laboratory results showed that the Respicon, modified PDM, and TEOM 1400 observed good linearity for all types of dust when compared with measurements made with a reference IOM sampler; the photometer-type dust monitors on the other hand showed little correlation. The Respicon also accurately measured the inhalable concentration, whereas the modified PDM underestimated it by ~27%. Photometer responses varied considerably with changing particle size, which resulted in appreciable errors in airborne inhalable dust concentration measurements. Similar trends were also observed during field trials. Despite having limitations, both the modified PDM and Respicon showed promise as real-time inhalable dust monitors.

The prevalence and diagnostic value of specific IgE antibodies to inhalant, animal and plant food, and ficus allergens in patients with natural rubber latex allergy.

PubMed

Ebo, D G; Bridts, C H; Hagendorens, M M; De Clerck, L S; Stevens, W J

2003-01-01

It is well recognised that natural rubber latex allergy can be associated with serological cross-reactivity to plant allergens, especially tropical fruits and Ficus. In contrast, data on the frequency and clinical value of specific IgE antibodies against these allergens remain rare. In addition, little is known about the prevalence and diagnostic value of specific IgE antibodies to classical inhalant and animal allergens in NRL allergic patients. The purpose of this study was to investigate the prevalence, the sensitivity, and the specificity of these different specific IgE antibodies in patients suffering from NRL allergy. Serum samples of 42 NRL allergic adults were investigated. All had a history of NRL allergy confirmed by a positive skin test for latex and a positive latex-specific IgE. Samples were analysed for IgE antibodies against 9 plant food allergens (avocado, banana, chestnut, fig, kiwi, papaya, peanut, pineapple and tomato) and Ficus benjamina. A specific IgE quantification for 3 animal food allergens (codfish, cow's milk, egg's white) and 8 common inhalant allergens (Dermatophagoïdes pteronyssinus, birch pollen, timothy grass pollen, mugwort pollen, cat and dog epithelium, Aspergillus fumigatus and Cladosporium herbarum) was also performed. Because double blind placebo-controlled challenges could not be considered, for ethical reasons, patient's food allergy or immediate hypersensitivity for Ficus and inhalant allergens was documented by a standardised questionnaire. Diagnosis of atopy was based on a relevant history and the presence of a specific IgE antibody to at least one classical inhalant allergen. For some IgE determinations presence or absence of cross-reactivity was investigated by CAP-inhibition tests. A specific IgE antibody to at least one of the investigated inhalant and animal food allergens was found in respectively 76% and 12% of the serum samples. A plant food-specific IgE antibody was observed in 88% of the serum samples, most frequently to papaya (71%) and least frequently to kiwi (17%). Twenty-nine percent of the serum samples contained Ficus-IgE. According to the questionnaire and the threshold of 0.35 kUa/L, sensitivity of the plant food IgE antibodies varied between 0% for papaya and 73% for avocado. Specificity varied between 28% for papaya and 91% for kiwi. For Ficus-IgE sensitivity was 20% and specificity 70%. For inhalant and animal food allergens sensitivity and specificity of the IgE quantification correlated generally well with the values obtained in non-NRL allergic adults. Determination of specific IgE to the investigated plant foods and Ficus was not always a sensitive neither a specific test to establish the clinical diagnosis of this allergy.

Interpretation of positive results of a methacholine inhalation challenge and 1 week of inhaled bronchodilator use in diagnosing and treating cough-variant asthma.

PubMed

Irwin, R S; French, C T; Smyrnios, N A; Curley, F J

1997-09-22

In diagnosing cough due to asthma, methacholine chloride inhalation challenge (MIC) interpreted in a traditional fashion has been shown to have positive predictive values from 60% to 82%. To determine whether any features of positive results of an MIC or the results of a 1-week trial of inhaled beta-agonist therapy were helpful in predicting when the cough was due to asthma. The study design was a prospective, randomized, double-blind, placebo-controlled, crossover format performed in adult, nonsmoking subjects, who were referred for diagnosis and treatment of chronic cough. The subjects had no other respiratory complaints or medical conditions for which they were taking medications, the results of baseline spirometry and chest roentgenograms were normal, and the results of MIC were positive. After obtaining baseline data, including MICs on 2 separate days, objective cough counting, and self-assessment of cough severity using a visual analog scale, subjects were randomized to receive 2 inhalations (1.3 mg) of metaproterenol sulfate or placebo by metered dose inhaler attached to a spacer device every 4 hours while awake. At 1 week, data identical to baseline were collected, and subjects received the other metered dose inhaler for 7 days. At 1 week, data identical to baseline were collected. After completion of the protocol, subjects were followed up in the clinic to observe the final response of the cough to specific therapy. Based on the disappearance of the cough with specific therapy, the cough was due to asthma in 9 of 15 subjects and nonasthma in 6 of 15 subjects. Baseline data were similar between groups. With respect to MICs, there were no significant differences between groups in the cumulative dose of methacholine that provoked a 20% decrease in forced expiratory volume in 1 second from the postsaline baseline value (PD20 values), slopes of dose-response curves, and maximal-response plateaus. Cough severity significantly improved after 1 week of metaproterenol use compared with the severity of the cough at baseline (P = .03) and with placebo (P = .02) only in subjects with asthma. No matter how the results are analyzed, positive MIC results, without observing response to therapy, are only consistent with asthma as the cause of the cough. The results are only diagnostic of asthma when they are followed by a favorable response to asthma therapy. After 1 week of inhaled beta-agonist, only the cough due to cough-variant asthma is significantly better.

Reversible obstructive sleep apnea caused by occupational exposure to guar gum dust.

PubMed

Leznoff, A; Haight, J S; Hoffstein, V

1986-05-01

This report describes a case of reversible obstructive sleep apnea caused by occupational exposure to an inhaled allergen, guar gum powder. The patient, a pet food plant employee, also experienced severe cough, rhinitis, and conjunctivitis. Skin tests confirmed the specific guar allergy. Pharyngeal cross-sectional area was smaller than normal. Pulmonary function studies, histamine challenge tests, nasal air-flow resistance measurements, and nocturnal polysomnography were performed on 3 separate occasions: while the patient was working at his usual occupation, at the end of a 3-wk holiday, and after a guar dust challenge in an inhalation chamber. Pulmonary function and histamine challenge tests were consistently normal. At the time of the initial tests, nasal resistance was elevated, and nocturnal polysomnography revealed obstructive sleep apnea. After absence from work, obstructive sleep apnea resolved, and the nasal resistance returned to normal. After challenge with guar gum dust, the patient developed increased resistance to nasal air flow, and obstructive sleep apnea reappeared. This case demonstrates that allergy can cause reversible obstructive sleep apnea and that occupational exposure should be considered in the assessment of patients with this disease.

Role of tachykinins in ozone-induced airway hyperresponsiveness to cigarette smoke in guinea pigs.

PubMed

Wu, Z X; Morton, R F; Lee, L Y

1997-09-01

Acute exposure to ozone (O3) induces airway hyperresponsiveness to various inhaled bronchoactive substances. Inhalation of cigarette smoke, a common inhaled irritant in humans, is known to evoke a transient bronchoconstrictive effect. To examine whether O3 increases airway responsiveness to cigarette smoke, effects of smoke inhalation challenge on total pulmonary resistance (RL) and dynamic lung compliance (Cdyn) were compared before and after exposure to O3 (1.5 ppm, 1 h) in anesthetized guinea pigs. Before O3 exposure, inhalation of two breaths of cigarette smoke (7 ml) at a low concentration (33%) induced a mild and reproducible bronchoconstriction that slowly developed and reached its peak (DeltaRL = 67 +/- 19%, DeltaCdyn = -29 +/- 6%) after a delay of >1 min. After exposure to O3 the same cigarette smoke inhalation challenge evoked an intense bronchoconstriction that occurred more rapidly, reaching its peak (DeltaRL = 620 +/- 224%, DeltaCdyn = -35 +/- 7%) within 20 s, and was sustained for >2 min. By contrast, sham exposure to room air did not alter the bronchomotor response to cigarette smoke challenge. Pretreatment with CP-99994 and SR-48968, the selective antagonists of neurokinin type 1 and 2 receptors, respectively, completely blocked the enhanced responses of RL and Cdyn to cigarette smoke challenge induced by O3. These results show that O3 exposure induces airway hyperresponsiveness to inhaled cigarette smoke and that the enhanced responses result primarily from the bronchoconstrictive effect of endogenous tachykinins.

Occupational vocal cord dysfunction due to exposure to wood dust and xerographic toner.

PubMed

Muñoz, Xavier; Roger, Alex; De la Rosa, David; Morell, Ferran; Cruz, Maria J

2007-04-01

Vocal cord dysfunction is a poorly understood entity that is often misdiagnosed as asthma. Both irritant and non-irritant vocal cord dysfunction have been described. This report presents two cases of irritant vocal cord dysfunction secondary to specific environmental exposure, the first to iroko and western red cedar wood (a carpenter) and the second to xerographic printing toner (a secretary). Several tests were performed, including chest radiographs, measurements of total serum immunoglobulin E, skin prick tests with common pneumoallergens (as well as iroko and western red cedar in the first case), pulmonary function studies, methacholine challenge testing, specific inhalation challenge performed with suspected agents in a single-blinded fashion, and peak expiratory flow testing and fiberoptic rhinolaryngoscopy (in case 1). During the specific inhalation challenge, the patients showed dysphonia, chest tightness, inspiratory stridor, and flattening of the inspiratory limb of the maximum flow-volume loop in spirometry, with no significant decreases in the level of forced expiratory volume in 1 second; fiberoptic rhinolaryngoscopy confirmed the diagnosis of vocal cord dysfunction in case 1. It is important to know that agents that can cause occupational asthma can also cause vocal cord dysfunction. The mechanisms by which these agents produce vocal cord dysfunction are unknown. The differences in the clinical presentation of the patients described relative to the reported cases suggest that more than one pathophysiological mechanism may be implicated in the genesis of this entity.

Occupational asthma induced by tall oil in the rubber tyre industry.

PubMed

Tarlo, S M

1992-01-01

A worker in the rubber tyre industry is described with occupational asthma from exposure to a solution of tall oil, a pine resin, confirmed by specific inhalation challenge. This supports studies of contact dermatitis which have suggested abietic and dehydroabietic acid oxidants to be the cause of colophony induced allergic reactions.

Nano-TiO₂--feasibility and challenges for human health risk assessment based on open literature.

PubMed

Christensen, Frans M; Johnston, Helinor J; Stone, Vicki; Aitken, Robert J; Hankin, Steve; Peters, Sheona; Aschberger, Karin

2011-06-01

This study aims at investigating feasibility and challenges associated with conducting a human health risk assessment for nano-titanium-dioxide (nano-TiO₂) based on the open literature by following an approach similar to a classical regulatory risk assessment. Gaps in the available data set, both in relation to exposures and hazard, do not allow reaching any definite conclusions that could be used for regulatory decision-making. Results show that repeated inhalation in the workplace and possibly consumer inhalation may cause risks. Also short-term inhalation following spray applications may cause risks. Main future work should focus on generating occupational and consumer inhalation exposure data, as well as toxicity data on absorption following inhalation, repeated dermal contact, and contact with damaged skin. Also relevant seems further information on possible neurotoxicity and genotoxicity/carcinogenicity, as well as establishing a No Observed Adverse Effect Level (NOAEL) for acute inhalation of nano-TiO₂.

Toxicological perspectives of inhaled therapeutics and nanoparticles.

PubMed

Hayes, Amanda J; Bakand, Shahnaz

2014-07-01

The human respiratory system is an important route for the entry of inhaled therapeutics into the body to treat diseases. Inhaled materials may consist of gases, vapours, aerosols and particulates. In all cases, assessing the toxicological effect of inhaled therapeutics has many challenges. This article provides an overview of in vivo and in vitro models for testing the toxicity of inhaled therapeutics and nanoparticles implemented in drug delivery. Traditionally, inhalation toxicity has been performed on test animals to identify the median lethal concentration of airborne materials. Later maximum tolerable concentration denoted by LC0 has been introduced as a more ethically acceptable end point. More recently, in vitro methods have been developed, allowing the direct exposure of airborne material to cultured human target cells on permeable porous membranes at the air-liquid interface. Modifications of current inhalation therapies, new pulmonary medications for respiratory diseases and implementation of the respiratory tract for systemic drug delivery are providing new challenges when conducting well-designed inhalation toxicology studies. In particular, the area of nanoparticles and nanocarriers is of critical toxicological concern. There is a need to develop toxicological test models, which characterise the toxic response and cellular interaction between inhaled particles and the respiratory system.

Corticosteroid-induced gene expression in allergen-challenged asthmatic subjects taking inhaled budesonide

PubMed Central

Kelly, MM; King, EM; Rider, CF; Gwozd, C; Holden, NS; Eddleston, J; Zuraw, B; Leigh, R; O'Byrne, PM; Newton, R

2012-01-01

BACKGROUND AND PURPOSE Inhaled corticosteroids (ICS) are the cornerstone of asthma pharmacotherapy and, acting via the glucocorticoid receptor (GR), reduce inflammatory gene expression. While this is often attributed to a direct inhibitory effect of the GR on inflammatory gene transcription, corticosteroids also induce the expression of anti-inflammatory genes in vitro. As there are no data to support this effect in asthmatic subjects taking ICS, we have assessed whether ICS induce anti-inflammatory gene expression in subjects with atopic asthma. EXPERIMENTAL APPROACH Bronchial biopsies from allergen-challenged atopic asthmatic subjects taking inhaled budesonide or placebo were subjected to gene expression analysis using real-time reverse transcriptase-PCR for the corticosteroid-inducible genes (official gene symbols with aliases in parentheses): TSC22D3 [glucocorticoid-induced leucine zipper (GILZ)], dual-specificity phosphatase-1 (MAPK phosphatase-1), both anti-inflammatory effectors, and FKBP5 [FK506-binding protein 51 (FKBP51)], a regulator of GR function. Cultured pulmonary epithelial and smooth muscle cells were also treated with corticosteroids before gene expression analysis. KEY RESULTS Compared with placebo, GILZ and FKBP51 mRNA expression was significantly elevated in budesonide-treated subjects. Budesonide also increased GILZ expression in human epithelial and smooth muscle cells in culture. Immunostaining of bronchial biopsies revealed GILZ expression in the airways epithelium and smooth muscle of asthmatic subjects. CONCLUSIONS AND IMPLICATIONS Expression of the corticosteroid-induced genes, GILZ and FKBP51, is up-regulated in the airways of allergen-challenged asthmatic subjects taking inhaled budesonide. Consequently, the biological effects of corticosteroid-induced genes should be considered when assessing the actions of ICS. Treatment modalities that increase or decrease GR-dependent transcription may correspondingly affect corticosteroid efficacy. PMID:21827450

Immunoglobulin and antibody levels in bronchoalveolar lavage fluid from symptomatic and asymptomatic pigeon breeders.

PubMed Central

Reynolds, S P; Edwards, J H; Jones, K P; Davies, B H

1991-01-01

Twenty-one symptomatic subjects with pigeon breeders' lung (PBL) and 10 asymptomatic pigeon breeders, with a similar exposure to pigeon antigens, underwent bronchoalveolar lavage. Total IgG, IgM and IgA in lavage fluid were determined as were specific antibody levels against antigens in pigeon serum and droppings. Results were converted to levels in epithelial lining fluid (ELF) using lavage and serum urea ratios. It was found that symptomatics represent a group that is hyperreactive to pigeon antigens compared with the asymptomatic group with significantly higher IgG, IgM, IgA levels as well as specific antibody levels against pigeon serum and droppings. Paired serum and ELF samples from 12 symptomatic subjects showed significantly elevated IgG, IgM and IgA levels in ELF compared with serum when values were expressed in terms of albumin. This strongly supports the concept of local production of immunoglobulins within the lung after inhaling immunogens as opposed to their diffusion from the vasculature. Results for IgA indicate that any putative protective role for this immunoglobulin is not valid in relation to the prevention of extrinsic allergic alveolitis. Analysis of smoking habits, lung immunoglobulins and response to inhalation challenge confirm the negative influence of smoking on total and functional lung immunoglobulins; however, levels in the ELF of ex-smokers suggest that the effect of smoking is not permanent. Smoking did not prevent responses to inhalation challenge. PMID:1934595

Vagal afferents contribute to exacerbated airway responses following ozone and allergen challenge

PubMed Central

Schelegle, Edward S.; Walby, William F.

2012-01-01

Brown-Norway rats (n = 113) sensitized and challenged with nDer f 1 allergen were used to examine the contribution of lung sensory nerves to ozone (O3) exacerbation of asthma. Prior to their third challenge rats inhaled 1.0 ppm O3 for 8 hours. There were three groups: 1) control; 2) vagus perineural capsaicin treatment (PCT) with or without hexamethonium; and 3) vagotomy. O3 inhalation resulted in a significant increase in lung resistance (RL) and an exaggerated response to subsequent allergen challenge. PCT abolished the O3-induced increase in RL and significantly reduced the increase in RL induced by a subsequent allergen challenge, while hexamethonium treatment reestablished bronchoconstriction induced by allergen challenge. Vagotomy resulted in a significant increase in the bronchoconstriction induced by O3 inhalation and subsequent challenge with allergen. In this model of O3 exacerbation of asthma, vagal C-fibers initiate reflex bronchoconstriction, vagal myelinated fibers initiate reflex bronchodilation, and mediators released within the airway initiate bronchoconstriction. PMID:22525484

Disposition and safety of inhaled biodegradable nanomedicines: Opportunities and challenges.

PubMed

Haque, Shadabul; Whittaker, Michael R; McIntosh, Michelle P; Pouton, Colin W; Kaminskas, Lisa M

2016-08-01

The inhaled delivery of nanomedicines can provide a novel, non-invasive therapeutic strategy for the more localised treatment of lung-resident diseases and potentially also enable the systemic delivery of therapeutics that are otherwise administered via injection alone. However, the clinical translation of inhalable nanomedicine is being hampered by our lack of understanding about their disposition and clearance from the lungs. This review provides a comprehensive overview of the biodegradable nanomaterials that are currently being explored as inhalable drug delivery systems and our current understanding of their disposition within, and clearance from the lungs. The safety of biodegradable nanomaterials in the lungs is discussed and latest updates are provided on the impact of inflammation on the pulmonary pharmacokinetics of inhaled nanomaterials. Overall, the review provides an in-depth and critical assessment of the lung clearance mechanisms for inhaled biodegradable nanomedicines and highlights the opportunities and challenges for their translation into the clinic. Copyright © 2016 Elsevier Inc. All rights reserved.

Laboratory approach for diagnosis of toluene-based inhalant abuse in a clinical setting

PubMed Central

Jain, Raka; Verma, Arpita

2016-01-01

The steady increase of inhalant abuse is a great challenge for analytical toxicologists. This review describes an overview of inhalant abuse including the extent of the problem, types of products abused, modes of administration, pharmacology and effects of inhalants, the role of laboratory, interpretation of laboratory results and clinical considerations. Regular laboratory screening for inhalant abuse as well as other substance abuse and health risk behaviors must be a part of standard clinical care. PMID:26957863

Airway inflammation and mannitol challenge test in COPD

PubMed Central

2011-01-01

Background Eosinophilic airway inflammation has successfully been used to tailor anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). Airway hyperresponsiveness (AHR) by indirect challenges is associated with airway inflammation. We hypothesized that AHR to inhaled mannitol captures eosinophilia in induced sputum in COPD. Methods Twenty-eight patients (age 58 ± 7.8 yr, packyears 40 ± 15.5, post-bronchodilator FEV1 77 ± 14.0%predicted, no inhaled steroids ≥4 wks) with mild-moderate COPD (GOLD I-II) completed two randomized visits with hypertonic saline-induced sputum and mannitol challenge (including sputum collection). AHR to mannitol was expressed as response-dose-ratio (RDR) and related to cell counts, ECP, MPO and IL-8 levels in sputum. Results There was a positive correlation between RDR to mannitol and eosinophil numbers (r = 0.47, p = 0.03) and level of IL-8 (r = 0.46, p = 0.04) in hypertonic saline-induced sputum. Furthermore, significant correlations were found between RDR and eosinophil numbers (r = 0.71, p = 0.001), level of ECP (r = 0.72, p = 0.001), IL-8 (r = 0.57, p = 0.015) and MPO (r = 0.64, p = 0.007) in sputum collected after mannitol challenge. ROC-curves showed 60% sensitivity and 100% specificity of RDR for >2.5% eosinophils in mannitol-induced sputum. Conclusions In mild-moderate COPD mannitol hyperresponsiveness is associated with biomarkers of airway inflammation. The high specificity of mannitol challenge suggests that the test is particularly suitable to exclude eosinophilic airways inflammation, which may facilitate individualized treatment in COPD. Trial registration Netherlands Trial Register (NTR): NTR1283 PMID:21241520

Position paper of the EAACI: food allergy due to immunological cross-reactions with common inhalant allergens.

PubMed

Werfel, T; Asero, R; Ballmer-Weber, B K; Beyer, K; Enrique, E; Knulst, A C; Mari, A; Muraro, A; Ollert, M; Poulsen, L K; Vieths, S; Worm, M; Hoffmann-Sommergruber, K

2015-09-01

In older children, adolescents, and adults, a substantial part of all IgE-mediated food allergies is caused by cross-reacting allergenic structures shared by inhalants and foods. IgE stimulated by a cross-reactive inhalant allergen can result in diverse patterns of allergic reactions to various foods. Local, mild, or severe systemic reactions may occur already after the first consumption of a food containing a cross-reactive allergen. In clinical practice, clinically relevant sensitizations are elucidated by skin prick testing or by the determination of specific IgE in vitro. Component-resolved diagnosis may help to reach a diagnosis and may predict the risk of a systemic reaction. Allergy needs to be confirmed in cases of unclear history by oral challenge tests. The therapeutic potential of allergen immunotherapy with inhalant allergens in pollen-related food allergy is not clear, and more placebo-controlled studies are needed. As we are facing an increasing incidence of pollen allergies, a shift in sensitization patterns and changes in nutritional habits, and the occurrence of new, so far unknown allergies due to cross-reactions are expected. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Enhancement of systemic and sputum granulocyte response to inhaled endotoxin in people with the GSTM1 null genotype

EPA Science Inventory

To determine if the GSTM1 null genotype is a risk factor for increased inflammatory response to inhaled endotoxin. Methods 35 volunteers who had undergone inhalation challenge with a 20 000 endotoxin unit dose of Clinical Center Reference Endotoxin (CCRE) were genotyped for the G...

Vagal afferents contribute to exacerbated airway responses following ozone and allergen challenge.

PubMed

Schelegle, Edward S; Walby, William F

2012-05-31

Brown-Norway rats (n=113) sensitized and challenged with nDer f 1 allergen were used to examine the contribution of lung sensory nerves to ozone (O(3)) exacerbation of asthma. Prior to their third challenge rats inhaled 1.0ppm O(3) for 8h. There were three groups: (1) control; (2) vagus perineural capsaicin treatment (PCT) with or without hexamethonium; and (3) vagotomy. O(3) inhalation resulted in a significant increase in lung resistance (R(L)) and an exaggerated response to subsequent allergen challenge. PCT abolished the O(3)-induced increase in R(L) and significantly reduced the increase in R(L) induced by a subsequent allergen challenge, while hexamethonium treatment reestablished bronchoconstriction induced by allergen challenge. Vagotomy resulted in a significant increase in the bronchoconstriction induced by O(3) inhalation and subsequent challenge with allergen. In this model of O(3) exacerbation of asthma, vagal C-fibers initiate reflex bronchoconstriction, vagal myelinated fibers initiate reflex bronchodilation, and mediators released within the airway initiate bronchoconstriction. Copyright © 2012 Elsevier B.V. All rights reserved.

Exposure to Inhalable, Respirable, and Ultrafine Particles in Welding Fume

PubMed Central

Pesch, Beate

2012-01-01

This investigation aims to explore determinants of exposure to particle size-specific welding fume. Area sampling of ultrafine particles (UFP) was performed at 33 worksites in parallel with the collection of respirable particles. Personal sampling of respirable and inhalable particles was carried out in the breathing zone of 241 welders. Median mass concentrations were 2.48 mg m−3 for inhalable and 1.29 mg m−3 for respirable particles when excluding 26 users of powered air-purifying respirators (PAPRs). Mass concentrations were highest when flux-cored arc welding (FCAW) with gas was applied (median of inhalable particles: 11.6 mg m−3). Measurements of particles were frequently below the limit of detection (LOD), especially inside PAPRs or during tungsten inert gas welding (TIG). However, TIG generated a high number of small particles, including UFP. We imputed measurements

Exposure to inhalable, respirable, and ultrafine particles in welding fume.

PubMed

Lehnert, Martin; Pesch, Beate; Lotz, Anne; Pelzer, Johannes; Kendzia, Benjamin; Gawrych, Katarzyna; Heinze, Evelyn; Van Gelder, Rainer; Punkenburg, Ewald; Weiss, Tobias; Mattenklott, Markus; Hahn, Jens-Uwe; Möhlmann, Carsten; Berges, Markus; Hartwig, Andrea; Brüning, Thomas

2012-07-01

This investigation aims to explore determinants of exposure to particle size-specific welding fume. Area sampling of ultrafine particles (UFP) was performed at 33 worksites in parallel with the collection of respirable particles. Personal sampling of respirable and inhalable particles was carried out in the breathing zone of 241 welders. Median mass concentrations were 2.48 mg m(-3) for inhalable and 1.29 mg m(-3) for respirable particles when excluding 26 users of powered air-purifying respirators (PAPRs). Mass concentrations were highest when flux-cored arc welding (FCAW) with gas was applied (median of inhalable particles: 11.6 mg m(-3)). Measurements of particles were frequently below the limit of detection (LOD), especially inside PAPRs or during tungsten inert gas welding (TIG). However, TIG generated a high number of small particles, including UFP. We imputed measurements

Determination of albumin adducts of 4,4'-methylenediphenyl diisocyanate after specific inhalative challenge tests in workers.

PubMed

Sabbioni, Gabriele; Dongari, Nagaraju; Kumar, Anoop; Baur, Xaver

2016-10-17

4,4'-Methylenediphenyl diisocyanate (MDI) is the most important isocyanate used in the industry. Lung sensitization with bronchial asthma is the main disorder in exposed workers. Albumin adducts of MDI might be involved in specific immunological reactions. MDI adducts with lysine (MDI-Lys) of albumin have been found in MDI-workers and construction workers. MDI-Lys is an isocyanate-specific adduct of MDI with albumin. In the present study, we report MDI-adducts in workers undergoing diagnostic MDI challenge tests. The workers were exposed for 2h to 5ppb of MDI. The adduct levels increase significantly after the exposure to MDI in the challenge chamber. About 0.6% of the dose was bound to albumin. So far, only urinary metabolites of MDI were measured to monitor isocyanate workers. However, such urinary metabolites are not isocyanate specific. Therefore, we propose to measure albumin adducts for monitoring MDI exposed subjects. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Epitope-focused peptide immunogens in human use adjuvants protect rabbits from experimental inhalation anthrax.

PubMed

Oscherwitz, Jon; Feldman, Daniel; Yu, Fen; Cease, Kemp B

2015-01-09

Anthrax represents a formidable bioterrorism threat for which new, optimized vaccines are required. We previously demonstrated that epitope-focused multiple antigenic peptides or a recombinant protein in Freund's adjuvant can elicit Ab against the loop neutralizing determinant (LND), a cryptic linear neutralizing epitope in the 2ß2-2ß3 loop of protective antigen from Bacillus anthracis, which mediated protection of rabbits from inhalation challenge with B. anthracis Ames strain. However, demonstration of efficacy using human-use adjuvants is required before proceeding with further development of an LND vaccine for testing in non-human primates and humans. To optimize the LND immunogen, we first evaluated the protective efficacy and immune correlates associated with immunization of rabbits with mixtures containing two molecular variants of multiple antigenic peptides in Freunds adjuvant, termed BT-LND(2) and TB-LND(2). TB-LND(2) was then further evaluated for protective efficacy in rabbits employing human-use adjuvants. Immunization of rabbits with TB-LND(2) in human-use adjuvants elicited protection from Ames strain spore challenge which was statistically indistinguishable from that elicited through immunization with protective antigen. All TB-LND(2) rabbits with any detectable serum neutralization prior to challenge were protected from aerosolized spore exposure. Remarkably, rabbits immunized with TB-LND(2) in Alhydrogel/CpG had significant anamnestic increases in post-challenge LND-specific Ab and neutralization titers despite little evidence of spore germination in these rabbits. An LND-specific epitope-focused vaccine may complement PA-based vaccines and may represent a complementary stand-alone vaccine for anthrax. Copyright © 2014 Elsevier Ltd. All rights reserved.

In Silico Models of Aerosol Delivery to the Respiratory Tract – Development and Applications

PubMed Central

Longest, P. Worth; Holbrook, Landon T.

2011-01-01

This review discusses the application of computational models to simulate the transport and deposition of inhaled pharmaceutical aerosols from the site of particle or droplet formation to deposition within the respiratory tract. Traditional one-dimensional (1-D) whole-lung models are discussed briefly followed by a more in-depth review of three-dimensional (3-D) computational fluid dynamics (CFD) simulations. The review of CFD models is organized into sections covering transport and deposition within the inhaler device, the extrathoracic (oral and nasal) region, conducting airways, and alveolar space. For each section, a general review of significant contributions and advancements in the area of simulating pharmaceutical aerosols is provided followed by a more in-depth application or case study that highlights the challenges, utility, and benefits of in silico models. Specific applications presented include the optimization of an existing spray inhaler, development of charge-targeted delivery, specification of conditions for optimal nasal delivery, analysis of a new condensational delivery approach, and an evaluation of targeted delivery using magnetic aerosols. The review concludes with recommendations on the need for more refined model validations, use of a concurrent experimental and CFD approach for developing aerosol delivery systems, and development of a stochastic individual path (SIP) model of aerosol transport and deposition throughout the respiratory tract. PMID:21640772

Cough reflex testing with inhaled capsaicin and TRPV1 activation in asthma and comorbid conditions.

PubMed

Couto, M; de Diego, A; Perpiñi, M; Delgado, L; Moreira, A

2013-01-01

A high parasympathetic tone leading to bronchoconstriction and neurogenic inflammation is thought to have a major role in the pathogenesis of asthma. Transient receptor potential vanilloid 1 (TRPV1) is the hub of almost all neuronal inflammatory signaling pathways. A critical determinant of neurogenic inflammation, TRPV1 functions as a sensor for detecting irritants in the lung by transmitting noxious stimuli to the central nervous system and inducing the release of a variety of proinflammatory neuropeptides at the peripheral terminals. Challenge with inhaled capsaicin, an exogenous agonist of TRPV1, has been used to measure the sensitivity of the cough reflex. However, inhalation of capsaicin is also associated with parasympathetic bronchoconstriction, mucus hypersecretion, vasodilatation, and the sensation of dyspnea. Therefore, inhaled capsaicin challenge is expected to have other potential applications in asthma and comorbid conditions, such as rhinitis and gastroesophageal reflux disease, both of which produce cough. Capsaicin challenge has established itself as a useful objective method for evaluating airway hypersensitivity; however, it is potentially valuable in many other situations, which will be reviewed in this paper.

The Rationale and Evidence for Use of Inhaled Antibiotics to Control Pseudomonas aeruginosa Infection in Non-cystic Fibrosis Bronchiectasis

PubMed Central

2018-01-01

Abstract Non-cystic fibrosis bronchiectasis (NCFBE) is a chronic inflammatory lung disease characterized by irreversible dilation of the bronchi, symptoms of persistent cough and expectoration, and recurrent infective exacerbations. The prevalence of NCFBE is on the increase in the United States and Europe, but no licensed therapies are currently available for its treatment. Although there are many similarities between NCFBE and cystic fibrosis (CF) in terms of respiratory symptoms, airway microbiology, and disease progression, there are key differences, for example, in response to treatment, suggesting differences in pathogenesis. This review discusses possible reasons underlying differences in response to inhaled antibiotics in people with CF and NCFBE. Pseudomonas aeruginosa infections are associated with the most severe forms of bronchiectasis. Suboptimal levels of antibiotics in the lung increase the mutation frequency of P. aeruginosa and lead to the development of mucoid strains characterized by formation of a protective polysaccharide biofilm. Mucoid strains of P. aeruginosa are associated with a chronic infection stage, requiring long-term antibiotic therapy. Inhaled antibiotics provide targeted delivery to the lung with minimal systemic toxicity and adverse events compared with oral/intravenous routes of administration, and they could be alternative treatment options to help address some of the treatment challenges in the management of severe cases of NCFBE. This review provides an overview of completed and ongoing trials that evaluated inhaled antibiotic therapy for NCFBE. Recently, several investigators conducted phase 3 randomized controlled trials with inhaled aztreonam and ciprofloxacin in patients with NCFBE. While the aztreonam trial results were not associated with significant clinical benefit in NCFBE, initial results reported from the inhaled ciprofloxacin (dry powder for inhalation and liposome-encapsulated/dual-release formulations) trials hold promise. A more targeted approach could identify specific populations of NCFBE patients who benefit from inhaled antibiotics. PMID:29077527

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs.

PubMed

Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kloft, Charlotte

2015-07-01

During the last decades, the importance of modeling and simulation in clinical drug development, with the goal to qualitatively and quantitatively assess and understand mechanisms of pharmacokinetic processes, has strongly increased. However, this increase could not equally be observed for orally inhaled drugs. The objectives of this review are to understand the reasons for this gap and to demonstrate the opportunities that mathematical modeling of pharmacokinetics of orally inhaled drugs offers. To achieve these objectives, this review (i) discusses pulmonary physiological processes and their impact on the pharmacokinetics after drug inhalation, (ii) provides a comprehensive overview of published pharmacokinetic models, (iii) categorizes these models into physiologically based pharmacokinetic (PBPK) and (clinical data-derived) empirical models, (iv) explores both their (mechanistic) plausibility, and (v) addresses critical aspects of different pharmacometric approaches pertinent for drug inhalation. In summary, pulmonary deposition, dissolution, and absorption are highly complex processes and may represent the major challenge for modeling and simulation of PK after oral drug inhalation. Challenges in relating systemic pharmacokinetics with pulmonary efficacy may be another factor contributing to the limited number of existing pharmacokinetic models for orally inhaled drugs. Investigations comprising in vitro experiments, clinical studies, and more sophisticated mathematical approaches are considered to be necessary for elucidating these highly complex pulmonary processes. With this additional knowledge, the PBPK approach might gain additional attractiveness. Currently, (semi-)mechanistic modeling offers an alternative to generate and investigate hypotheses and to more mechanistically understand the pulmonary and systemic pharmacokinetics after oral drug inhalation including the impact of pulmonary diseases.

Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen-induced airway responses in neonatally immunised rabbits.

PubMed Central

Gozzard, N.; el-Hashim, A.; Herd, C. M.; Blake, S. M.; Holbrook, M.; Hughes, B.; Higgs, G. A.; Page, C. P.

1996-01-01

1. The effects of the inhaled corticosteroid budesonide and a novel PDE 4 inhibitor CDP840 given systematically, were evaluated in a model of antigen-induced airway inflammation in the rabbit. 2. Adult litter-matched NZW rabbits (2.4-3.5 kg) immunised within 24 h of birth with Alternaria tenuis antigen were pretreated with budesonide (total dose 100 micrograms, inhaled over 2 days) or CDP840 (total dose 7 mg kg-1, i.p. over 3 days), before antigen challenge. For each drug-treated group a parallel group of rabbits was pretreated with the appropriate vehicle. In all groups airway responsiveness to inhaled histamine was assessed and bronchoalveolar lavage (BAL) performed 24 h before and after antigen challenge. 3. Basal lung function in terms of total lung resistance (RL; cmH2O l 1s-1) and dynamic compliance (Cdyn; ml cmH2O-1) were unaltered by pretreatment with budesonide or CDP840 compared to their respective vehicles 24 h before or after antigen challenge. 4. The RL component of the acute bronchoconstriction induced by inhaled Alternaria tenuis aerosol was unaffected by pretreatment with budesonide. However, budesonide prevented the fall in Cdyn due to antigen. Treatment with CDP840 significantly reduced antigen-induced acute bronchoconstriction in terms of both RL and Cdyn. 5. Airway hyperresponsiveness (AHR) to inhaled histamine was indicated by reduced RL PC50 (2.4-4.5 fold) and Cdyn PC35 (2.1-3.9 fold) values 24 h after antigen challenge. Treatment with either budesonide or CDP840 abolished the antigen-induced increase in responsiveness to inhaled histamine. 6. Total cells recovered per ml of BAL fluid increased 24 h after antigen challenge. Antigen-induced pulmonary eosinophilia was reduced (93%) in budesonide and (85%) in CDP840 treated rabbits. Antigen-induced increases in neutrophil numbers were reduced (76%) with budesonide but not CDP840 pretreatment. 7. Inhalation of Alternaria tenuis aerosol elicited an acute bronchoconstriction, followed 24 hours later by an increased responsiveness to inhaled histamine and pulmonary neutrophil and eosinophil recruitment. CDP840 was more effective than budesonide in preventing the antigen-induced increase in total lung resistance (RL); however, both drugs prevented the antigen-induced reduction in dynamic compliance (Cdyn). CDP840 and budesonide also prevented antigen-induced AHR and eosinophilia in the immunised rabbit. PMID:8818344

Inhalant allergies in children.

PubMed

Mims, James W; Veling, Maria C

2011-06-01

Children with chronic or recurrent upper respiratory inflammatory disease (rhinitis) should be considered for inhalant allergies. Risk factors for inhalant allergies in children include a first-degree relative with allergies, food allergy in infancy, and atopic dermatitis. Although inhalant allergies are rare in infancy, inhalant allergies are common in older children and impair quality of life and productivity. Differentiating between viral and allergic rhinitis can be challenging in children, but the child's age, history, and risk factors can provide helpful information. Allergic rhinitis is a risk factor for asthma, and if one is present, medical consideration of the other is warranted. Copyright © 2011 Elsevier Inc. All rights reserved.

Changes in the highest frequency of breath sounds without wheezing during methacholine inhalation challenge in children.

PubMed

Habukawa, Chizu; Murakami, Katsumi; Mochizuki, Hiroyuki; Takami, Satoru; Muramatsu, Reiko; Tadaki, Hiromi; Hagiwara, Satomi; Mizuno, Takahisa; Arakawa, Hirokazu; Nagasaka, Yukio

2010-04-01

It is difficult for clinicians to identify changes in breath sounds caused by bronchoconstriction when wheezing is not audible. A breath sound analyser can identify changes in the frequency of breath sounds caused by bronchoconstriction. The present study aimed to identify the changes in the frequency of breath sounds during bronchoconstriction and bronchodilatation using a breath sound analyser. Thirty-six children (8.2 +/- 3.7 years; males : females, 22 : 14) underwent spirometry, methacholine inhalation challenge and breath sound analysis. Methacholine inhalation challenge was performed and baseline respiratory resistance, minimum dose of methacholine (bronchial sensitivity) and speed of bronchoconstriction in response to methacholine (Sm: bronchial reactivity) were calculated. The highest frequency of inspiratory breath sounds (HFI), the highest frequency of expiratory breath sounds (HFE) and the percentage change in HFI and HFE were determined. The HFI and HFE were compared before methacholine inhalation (pre-HFI and pre-HFE), when respiratory resistance reached double the baseline value (max HFI and max HFE), and after bronchodilator inhalation (post-HFI and post-HFE). Breath sounds increased during methacholine-induced bronchoconstriction. Max HFI was significantly greater than pre-HFI (P < 0.001), and decreased to the basal level after bronchodilator inhalation. Post-HFI was significantly lower than max HFI (P < 0.001). HFI and HFE were also significantly changed (P < 0.001). The percentage change in HFI showed a significant correlation with the speed of bronchoconstriction in response to methacholine (P = 0.007). Methacholine-induced bronchoconstriction significantly increased HFI, and the increase in HFI was correlated with bronchial reactivity.

Effect of inhaled furosemide and torasemide on bronchial response to ultrasonically nebulized distilled water in asthmatic subjects.

PubMed

Foresi, A; Pelucchi, A; Mastropasqua, B; Cavigioli, G; Carlesi, R M; Marazzini, L

1992-08-01

Inhaled furosemide has been shown to reduce the bronchoconstriction induced by several indirect stimuli, including ultrasonically nebulized distilled water (UNDW). Because the protective effect could be due to the inhibition of the Na(+)-2Cl(-)-K+ cotransport system of bronchial epithelium, we have compared the protective effect of inhaled furosemide with that of inhaled torasemide, a new and more potent loop diuretic, on UNDW-induced bronchoconstriction in a group of 12 asthmatic subjects. UNDW challenge was performed by constructing a stimulus-response curve with five increasing volume outputs of distilled water (from 0.5 to 5.2 ml/min) and the bronchial response expressed as the provocative output causing a 20% fall in FEV1 (PO20UNDW). On different days, each subject inhaled an equal dose (28 mg) of furosemide and torasemide in a randomized, double-blind, placebo-controlled study 5 min prior to an UNDW challenge. Furosemide and torasemide had no significant effect on resting lung function. The geometric mean value of PO20UNDW measured after placebo was 1.73 ml/min. This was significantly lower than that recorded after furosemide (4.25 ml/min; p < 0.025), but not after torasemide (3.05 ml/min; p = 0.07). Inhaled furosemide totally blocked bronchial response to UNDW in five subjects. In two of five subjects the response was also blocked by inhaled torasemide. A remarkable increase in diuresis was noted only after torasemide in most subjects. We conclude that inhaled furosemide has a better protective effect than does inhaled torasemide against UNDW-induced bronchoconstriction. However, the protective effect of furosemide is variable, with some asthmatic patients showing no change in bronchial response to UNDW.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhaled antibiotics in the treatment of non-cystic fibrosis bronchiectasis: clinical and drug delivery perspectives.

PubMed

Sugianto, Tiffanie Daisy; Chan, Hak-Kim

2016-01-01

Non-cystic fibrosis bronchiectasis (NCFB) is a chronic, progressive, suppurative lung disease characterized by permanent dilatation of bronchial subdivisions, which further causes accumulation of sputum and bacterial infections. The advent of inhaled antibiotics over the past two decades has been expected to effectively attenuate the problem of chronic bacterial infections in CF and NCFB subjects with higher, local drug concentrations and minimal systemic side effects. This review summarizes and evaluates current clinical evidence of efficacy and adverse effects of inhaled antibiotics in NCFB, as well as ongoing preclinical and clinical studies, followed by a discussion of issues and challenges in clinical practice and drug delivery strategies, together with future research directions. The evidence base of the clinical efficacy of inhaled antibiotics in NCFB is limited and the degrees of reported clinical benefits have been modest and conflicting. Challenges surrounding inhaled antibiotics application and development include the lack of knowledge of disease factors and optimum management strategies, unreceptive lung pathophysiology and the lack of factors that support compliance and tolerability. Nonetheless, research continues to give birth to new clinical findings and novel formulations such as combination antibiotics and sustained-release formulations, which add great value to the development of efficacious, safe and convenient inhalable antibiotics of the future.

Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol

PubMed Central

Woods, Conor P; Argese, Nicola; Chapman, Matthew; Boot, Christopher; Webster, Rachel; Dabhi, Vijay; Grossman, Ashley B; Toogood, Andrew A; Arlt, Wiebke; Stewart, Paul M; Crowley, Rachel K; Tomlinson, Jeremy W

2015-01-01

Context Up to 3% of US and UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo–pituitary–adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy. The 250 μg short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost. Methods We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting. Results In total, 2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008 and 2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion. Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348 nmol/l provided 100% specificity for passing the SST; a cortisol value <34 nmol/l had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary. Conclusion Adrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function. PMID:26294794

Evaluation of Inhaled Versus Deposited Dose Using the Exponential Dose-Response Model for Inhalational Anthrax in Nonhuman Primate, Rabbit, and Guinea Pig.

PubMed

Gutting, Bradford W; Rukhin, Andrey; Mackie, Ryan S; Marchette, David; Thran, Brandolyn

2015-05-01

The application of the exponential model is extended by the inclusion of new nonhuman primate (NHP), rabbit, and guinea pig dose-lethality data for inhalation anthrax. Because deposition is a critical step in the initiation of inhalation anthrax, inhaled doses may not provide the most accurate cross-species comparison. For this reason, species-specific deposition factors were derived to translate inhaled dose to deposited dose. Four NHP, three rabbit, and two guinea pig data sets were utilized. Results from species-specific pooling analysis suggested all four NHP data sets could be pooled into a single NHP data set, which was also true for the rabbit and guinea pig data sets. The three species-specific pooled data sets could not be combined into a single generic mammalian data set. For inhaled dose, NHPs were the most sensitive (relative lowest LD50) species and rabbits the least. Improved inhaled LD50 s proposed for use in risk assessment are 50,600, 102,600, and 70,800 inhaled spores for NHP, rabbit, and guinea pig, respectively. Lung deposition factors were estimated for each species using published deposition data from Bacillus spore exposures, particle deposition studies, and computer modeling. Deposition was estimated at 22%, 9%, and 30% of the inhaled dose for NHP, rabbit, and guinea pig, respectively. When the inhaled dose was adjusted to reflect deposited dose, the rabbit animal model appears the most sensitive with the guinea pig the least sensitive species. © 2014 Society for Risk Analysis.

Phenotype-Driven Therapeutics in Severe Asthma.

PubMed

Opina, Maria Theresa D; Moore, Wendy C

2017-02-01

Inhaled corticosteroids are the mainstay of asthma treatment using a step-up approach with incremental dosing and additional controller medications in order to achieve symptom control and prevent exacerbations. While most patients respond well to this treatment approach, some patients remain refractory despite high doses of inhaled corticosteroids and a long-acting β-agonist. The problem lies in the heterogeneity of severe asthma, which is further supported by the emergence of severe asthma phenotypes. This heterogeneity contributes to the variability in treatment response. Randomized controlled trials involving add-on therapies in poorly controlled asthma have challenged the idea of a "one size fits all" approach targeting specific phenotypes in their subject selection. This review discusses severe asthma phenotypes from unbiased clustering approaches and the most recent scientific evidence on novel treatments to provide a guide in personalizing severe asthma treatment.

Cough and expiration reflexes elicited by inhaled irritant gases are intensified in ovalbumin-sensitized mice.

PubMed

Zhang, Cheng; Lin, Ruei-Lung; Hong, Jeff; Khosravi, Mehdi; Lee, Lu-Yuan

2017-05-01

This study was designed to determine the effect of active sensitization with ovalbumin (Ova) on cough responses to inhaled irritant gases in mice. Conscious mice moved freely in a recording chamber, while the pressure change in the chamber and audio and video signals of the mouse movements were recorded simultaneously to measure the frequencies of cough reflex (CR) and expiration reflex (ER). To further verify the accuracy of cough analysis, the intrapleural pressure was also recorded by a telemetry sensor surgically implanted in the intrapleural space in a subgroup of mice. During the irritant gas inhalation challenge, sulfur dioxide (SO 2 ; 200 and 400 ppm) or ammonia (NH 3 ; 0.1% and 0.2%) was drawn into the chamber at a constant flow rate for 8 min. Ova sensitization and sham sensitization with vehicle (Veh) were performed over a 25-day period in separate groups of mice. Our results showed that 1 ) both SO 2 and NH 3 inhalation challenges increased CR and ER frequencies in a concentration-dependent manner before Ova sensitization; 2 ) the baseline CR frequency was significantly elevated after Ova sensitization, accompanied by pronounced airway inflammation; and 3 ) Ova sensitization also markedly augmented the responses of CR and ER to both SO 2 and NH 3 inhalation challenges; in sharp contrast, the cough responses did not change after sham sensitization in the Veh group. In conclusion, Ova sensitization caused distinct and lingering increases in baseline cough frequency, and also intensified both CR and ER responses to inhaled irritant gases, which probably resulted from an allergic inflammation-induced hypersensitivity of airway sensory nerves. Copyright © 2017 the American Physiological Society.

Prediction of challenge test results by flour-specific IgE and skin prick test in symptomatic bakers.

PubMed

van Kampen, V; Rabstein, S; Sander, I; Merget, R; Brüning, T; Broding, H C; Keller, C; Müsken, H; Overlack, A; Schultze-Werninghaus, G; Walusiak, J; Raulf-Heimsoth, M

2008-07-01

Wheat and rye flours are among the most important allergens causing occupational asthma. Usually, the diagnosis of baker's asthma is based on inhalation challenge tests with flours. To evaluate the relevance of flour-specific serum immunoglobulin E (IgE) and skin prick test (SPT) in the diagnosis of baker's asthma and to define flour-specific IgE concentrations and wheal sizes that allow a prediction of the outcome of challenge testing. Bronchial and nasal challenge tests with wheat (rye) flour were performed in 71 (95) symptomatic bakers. Determinations of flour-specific IgE as well as SPTs were performed in all subjects. Analyses included the calculation of sensitivity, specificity, positive (PPV) and negative predictive values (NPV) at different IgE concentrations and different wheal sizes, and receiver-operating characteristics (ROC) plots with the challenge result as gold standard. Thirty-seven bakers were positive in the challenge with wheat flour, while 63 were positive with rye flour. Depending on the flour-specific IgE concentrations (wheal size), PPV was 74-100% (74-100%) for wheat and 82-100% (91-100%) for rye flour, respectively. The minimal cut-off values with a PPV of 100% were 2.32 kU/l (5.0 mm) for wheat flour and 9.64 kU/l (4.5 mm) for rye flour. The shapes of the ROC plots were similar for wheat and rye flour. High concentrations of flour-specific IgE and clear SPT results in symptomatic bakers are good predictors for a positive challenge test. Challenge tests with flours may be avoided in strongly sensitized bakers.

Analysis of the interrelationship of the pulmonary irritation and elicitation thresholds in rats sensitized with 1,6-hexamethylene diisocyanate (HDI)

PubMed Central

Pauluhn, Jürgen

2015-01-01

Abstract This paper summarizes a range of experimental data central for developing a science-based approach for hazard identification of monomeric and polymeric aliphatic 1,6-hexamethylene diisocyanate (HDI). The dose–response curve of HDI-induced pulmonary responses in naïve or dermally sensitized rats after one or several inhalation priming exposures was examined in the Brown Norway (BN) rat asthma model. Emphasis was directed to demonstrate the need and the difficulty in selecting an appropriate pulmonary dose when much of the inhaled chemically reactive vapor may concentration dependently be retained in the upper airways of obligate nose-breathing rats. The course taken acknowledges the experimental challenges in identifying an elicitation threshold for HDI-monomer near or above the saturated vapor concentration or in the presence of a HDI-polymer aerosol. The inhalation threshold dose on elicitation was determined based on a fixed concentration (C) × variable exposure duration (t) protocol for improving inhalation dosimetry of the lower airways. Neutrophilic granulocytes (PMN) in bronchoalveolar lavage (BAL) fluid in equally inhalation primed naïve and dermally sensitized rats were used to define the inhalation elicitation threshold C × t. Sensitized rats elaborated markedly increased PMN challenged sensitized rats relative to equally challenged naïve rats at 5625 mg HDI/m3 × min (75 mg/m3 for 75 min). PMN were essentially indistinguishable at 900 mg HDI/m3 × min. By applying adjustment factors accounting for both inter-species differences in inhalation dosimetry and intra-species susceptibility, the workplace human-equivalent threshold C × t was estimated to be in the range of the current ACGIH TLV® of HDI. Thus, this rat “asthma” model was suitable to demonstrate elicitation thresholds for HDI-vapor after one or several inhalation priming exposures and seems to be suitable to derive occupational exposure values (OELs) for diisocyanates in general. PMID:25924102

Customizing inhaled therapy to meet the needs of COPD patients.

PubMed

Fromer, Leonard; Goodwin, Elizabeth; Walsh, John

2010-03-01

Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by airflow limitation resulting from emphysema and chronic bronchitis. Inhaled therapy is the major therapeutic approach for treating COPD. Multiple inhaler medications are available in the United States and are delivered by a variety of different devices: metered-dose inhalers, dry powdered inhalers, and nebulizers. Each inhaler device has unique requirements for use that must be correctly performed by the patient for successful drug delivery. Patients with COPD represent a medically diverse population, with each patient having distinct characteristics, such as lung function, comorbidities, cognitive functions, hand strength, and lifestyle. These characteristics impact the patient's ability to properly use specific inhaler devices and therefore affect adherence to therapy, therapeutic outcomes, and quality of life. It is estimated that between 28% to 68% of patients do not use metered-dose inhalers or dry powder inhalers correctly. Worsening symptoms or increased frequency of exacerbations may not always indicate disease progression but may indicate a patient's inability to use their inhaler device properly. This review discusses the patient- and device-specific factors to be considered when choosing an inhaled therapy, which will be concordant with the patient's medical needs, preferences, and lifestyle. The review also considers how the ideas underlying the patient-centered medical home model can be incorporated into the choice and use of inhaler device for a given patient with COPD to improve treatment outcomes.

The airway antigen sampling system: respiratory M cells as an alternative gateway for inhaled antigens.

PubMed

Kim, Dong-Young; Sato, Ayuko; Fukuyama, Satoshi; Sagara, Hiroshi; Nagatake, Takahiro; Kong, Il Gyu; Goda, Kaoru; Nochi, Tomonori; Kunisawa, Jun; Sato, Shintaro; Yokota, Yoshifumi; Lee, Chul Hee; Kiyono, Hiroshi

2011-04-01

In this study, we demonstrated a new airway Ag sampling site by analyzing tissue sections of the murine nasal passages. We revealed the presence of respiratory M cells, which had the ability to take up OVA and recombinant Salmonella typhimurium expressing GFP, in the turbinates covered with single-layer epithelium. These M cells were also capable of taking up respiratory pathogen group A Streptococcus after nasal challenge. Inhibitor of DNA binding/differentiation 2 (Id2)-deficient mice, which are deficient in lymphoid tissues, including nasopharynx-associated lymphoid tissue, had a similar frequency of M cell clusters in their nasal epithelia to that of their littermates, Id2(+/-) mice. The titers of Ag-specific Abs were as high in Id2(-/-) mice as in Id2(+/-) mice after nasal immunization with recombinant Salmonella-ToxC or group A Streptococcus, indicating that respiratory M cells were capable of sampling inhaled bacterial Ag to initiate an Ag-specific immune response. Taken together, these findings suggest that respiratory M cells act as a nasopharynx-associated lymphoid tissue-independent alternative gateway for Ag sampling and subsequent induction of Ag-specific immune responses in the upper respiratory tract.

Repeated allergen exposure enhances excitatory nonadrenergic noncholinergic nerve-mediated bronchoconstriction in sensitized guinea-pigs.

PubMed

Kageyama, N; Ichinose, M; Igarashi, A; Miura, M; Yamauchi, H; Sasaki, Y; Ishikawa, J; Tomaki, M; Shirato, K

1996-07-01

The effect of repeated allergen inhalation challenge on the airway excitatory nonadrenergic noncholinergic (e-NANC) nerve-mediated bronchoconstrictor response was studied in ovalbumin (OA) sensitized guinea-pigs. Three weeks after sensitization, OA inhalation, 0.03% for 3 min (challenged group), or saline inhalation (control group) was repeated every day for 4 weeks. The e-NANC nerve function was examined in vitro by means of isometric tension measurement of main bronchi. After pretreatment with atropine (10(-6) M) and propranolol (10(-6) M), we performed electrical field stimulation (EFS) or exogenous neurokinin A (NKA) administration. In the challenged group, EFS-induced main bronchial contraction was significantly greater than that of the control group (p < 0.05 or p < 0.01), but exogenous NKA-mediated responses were almost the same in both groups. The e-NANC-induced main bronchial contractions after EFS were enhanced by pretreatment with the neutral endopeptidase inhibitor, phosphoramidon, to the same degree in the control and challenged groups, indicating that the peptide degradation mechanisms were not impaired even in the challenged group. Substance P immunoreactivities in the lung of the challenged group were significantly higher than those of the control group. These results suggest that chronic airway inflammation after repeated allergen challenge increases excitatory nonadrenergic noncholinergic nerve function, possibly by enhancing sensory neuropeptide production and/or release.

STATUS REPORT: EVIDENCE BASED ADVANCES IN INHALATION DOSIMETRY FOR GASES WITH EFFECTS IN THE LOWER RESPIRATORY TRACT AND IN THE BODY

EPA Science Inventory

This report summarizes the status of specific inhalation dosimetry procedures for gases as outlined in U.S. EPA’s 1994 Methods for Derivation of Inhalation Reference Concentrations and Applications of Inhalation Dosimetry (U.S. EPA 1994) and reviews recent scientific advances in...

Diagnostic approach in cases with suspected work-related asthma

PubMed Central

2013-01-01

Background Work-related asthma (WRA) is a major cause of respiratory disease in modern societies. The diagnosis and consequently an opportunity for prevention are often missed in practice. Methods Based on recent studies and systematic reviews of the literature methods for detection of WRA and identification of specific causes of allergic WRA are discussed. Results and Conclusions All workers should be asked whether symptoms improve on days away from work or on holidays. Positive answers should lead to further investigation. Spirometry and non-specific bronchial responsiveness should be measured, but carefully performed and validly analysed serial peak expiratory flow or forced expiratory volume in one second (FEV1) measurements are more specific and confirm occupational asthma in about 82% of those still exposed to the causative agent. Skin prick testing or specific immunoglobulin E assays are useful to document allergy to high molecular weight allergens. Specific inhalational challenge tests come closest to a gold standard test, but lack standardisation, availability and sensitivity. Supervised workplace challenges can be used when specific challenges are unavailable or the results non-diagnostic, but methodology lacks standardisation. Finally, if the diagnosis remains unclear a follow-up with serial measurements of FEV1 and non-specific bronchial hyperresponsiveness should detect those likely to develop permanent impairment from their occupational exposures. PMID:23768266

Occupational asthma caused by guar gum.

PubMed

Lagier, F; Cartier, A; Somer, J; Dolovich, J; Malo, J L

1990-04-01

Some vegetable gums have been reported to cause asthma. We describe three subjects who were exposed at work to guar gum, which is derived from the outer part of Cyanopsis tetragonolobus, a vegetable that grows in India. The first subject worked for a pharmaceutical company; the second and third subjects worked at a carpet-manufacturing plant. All three subjects developed symptoms of rhinitis and asthma after the onset of exposure to guar gum. All subjects were atopic and demonstrated mild bronchial hyperresponsiveness to inhaled histamine at the time they were observed. Skin prick tests demonstrated an immediate skin reaction to guar gum. All three subjects had high levels of serum IgE antibodies to guar gum. Specific inhalation challenges in which the three subjects were exposed for short intervals (less than or equal to 4 minutes) to powder of guar gum elicited isolated immediate bronchospastic reactions in two subjects and a dual reaction in the other subject.

[Occurrence of inhalation allergy in children with food allergy].

PubMed

Hofman, T

2000-10-01

The aim of this study has been analysis of the relationship between appearance inhalant allergy and incidence allergy to food in early childhood. The author has been established that overall 29.7% children with food allergy developed hypersensitivity against inhalant allergens. In 20.9% children with food allergy the inhalant hypersensitivity appearance to age 4 years, in 31.4% to age 8 years, and in 56.4% to age 12. Inhalant allergy has been the most against house dust, grass pollen and fur cat and dog, and rare to tree and weeds pollen. Together with age decreased prevalence of incidence food allergy but increased inhalant allergy. It has been showed. The statistical significant relationship between incidence specific IgE against nuts in early childhood and elicited house dust allergy and between present specific IgE against wheat and nuts and elicited allergy to fur dog and cat.

Occupational asthma due to turpentine in art painter--case report.

PubMed

Dudek, Wojciech; Wittczak, Tomasz; Swierczyńska-Machura, Dominika; Walusiak-Skorupa, Jolanta; Pałczyński, Cezary

2009-01-01

Turpentine is a fluid obtained by distillation of wood resins containing mixture of terpens. It can act as an irritant and sensitiser. Most common health problem among workers exposed to turpentine is contact dermatitis. Little is know about turpentine to cause type I hypersensitivity reaction. We present a case of a 27-year old art painter using turpentine as a thinner for oil-based paints. She developed asthmatic reactions after 5 years of working with turpentine. A number of clinical procedures were performed, including clinical examination, routine laboratory tests, total serum IgE, skin prick tests to common aeroallergens, metal salts, oil-based paints and balsamic turpentine, resting spirometry test, histamine challenge, and a single-blind, placebo-controlled specific inhalation challenge with balsamic turpentine. Clinical findings and laboratory test results were normal but a significant bronchial hyperreactivity was found. During the specific challenge, dyspnoea and decreased forced expiratory volume (FEV1) were observed in late phase of asthmatic reaction. An increased proportion of eosinophils in induced sputum could also be noted 24 h after the challenge. Positive clinical response to the specific challenge as well as the morphological changes found in induced sputum served as the basis for diagnosing occupational asthma. To our knowledge, this is the first well-documented case of turpentine-induced occupational asthma.

Pulmonary delivery of nanoparticle chemotherapy for the treatment of lung cancers: challenges and opportunities

PubMed Central

Mangal, Sharad; Gao, Wei; Li, Tonglei; Zhou, Qi (Tony)

2017-01-01

Lung cancer is the second most prevalent and the deadliest among all cancer types. Chemotherapy is recommended for lung cancers to control tumor growth and to prolong patient survival. Systemic chemotherapy typically has very limited efficacy as well as severe systemic adverse effects, which are often attributed to the distribution of anticancer drugs to non-targeted sites. In contrast, inhalation routes permit the delivery of drugs directly to the lungs providing high local concentrations that may enhance the anti-tumor effect while alleviating systemic adverse effects. Preliminary studies in animals and humans have suggested that most inhaled chemotherapies are tolerable with manageable pulmonary adverse effects, including cough and bronchospasm. Promoting the deposition of anticancer drugs in tumorous cells and minimizing access to healthy lung cells can further augment the efficacy and reduce the risk of local toxicities caused by inhaled chemotherapy. Sustained release and tumor localization characteristics make nanoparticle formulations a promising candidate for the inhaled delivery of chemotherapeutic agents against lung cancers. However, the physiology of respiratory tracts and lung clearance mechanisms present key barriers for the effective deposition and retention of inhaled nanoparticle formulations in the lungs. Recent research has focused on the development of novel formulations to maximize lung deposition and to minimize pulmonary clearance of inhaled nanoparticles. This article systematically reviews the challenges and opportunities for the pulmonary delivery of nanoparticle formulations for the treatment of lung cancers. PMID:28504252

Effect of inhaled dust mite allergen on regional particle deposition and mucociliary clearance in allergic asthmatics**

EPA Science Inventory

Background Acute exacerbations in allergic asthmatics may lead to impaired ability to clear mucus from the airways, a key factor in asthma morbidity. Objective The purpose of this study was to determine the effect of inhaled house dust mite challenge on the regional deposition of...

Diagnostic Utility of Total IgE in Foods, Inhalant, and Multiple Allergies in Saudi Arabia.

PubMed

Al-Mughales, Jamil A

2016-01-01

Objective. To assess the diagnostic significance of total IgE in foods, inhalant, and multiple allergies. Methods. Retrospective review of the laboratory records of patients who presented with clinical suspicion of food or inhalant allergy between January 2013 and December 2014. Total IgE level was defined as positive for a value >195 kU/L; and diagnosis was confirmed by the detection of specific IgE (golden standard) for at least one food or inhalant allergen and at least two allergens in multiple allergies. Results. A total of 1893 (male ratio = 0.68, mean age = 39.0 ± 19.2 years) patients were included. Total IgE had comparable sensitivity (55.8% versus 59.6%) and specificity (83.9% versus 84.4%) in food versus inhalant allergy, respectively, but a superior PPV in inhalant allergy (79.1% versus 54.4%). ROC curve analysis showed a better diagnostic value in inhalant allergies (AUC = 0.817 (95% CI = 0.796-0.837) versus 0.770 (95% CI = 0.707-0.833)). In multiple allergies, total IgE had a relatively good sensitivity (78.6%), while negative IgE testing (<195 kU/L) predicted the absence of multiple allergies with 91.5% certitude. Conclusion. Total IgE assay is not efficient as a diagnostic test for foods, inhalant, or multiple allergies. The best strategy should refer to specific IgE testing guided by a comprehensive atopic history.

Diagnostic Utility of Total IgE in Foods, Inhalant, and Multiple Allergies in Saudi Arabia

PubMed Central

Al-Mughales, Jamil A.

2016-01-01

Objective. To assess the diagnostic significance of total IgE in foods, inhalant, and multiple allergies. Methods. Retrospective review of the laboratory records of patients who presented with clinical suspicion of food or inhalant allergy between January 2013 and December 2014. Total IgE level was defined as positive for a value >195 kU/L; and diagnosis was confirmed by the detection of specific IgE (golden standard) for at least one food or inhalant allergen and at least two allergens in multiple allergies. Results. A total of 1893 (male ratio = 0.68, mean age = 39.0 ± 19.2 years) patients were included. Total IgE had comparable sensitivity (55.8% versus 59.6%) and specificity (83.9% versus 84.4%) in food versus inhalant allergy, respectively, but a superior PPV in inhalant allergy (79.1% versus 54.4%). ROC curve analysis showed a better diagnostic value in inhalant allergies (AUC = 0.817 (95% CI = 0.796–0.837) versus 0.770 (95% CI = 0.707–0.833)). In multiple allergies, total IgE had a relatively good sensitivity (78.6%), while negative IgE testing (<195 kU/L) predicted the absence of multiple allergies with 91.5% certitude. Conclusion. Total IgE assay is not efficient as a diagnostic test for foods, inhalant, or multiple allergies. The best strategy should refer to specific IgE testing guided by a comprehensive atopic history. PMID:27314052

3-(Bromomethyl)-2-chloro-4-(methylsulfonyl)- benzoic acid: a new cause of sensitiser induced occupational asthma, rhinitis and urticaria.

PubMed

Suojalehto, Hille; Karvala, Kirsi; Ahonen, Saana; Ylinen, Katriina; Airaksinen, Liisa; Suuronen, Katri; Suomela, Sari; Lindström, Irmeli

2018-04-01

3-(Bromomethyl)-2-chloro-4-(methylsulfonyl)-benzoic acid (BCMBA) has not previously been identified as a respiratory sensitiser. We detected two cases who presented respiratory and urticaria symptoms related to BCMBA and had positive skin prick tests to the agent. Subsequently, we conducted outbreak investigations at the BCMBA-producing factory and performed clinical examinations to confirm occupational diseases. The outbreak investigations included observations of work processes, assessment of exposure, a medical survey with a questionnaire and skin prick tests with 0.5% BCMBA water solution on 85 exposed workers and 9 unexposed workers. We used specific inhalation or nasal challenge and open skin application test to investigate BCMBA-related occupational asthma, rhinitis and contact urticaria. We identified nine workers with respiratory and/or skin symptoms and positive skin prick tests to BCMBA in a chemical factory. A survey among chemical factory workers indicated a BCMBA-related sensitisation rate of 8% among all exposed workers; the rate was highest (25%) among production workers in the production hall. Sensitisation was detected only in workers with the estimated highest exposure levels. Six cases of occupational asthma, rhinitis and/or contact urticaria caused by BCMBA were confirmed with challenge tests. Asthma-provoking doses in specific inhalation challenges were very low (0.03% or 0.3% BCMBA in lactose). We identified a new low molecular weight agent causing occupational asthma, rhinitis and contact urticaria. A typical clinical picture of allergic diseases and positive skin prick tests suggest underlying IgE-mediated disease mechanisms. Stringent exposure control measures are needed in order to prevent BCMBA-related diseases. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Challenges of curcumin bioavailability: novel aerosol remedies.

PubMed

Subramani, Parasuraman Aiya; Narala, Venkata R

2013-01-01

Nanoparticles are promising aids for drug delivery for previously challenging diseases, and many incurable ones. Curcumin (diferuloylmethane) is a pleiotropic molecule having various target molecules in the body. Despite its effects, curcumin-based drugs are not readily available in the market because of their low bioavailability. Although dietary intake and knowledge about the potential of curcumin are high in countries like India, studies indicate that the bioavailability problem still persists. However, administration of curcumin through inhalation has received little consideration. In this review we discuss the potential of curcumin, approaches made to overcome the bioavailability challenges, and novel approaches that could be applied in order to deliver curcumin in a pressurized metered dose inhaler (pMDI).

Neutrophilic respiratory tract inflammation and peripheral blood neutrophilia after grain sorghum dust extract challenge.

PubMed

Von Essen, S G; O'Neill, D P; McGranaghan, S; Olenchock, S A; Rennard, S I

1995-11-01

To determine if inhalation of grain sorghum dust in the laboratory would cause neutrophilic upper and lower respiratory tract inflammation in human volunteers, as well as systemic signs of illness. Prospective. University of Nebraska Medical Center. Thirty normal volunteers. Inhalation challenge with 20 mL of a nebulized solution of filter-sterilized grain sorghum dust extract (GSDE). One group received prednisone, 20 mg for 2 days, prior to the challenge. Bronchoscopy with bronchoalveolar lavage (BAL) was performed 24 h after challenge, with samples collected as bronchial and alveolar fractions. Findings included visible signs of airways inflammation, quantified as the bronchitis index. The percentage of bronchial neutrophils was significantly increased in those challenged with GSDE vs the control solution, Hanks' balanced salt solution (40.3 +/- 4.5% vs 14.3 +/- 5.1%, p < or = .01). Similar findings were seen in the alveolar fraction. Pretreatment with corticosteroids did not prevent the rise in neutrophils recovered by BAL. Peripheral blood neutrophils were also increased in volunteers challenged with the grain dust extract. To explain the increase in peripheral blood neutrophil counts, the capacity of the peripheral blood neutrophils to migrate in chemotaxis experiments was examined. The results demonstrate an increase in peripheral blood neutrophils and an increase in chemotactic responsiveness. Inhalation challenge with a grain dust extract causes respiratory tract inflammation and a peripheral blood neutrophilia. One reason for this may be an increase in activated peripheral blood neutrophils.

Delivery of inhaled drugs for infants and small children: a commentary on present and future needs.

PubMed

Fink, James B

2012-11-01

Although the manufacture of inhaled medications is a multibillion dollar industry, virtually no pharmaceutical drug/device combination has been approved for inhalation across the range of pediatric patient ages and sizes. The clinician who treats neonates, infants, or toddlers is often faced with the dilemma of prescribing inhaled medications that may be disease appropriate but have not been approved for use in patients in these age categories. Their use is thus technically "off label," with limited empirical data to guide both dose and device selection. This dilemma requires the prescribing physician to go beyond the limitations of the product label, often without benefit of appropriately designed clinical trials, in an attempt to select safe and effective doses for use with these smallest of patients. The vast majority of drugs approved for inhalation were studied by using aerosol devices designed for older children and adults using a mouthpiece interface, which may not be practical for use in infants and patients aged <4 years. The selection of the most age-appropriate device and interface is critical for the effective administration of the prescribed therapy. In the absence of industry-sponsored clinical trials in neonates, infants, and toddlers, in vitro and in vivo strategies may help guide age-appropriate dosing, device, and interface selection to better inform clinical practice. In this commentary, the challenges in developing and prescribing effective formulations for aerosol delivery across the range of pediatric ages and sizes are explored, with guidance for device and interface selection. Recommendations for future collaborative sharing of in vitro models and age-specific breathing patterns between academic and industry researchers could help regulators and clinicians better understand the impact age and size have on pulmonary drug delivery. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Hypersensitivity pneumonia-nonspecific interstitial pneumonia/fibrosis histopathologic presentation: a study in diagnosis and long-term management.

PubMed

Jacobs, Robert L; Andrews, Charles P

2003-02-01

Nonspecific interstitial pneumonia/fibrosis (NSIP) has been classified a form of idiopathic interstitial pneumonia/fibrosis. We have shown that cases of NSIP without demonstrable serum precipitins may be caused by inhalation of high levels of mold and/or bacteria in closed environments. We report a patient with a clinical and histopathologic diagnosis of NSIP without serum precipitins caused by a microbial contamination in her home. Her case was converted from an acute to an insidious clinical presentation by inadequate remediation. A prolonged avoidance-challenge technique demonstrated that this case of NSIP was a form of hypersensitivity pneumonia that was reversible by effective remediation. The patient was identified by compatible signs and symptoms, roentgenographic studies, pulmonary function tests, and a transbronchial lung biopsy. She was further evaluated with a detailed environmental history, serologic tests, and investigation of the home environment. An environmental avoidance and challenge technique was performed to confirm cause and effect and to determine that remediation had been effective. Review of the biopsy showed NSIP and failed to reveal any non-caseating granuloma formation. Investigation of the home revealed a Cladosporium species contamination of the air conditioning system and Penicillium species beneath an entryway carpet. Serum precipitins to commercial antigens of common mold to the south Texas area were negative. Avoidance and challenge techniques confirmed the home as the causative environment in this case of NSIP. The patient has been free of signs and symptoms and has taken no medication for interstitial lung disease over the past 30 months. Some cases of NSIP may be caused by inhalation of microbial antigen(s) in a closed environment. An environmental challenge technique was an effective method to determine the causative environment and confirm that remediation had been effective. Inadequate remediation may lead to symptomatic improvement, but may convert a patient from an acute to an insidious presenter. The environmental challenge obviates a need for specific challenges to determine specific causation. Remediation of or moving from an environmental contamination to achieve reversibility or prevent progression was the treatment of choice to avoid use of long-term immunosuppressive agents.

1alpha,25-dihydroxyvitamin D3 potentiates the beneficial effects of allergen immunotherapy in a mouse model of allergic asthma: role for IL-10 and TGF-beta.

PubMed

Taher, Yousef A; van Esch, Betty C A M; Hofman, Gerard A; Henricks, Paul A J; van Oosterhout, Antoon J M

2008-04-15

1alpha,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), a potent inhibitor of NF-kappaB expression, can prevent the maturation of dendritic cells in vitro leading to tolerogenic dendritic cells with increased potential to induce regulatory T cells. Herein, we investigated whether the combination of allergen immunotherapy with 1,25(OH)(2)D(3) potentiates the suppressive effects of immunotherapy and whether the immunoregulatory cytokines IL-10 and TGF-beta are involved in the effector phase. OVA-sensitized and challenged BALB/c mice displayed airway hyperresponsiveness (AHR) and increased serum OVA-specific IgE levels, bronchoalveolar lavage eosinophilia, and Th2 cytokine levels. In this model, the dose response of allergen immunotherapy 10 days before OVA inhalation challenge shows strong suppression of asthma manifestations at 1 mg of OVA, but partial suppression of bronchoalveolar lavage eosinophilia, IgE up-regulation, and no reduction of AHR at 100 microg. Interestingly, coadministration of 10 ng of 1,25(OH)(2)D(3) with 100 microg of OVA immunotherapy significantly inhibited AHR and potentiated the reduction of serum OVA-specific IgE levels, airway eosinophilia, and Th2-related cytokines concomitant with increased IL-10 levels in lung tissues and TGF-beta and OVA-specific IgA levels in serum. Similar effects on suboptimal immunotherapy were observed by inhibition of the NF-kappaB pathway using the selective IkappaB kinase 2 inhibitor PS-1145. The suppressive effects of this combined immunotherapy were partially reversed by treatment with mAb to either IL-10R or TGF-beta before OVA inhalation challenge but completely abrogated when both Abs were given. These data demonstrate that 1,25(OH)(2)D(3) potentiates the efficacy of immunotherapy and that the regulatory cytokines IL-10 and TGF-beta play a crucial role in the effector phase of this mouse model.

Optimizing the Delivery of Inhaled Medication for Respiratory Patients: The Role of Valved Holding Chambers.

PubMed

McIvor, R Andrew; Devlin, Hollie M; Kaplan, Alan

2018-01-01

Valved holding chambers (VHCs) have been used with pressurized metered-dose inhalers since the early 1980s. They have been shown to increase fine particle delivery to the lungs, decrease oropharyngeal deposition, and reduce side effects such as throat irritation, dysphonia, and oral candidiasis that are common with use of pressurized metered-dose inhalers (pMDIs) alone. VHCs act as aerosol reservoirs, allowing the user to actuate the pMDI device and then inhale the medication in a two-step process that helps users overcome challenges in coordinating pMDI actuation with inhalation. The design of VHC devices can have an impact on performance. Features such as antistatic properties, effective face-to-facemask seal feedback whistles indicating correct inhalation speed, and inhalation indicators all help improve function and performance, and have been demonstrated to improve asthma control, reduce the rate of exacerbations, and improve quality of life. Not all VHCs are the same, and they are not interchangeable. Each pairing of a pMDI device plus VHC should be considered as a unique delivery system.

Optimizing the Delivery of Inhaled Medication for Respiratory Patients: The Role of Valved Holding Chambers

PubMed Central

Devlin, Hollie M.

2018-01-01

Valved holding chambers (VHCs) have been used with pressurized metered-dose inhalers since the early 1980s. They have been shown to increase fine particle delivery to the lungs, decrease oropharyngeal deposition, and reduce side effects such as throat irritation, dysphonia, and oral candidiasis that are common with use of pressurized metered-dose inhalers (pMDIs) alone. VHCs act as aerosol reservoirs, allowing the user to actuate the pMDI device and then inhale the medication in a two-step process that helps users overcome challenges in coordinating pMDI actuation with inhalation. The design of VHC devices can have an impact on performance. Features such as antistatic properties, effective face-to-facemask seal feedback whistles indicating correct inhalation speed, and inhalation indicators all help improve function and performance, and have been demonstrated to improve asthma control, reduce the rate of exacerbations, and improve quality of life. Not all VHCs are the same, and they are not interchangeable. Each pairing of a pMDI device plus VHC should be considered as a unique delivery system. PMID:29849831

Assessing the effect of culturally specific audiovisual educational interventions on attaining self-management skills for chronic obstructive pulmonary disease in Mandarin- and Cantonese-speaking patients: a randomized controlled trial.

PubMed

Poureslami, Iraj; Kwan, Susan; Lam, Stephen; Khan, Nadia A; FitzGerald, John Mark

2016-01-01

Patient education is a key component in the management of chronic obstructive pulmonary disease (COPD). Delivering effective education to ethnic groups with COPD is a challenge. The objective of this study was to develop and assess the effectiveness of culturally and linguistically specific audiovisual educational materials in supporting self-management practices in Mandarin- and Cantonese-speaking patients. Educational materials were developed using participatory approach (patients involved in the development and pilot test of educational materials), followed by a randomized controlled trial that assigned 91 patients to three intervention groups with audiovisual educational interventions and one control group (pamphlet). The patients were recruited from outpatient clinics. The primary outcomes were improved inhaler technique and perceived self-efficacy to manage COPD. The secondary outcome was improved patient understanding of pulmonary rehabilitation procedures. Subjects in all three intervention groups, compared with control subjects, demonstrated postintervention improvements in inhaler technique (P<0.001), preparedness to manage a COPD exacerbation (P<0.01), ability to achieve goals in managing COPD (P<0.01), and understanding pulmonary rehabilitation procedures (P<0.05). Culturally appropriate educational interventions designed specifically to meet the needs of Mandarin and Cantonese COPD patients are associated with significantly better understanding of self-management practices. Self-management education led to improved proper use of medications, ability to manage COPD exacerbations, and ability to achieve goals in managing COPD. A relatively simple culturally appropriate disease management education intervention improved inhaler techniques and self-management practices. Further research is needed to assess the effectiveness of self-management education on behavioral change and patient empowerment strategies.

Assessing the effect of culturally specific audiovisual educational interventions on attaining self-management skills for chronic obstructive pulmonary disease in Mandarin- and Cantonese-speaking patients: a randomized controlled trial

PubMed Central

Poureslami, Iraj; Kwan, Susan; Lam, Stephen; Khan, Nadia A; FitzGerald, John Mark

2016-01-01

Background Patient education is a key component in the management of chronic obstructive pulmonary disease (COPD). Delivering effective education to ethnic groups with COPD is a challenge. The objective of this study was to develop and assess the effectiveness of culturally and linguistically specific audiovisual educational materials in supporting self-management practices in Mandarin- and Cantonese-speaking patients. Methods Educational materials were developed using participatory approach (patients involved in the development and pilot test of educational materials), followed by a randomized controlled trial that assigned 91 patients to three intervention groups with audiovisual educational interventions and one control group (pamphlet). The patients were recruited from outpatient clinics. The primary outcomes were improved inhaler technique and perceived self-efficacy to manage COPD. The secondary outcome was improved patient understanding of pulmonary rehabilitation procedures. Results Subjects in all three intervention groups, compared with control subjects, demonstrated postintervention improvements in inhaler technique (P<0.001), preparedness to manage a COPD exacerbation (P<0.01), ability to achieve goals in managing COPD (P<0.01), and understanding pulmonary rehabilitation procedures (P<0.05). Conclusion Culturally appropriate educational interventions designed specifically to meet the needs of Mandarin and Cantonese COPD patients are associated with significantly better understanding of self-management practices. Self-management education led to improved proper use of medications, ability to manage COPD exacerbations, and ability to achieve goals in managing COPD. Clinical implication A relatively simple culturally appropriate disease management education intervention improved inhaler techniques and self-management practices. Further research is needed to assess the effectiveness of self-management education on behavioral change and patient empowerment strategies. PMID:27536093

Two case studies of highly insoluble plutonium inhalation with implications for bioassay.

PubMed

Carbaugh, E H; La Bone, T R

2003-01-01

Two well characterised Pu inhalation cases show some remarkable similarities between substantially different types of Pu oxide. The circumstances of exposure, therapy, bioassay data, chemical solubility studies and dosimetry associated with these cases suggest that highly insoluble Pu may be more common than previously thought, and can pose significant challenges to bioassay programmes.

Two Case Studies of Highly Insoluble Plutonium Inhalation with Implications for Bioassay

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carbaugh, Eugene H.; La Bone, Thomas R.

2003-01-01

Two well-characterized Pu inhalation cases show some remarkable similarities between substantially different types of Pu oxide. The circumstances of exposure, therapy, bioassay data, chemical solubility studies, and dosimetry associated with these cases suggests taht highly insoluble Pu may be more common than previously thought, and can pose significant challenges to bioassay programs.

Characterization of the Burkholderia mallei tonB Mutant and Its Potential as a Backbone Strain for Vaccine Development

PubMed Central

Mott, Tiffany M.; Vijayakumar, Sudhamathi; Sbrana, Elena; Endsley, Janice J.; Torres, Alfredo G.

2015-01-01

Background In this study, a Burkholderia mallei tonB mutant (TMM001) deficient in iron acquisition was constructed, characterized, and evaluated for its protective properties in acute inhalational infection models of murine glanders and melioidosis. Methodology/Principal Findings Compared to the wild-type, TMM001 exhibits slower growth kinetics, siderophore hyper-secretion and the inability to utilize heme-containing proteins as iron sources. A series of animal challenge studies showed an inverse correlation between the percentage of survival in BALB/c mice and iron-dependent TMM001 growth. Upon evaluation of TMM001 as a potential protective strain against infection, we found 100% survival following B. mallei CSM001 challenge of mice previously receiving 1.5 x 104 CFU of TMM001. At 21 days post-immunization, TMM001-treated animals showed significantly higher levels of B. mallei-specific IgG1, IgG2a and IgM when compared to PBS-treated controls. At 48 h post-challenge, PBS-treated controls exhibited higher levels of serum inflammatory cytokines and more severe pathological damage to target organs compared to animals receiving TMM001. In a cross-protection study of acute inhalational melioidosis with B. pseudomallei, TMM001-treated mice were significantly protected. While wild type was cleared in all B. mallei challenge studies, mice failed to clear TMM001. Conclusions/Significance Although further work is needed to prevent chronic infection by TMM001 while maintaining immunogenicity, our attenuated strain demonstrates great potential as a backbone strain for future vaccine development against both glanders and melioidosis. PMID:26114445

Characterization of the Burkholderia mallei tonB Mutant and Its Potential as a Backbone Strain for Vaccine Development.

PubMed

Mott, Tiffany M; Vijayakumar, Sudhamathi; Sbrana, Elena; Endsley, Janice J; Torres, Alfredo G

2015-01-01

In this study, a Burkholderia mallei tonB mutant (TMM001) deficient in iron acquisition was constructed, characterized, and evaluated for its protective properties in acute inhalational infection models of murine glanders and melioidosis. Compared to the wild-type, TMM001 exhibits slower growth kinetics, siderophore hyper-secretion and the inability to utilize heme-containing proteins as iron sources. A series of animal challenge studies showed an inverse correlation between the percentage of survival in BALB/c mice and iron-dependent TMM001 growth. Upon evaluation of TMM001 as a potential protective strain against infection, we found 100% survival following B. mallei CSM001 challenge of mice previously receiving 1.5 x 10(4) CFU of TMM001. At 21 days post-immunization, TMM001-treated animals showed significantly higher levels of B. mallei-specific IgG1, IgG2a and IgM when compared to PBS-treated controls. At 48 h post-challenge, PBS-treated controls exhibited higher levels of serum inflammatory cytokines and more severe pathological damage to target organs compared to animals receiving TMM001. In a cross-protection study of acute inhalational melioidosis with B. pseudomallei, TMM001-treated mice were significantly protected. While wild type was cleared in all B. mallei challenge studies, mice failed to clear TMM001. Although further work is needed to prevent chronic infection by TMM001 while maintaining immunogenicity, our attenuated strain demonstrates great potential as a backbone strain for future vaccine development against both glanders and melioidosis.

Imagine the Superiority of Dry Powder Inhalers from Carrier Engineering

PubMed Central

2018-01-01

Inhalation therapy has strong history of more than 4000 years and it is well recognized around the globe within every culture. In early days, inhalation therapy was designed for treatment of local disorders such as asthma and other pulmonary diseases. Almost all inhalation products composed a simple formulation of a carrier, usually α-lactose monohydrate orderly mixed with micronized therapeutic agent. Most of these formulations lacked satisfactory pulmonary deposition and dispersion. Thus, various alternative carrier's molecules and powder processing techniques are increasingly investigated to achieve suitable aerodynamic performance. In view of this fact, more suitable and economic alternative carrier's molecules with advanced formulation strategies are discussed in the present review. Furthermore, major advances, challenges, and the future perspective are discussed. PMID:29568652

Anaphylaxis to the ingestion and inhalation of Tenebrio molitor (mealworm) and Zophobas morio (superworm).

PubMed

Freye, H B; Esch, R E; Litwin, C M; Sorkin, L

1996-01-01

It has been well documented, worldwide, that inhalation and/or contact with airborne particulate insect products has resulted in sensitivity to insect proteins and is manifested by such common entities as dermatitis, conjunctivitis, rhinitis, and asthma. However, the deliberate ingestion of a variety of insects (undertaken to prove their edibility and nutrient value) resulted in subsequent sensitization of some individuals. Such an outcome has not previously been reported in the literature. The objective was to document the anaphylactic reaction to the purposeful ingestion of mealworm in an individual known to be sensitized to the inhalation of beetle larvae. We used the occasion of the Centennial Celebration of The New York Entomological Society to expose members and guests of the Society to the ingestion of various insects. The subjects of the study consisted of: 1) Three members were adversely affected; 2) One individual with Baker's asthma; and 3) A number of controls with no known hypersensitivity to insect products. The investigation was undertaken by food challenges, inhalation challenges, skin testing to the individual insect allergens, a) Tenebrio molitor (TM), b) Zophobas morio (ZM), c) Blattella germanica (BG), skin testing to common indoors and outdoor allergens, and direct bind ELISA and ELISA inhibition. One individual manifesting hypersensitivity both by ingestion and inhalation to mealworm was identified. This sensitivity was documented clinically as well as by objective testing.

A synthetic peptide vaccine directed against the 2ß2-2ß3 loop of domain 2 of protective antigen protects rabbits from inhalation anthrax.

PubMed

Oscherwitz, Jon; Yu, Fen; Cease, Kemp B

2010-09-15

The current vaccines for anthrax in the United States and United Kingdom are efficacious in the two most accepted animal models of inhalation anthrax, nonhuman primates and rabbits, but require extensive immunization protocols. We previously demonstrated that a linear determinant in domain 2 of Bacillus anthracis protective Ag (PA) is a potentially important target for an epitope-specific vaccine for anthrax, as Abs specific for this site, referred to as the loop-neutralizing determinant (LND), neutralize lethal toxin in vitro, yet are virtually absent in PA-immunized rabbits. In this study, we evaluated the immunogenicity and protective efficacy in rabbits of multiple antigenic peptides (MAPs) consisting of aa 304-319 from the LND of PA colinearly synthesized at the C terminus (T-B MAP) or N terminus (B-T MAP) with a heterologous T cell epitope from Plasmodium falciparum. Immunogenicity studies demonstrated that both MAPs elicited toxin-neutralizing Ab in rabbits. To evaluate the MAPs as potential anthrax vaccines, we immunized groups of rabbits (n = 7) with each MAP in Freund's adjuvant and then exposed all rabbits to a 200-LD(50) challenge with aerosolized spores of B. anthracis Ames strain. All seven rabbits immunized with the B-T MAP and 89% (six of seven) of rabbits immunized with the T-B MAP survived the spore challenge. Corollary studies with reference sera from human vaccinees immunized with rPA or anthrax vaccine absorbed and nonhuman primates immunized with PA revealed no detectable Ab with specificity for the LND. We conclude that a synthetic peptide vaccine targeting the LND would be a potentially efficacious vaccine for anthrax.

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

Investigation of inhalation anthrax case, United States.

PubMed

Griffith, Jayne; Blaney, David; Shadomy, Sean; Lehman, Mark; Pesik, Nicki; Tostenson, Samantha; Delaney, Lisa; Tiller, Rebekah; DeVries, Aaron; Gomez, Thomas; Sullivan, Maureen; Blackmore, Carina; Stanek, Danielle; Lynfield, Ruth

2014-02-01

Inhalation anthrax occurred in a man who vacationed in 4 US states where anthrax is enzootic. Despite an extensive multi-agency investigation, the specific source was not detected, and no additional related human or animal cases were found. Although rare, inhalation anthrax can occur naturally in the United States.

Graphical Arrays of Chemical-Specific Health Effect Reference Values for Inhalation Exposures (2009 Final Report)

EPA Science Inventory

This document provides graphical arrays and tables of key information on the derivation of human inhalation health effect reference values for specific chemicals, allowing comparisons across durations, populations, and intended use. A number of program offices within the Agency, ...

Inhaled beclomethasone dipropionate improves acoustic measures of voice in patients with asthma.

PubMed

Balter, M S; Adams, S G; Chapman, K R

2001-12-01

Inhaled corticosteroids have the potential to produce upper-airway side effects such as hoarseness. As new compounds and delivery devices are developed and compared, it is difficult to quantify their adverse upper-airway effects. We undertook the following study to test the ability of an acoustic analysis technique to quantify changes in vocal function in steroid-naive patients with asthma who receive inhaled beclomethasone dipropionate (BDP), 1,000 microg/d for 4 months. Patients self-administered one of four regimens of inhaled BDP. Group 1 patients received one 250-microg puff qid via metered-dose inhaler (MDI); group 2 patients received one 250-microg puff qid via MDI with a holding chamber; group 3 patients received two 250-microg puffs bid via MDI; and group 4 patients received two 250-microg puffs bid via MDI with a holding chamber. A smaller cohort of nonsmoking asthmatic patients was managed without steroid intervention for 4 months. At baseline and again at 8 weeks and 16 weeks after the initiation of BDP treatment, patients underwent spirometry and methacholine challenge. At baseline and again at 2, 4, 8, 12, and 16 weeks, patients underwent voice recording for analysis of voice parameters. The recorded vowels were low-pass filtered (10 KHz), digitized (22 KHz), and analyzed by software to obtain two acoustic measures: (1) jitter, the cycle-to-cycle variation in the time period of the voice signal; and (2) shimmer, the cycle-to-cycle variation in voice signal amplitude. We recruited 77 patients for randomization to inhaled steroid therapy and 10 patients who continued to receive only occasional inhaled bronchodilator therapy. In all active treatment groups, FEV(1), FVC, and provocative concentration of methacholine causing a 20% fall in FEV(1) improved significantly after BDP treatment. Mean jitter scores, a measurement of variation in voice pitch, were not significantly influenced by BDP treatment. However, mean shimmer scores, a reflection of perturbation in vocal amplitude, fell significantly (p < 0.05) in the active treatment groups. These reductions in shimmer scores were not significantly different in the active treatment groups. Shimmer scores in the bronchodilator-treated group were unchanged during the 16 weeks of follow-up. Our data show that a simple and noninvasive acoustic analysis of voice is sensitive to subclinical changes associated with inhaled corticosteroid therapy. We have shown that 1,000 microg/d of inhaled BDP actually improves specific acoustic measures of voice in patients with inadequately controlled asthma. These improvements were uninfluenced by dosing schedule and whether a spacing chamber was used.

Occupational allergy to Spagulax®(Plantago ovata seed).

PubMed

Viñas, M; Pineda, F; Izquierdo-Domínguez, A; Castillo, M; Castillo, M J; Hernández, N; Ibero, M

2017-11-01

We report the case of a 36-year-old male pharmaceutical laboratory worker. On handling Spagulax ® sachets whose content is a laxative called Plantago ovata, he immediately presented rhinoconjunctivitis. Methods. Specific allergy study included SDS-PAGE with Western Blot and specific nasal challenge to Plantago ovata extract. Results. Prick by prick for Spagulax ® was negative. Total IgE: 126.5 U/mL. Western Blot recognized two proteins of 15 and 20 kDa in the extract of Plantago ovata and three proteins of 15, 18 and 50 kDa in the extract of Plantago lanceolata. Conclusions. We present a case of occupational allergy due to inhalation of and/or contact with Plantago ovata seeds.

Prevalidation of an Acute Inhalation Toxicity Test Using the EpiAirway In Vitro Human Airway Model

PubMed Central

Jackson, George R.; Maione, Anna G.; Klausner, Mitchell

2018-01-01

Abstract Introduction: Knowledge of acute inhalation toxicity potential is important for establishing safe use of chemicals and consumer products. Inhalation toxicity testing and classification procedures currently accepted within worldwide government regulatory systems rely primarily on tests conducted in animals. The goal of the current work was to develop and prevalidate a nonanimal (in vitro) test for determining acute inhalation toxicity using the EpiAirway™ in vitro human airway model as a potential alternative for currently accepted animal tests. Materials and Methods: The in vitro test method exposes EpiAirway tissues to test chemicals for 3 hours, followed by measurement of tissue viability as the test endpoint. Fifty-nine chemicals covering a broad range of toxicity classes, chemical structures, and physical properties were evaluated. The in vitro toxicity data were utilized to establish a prediction model to classify the chemicals into categories corresponding to the currently accepted Globally Harmonized System (GHS) and the Environmental Protection Agency (EPA) system. Results: The EpiAirway prediction model identified in vivo rat-based GHS Acute Inhalation Toxicity Category 1–2 and EPA Acute Inhalation Toxicity Category I–II chemicals with 100% sensitivity and specificity of 43.1% and 50.0%, for GHS and EPA acute inhalation toxicity systems, respectively. The sensitivity and specificity of the EpiAirway prediction model for identifying GHS specific target organ toxicity-single exposure (STOT-SE) Category 1 human toxicants were 75.0% and 56.5%, respectively. Corrosivity and electrophilic and oxidative reactivity appear to be the predominant mechanisms of toxicity for the most highly toxic chemicals. Conclusions: These results indicate that the EpiAirway test is a promising alternative to the currently accepted animal tests for acute inhalation toxicity. PMID:29904643

Prevalidation of an Acute Inhalation Toxicity Test Using the EpiAirway In Vitro Human Airway Model.

PubMed

Jackson, George R; Maione, Anna G; Klausner, Mitchell; Hayden, Patrick J

2018-06-01

Introduction: Knowledge of acute inhalation toxicity potential is important for establishing safe use of chemicals and consumer products. Inhalation toxicity testing and classification procedures currently accepted within worldwide government regulatory systems rely primarily on tests conducted in animals. The goal of the current work was to develop and prevalidate a nonanimal ( in vitro ) test for determining acute inhalation toxicity using the EpiAirway™ in vitro human airway model as a potential alternative for currently accepted animal tests. Materials and Methods: The in vitro test method exposes EpiAirway tissues to test chemicals for 3 hours, followed by measurement of tissue viability as the test endpoint. Fifty-nine chemicals covering a broad range of toxicity classes, chemical structures, and physical properties were evaluated. The in vitro toxicity data were utilized to establish a prediction model to classify the chemicals into categories corresponding to the currently accepted Globally Harmonized System (GHS) and the Environmental Protection Agency (EPA) system. Results: The EpiAirway prediction model identified in vivo rat-based GHS Acute Inhalation Toxicity Category 1-2 and EPA Acute Inhalation Toxicity Category I-II chemicals with 100% sensitivity and specificity of 43.1% and 50.0%, for GHS and EPA acute inhalation toxicity systems, respectively. The sensitivity and specificity of the EpiAirway prediction model for identifying GHS specific target organ toxicity-single exposure (STOT-SE) Category 1 human toxicants were 75.0% and 56.5%, respectively. Corrosivity and electrophilic and oxidative reactivity appear to be the predominant mechanisms of toxicity for the most highly toxic chemicals. Conclusions: These results indicate that the EpiAirway test is a promising alternative to the currently accepted animal tests for acute inhalation toxicity.

Protein- and DNA-based anthrax toxin vaccines confer protection in guinea pigs against inhalational challenge with Bacillus cereus G9241.

PubMed

Palmer, John; Bell, Matt; Darko, Christian; Barnewall, Roy; Keane-Myers, Andrea

2014-11-01

In the past decade, several Bacillus cereus strains have been isolated from otherwise healthy individuals who succumbed to bacterial pneumonia presenting symptoms resembling inhalational anthrax. One strain was indistinguishable from B. cereus G9241, previously cultured from an individual who survived a similar pneumonia-like illness and which was shown to possess a complete set of plasmid-borne anthrax toxin-encoding homologs. The finding that B. cereus G9241 pathogenesis in mice is dependent on pagA1-derived protective antigen (PA) synthesis suggests that an anthrax toxin-based vaccine may be effective against this toxin-encoding B. cereus strain. Dunkin Hartley guinea pigs were immunized with protein- and DNA-based anthrax toxin-based vaccines, immune responses were evaluated and survival rates were calculated after lethal aerosol exposure with B. cereus G9241 spores. Each vaccine induced seroconversion with the protein immunization regimen eliciting significantly higher serum levels of antigen-specific antibodies at the prechallenge time-point compared with the DNA-protein prime-boost immunization schedule. Complete protection against lethal challenge was observed in all groups with a detectable prechallenge serum titer of toxin neutralizing antibodies. For the first time, we demonstrated that the efficacy of fully defined anthrax toxin-based vaccines was protective against lethal B. cereus G9241 aerosol challenge in the guinea pig animal model. Published 2014. This article is a US Government work and is in the public domain in the USA.

Assessing fullness of asthma patients' aerosol inhalers.

PubMed

Rickenbach, M A; Julious, S A

1994-07-01

The importance of regular medication in order to control asthma symptoms is recognized. However, there is no accurate mechanism for assessing the fullness of aerosol inhalers. The contribution to asthma morbidity of unexpectedly running out of inhaled medication is unknown. A study was undertaken to determine how patients assess inhaler fullness and the accuracy of their assessments, and to evaluate the floatation method of assessing inhaler fullness. An interview survey of 98 patients (51% of those invited to take part), using 289 inhalers, was completed at one general practice in Hampshire. One third of participants said they had difficulty assessing aerosol inhaler fullness and those aged 60 years and over were found to be more inaccurate in assessing fullness than younger participants. Shaking the inhaler to feel the contents move was the commonest method of assessment. When placed in water, an inhaler canister floating on its side with a corner of the canister valve exposed to air indicates that the canister is less than 15% full (sensitivity 90%, specificity 99%). Floating a canister in water provides an objective measurement of aerosol inhaler fullness. Providing the method is recommended by the aerosol inhaler manufacturer, general practitioners should demonstrate the floatation method to patients experiencing difficulty in assessing inhaler fullness.

A Recombinant 63-kDa Form of Bacillus anthracis Protective Antigen Produced in the Yeast Saccharomyces cerevisiae Provides Protection in Rabbit and Primate Inhalational Challenge Models of Anthrax Infection

DTIC Science & Technology

2005-10-21

provides protection in rabbit and primate inhalational challenge models of anthrax infection Robert W. Hepler a, 1 , Rosemarie Kelly b,∗, 1 , Tessie B. McNeely a...October 2005 A t t y i H k r e a © K 1 B 9 9 0 d Approved for public release. Distribution is unlimited.bstract Infection by Bacillus anthracis is...Corresponding author. Tel.: + 1 732 594 6385; fax: + 1 732 594 1399. E-mail address: rosemarie kelly@merck.com (R. Kelly). 1 Authors made an equal contribution to

Spice allergy.

PubMed

Chen, James L; Bahna, Sami L

2011-09-01

To provide a review on spice allergy and its implementation in clinical practice. PubMed searches were performed using spice allergy as the keyword for original and review articles. Selected references were also procured from the reviewed articles' references list. Articles were selected based on their relevance to the topic. Spices are available in a large variety and are widely used, often as blends. Spice allergy seems to be rare, reportedly affecting between 4 and 13 of 10,000 adults and occurring more often in women because of cosmetic use. No figures were available on children. Most spice allergens are degraded by digestion; therefore, IgE sensitization is mostly through inhalation of cross-reacting pollens, particularly mugwort and birch. The symptoms are more likely to be respiratory when exposure is by inhalation and cutaneous if by contact. Studies on skin testing and specific IgE assays are limited and showed low reliability. The diagnosis primarily depends on a good history taking and confirmation with oral challenge. The common use of spice blends makes identifying the particular offending component difficult, particularly because their components are inconsistent. Spices are widely used and contain multiple allergens, yet spice allergy is probably markedly underdiagnosed. There is a need for reliable skin testing extracts and serum specific IgE assays. Currently, the diagnosis depends on a good history taking and well-designed titrated challenge testing. Until immunotherapy becomes developed, treatment is strict avoidance, which may be difficult because of incomplete or vague labeling. Copyright © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Inhalation of concentrated PM2.5 from Mexico City acts as an adjuvant in a guinea pig model of allergic asthma.

PubMed

Falcon-Rodriguez, Carlos Iván; De Vizcaya-Ruiz, Andrea; Rosas-Pérez, Irma Aurora; Osornio-Vargas, Álvaro Román; Segura-Medina, Patricia

2017-09-01

Exposure to Particulate Matter (PM) could function as an adjuvant depending on the city of origin in mice allergic asthma models. Therefore, our aim was to determine whether inhalation of fine particles (PM2.5) from Mexico City could act as an adjuvant inducing allergic sensitization and/or worsening the asthmatic response in guinea pig, as a suitable model of human asthma. Experimental groups were Non-Sensitized (NS group), sensitized with Ovalbumin (OVA) plus Aluminum hydroxide (Al(OH)3) as adjuvant (S + Adj group), and sensitized (OVA) without adjuvant (S group). All the animals were exposed to Filtered Air (FA) or concentrated PM2.5 (5 h/daily/3 days), employing an aerosol concentrator system, PM2.5 composition was characterized. Lung function was evaluated by barometric plethysmography (Penh index). Inflammatory cells present in bronchoalveolar lavage were counted as well as OVA-specific IgG1 and IgE were determined by ELISA assay. Our results showed in sensitized animals without Al(OH)3, that the PM2.5 exposure (609 ± 12.73 μg/m3) acted as an adjuvant, triggering OVA-specific IgG1 and IgE concentration. Penh index increased ∼9-fold after OVA challenge in adjuvant-sensitized animals as well as in S + PM2.5 group (∼6-fold), meanwhile NS + FA and S + FA lacked response. S + Adj + PM2.5 group showed an increase significantly of eosinophils and neutrophils in bronchoalveolar lavage. PM2.5 composition was made up of inorganic elements and Polycyclic Aromatic Hydrocarbons, as well as endotoxins and β-glucan, all these components could act as adjuvant. Our study demonstrated that acute inhalation of PM2.5 acted as an adjuvant, similar to the aluminum hydroxide effect, triggering allergic asthma in a guinea pig model. Furthermore, in sensitized animals with aluminum hydroxide an enhancing influence of PM2.5 exposure was observed as specific-hyperresponsiveness to OVA challenge (quickly response) and eosinophilic and neutrophilic airway inflammation. Fine particles from Mexico City is a complex mix, which play a significant role as adjuvant in allergic asthma. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of pulmonary irradiation from inhaled /sup 90/Y on immunity to Listeria monocytogenes in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanchez, A.; Lundgren, D.L.; McClellan, R.O.

1976-01-01

The immunological response of mice subjected to irradiation from particles deposited in the lungs and challenged with Listeria monocytogenes was investigated. Mice, exposed by inhalation to /sup 90/Y (a beta-emitting radionuclide) in relatively insoluble fused aluminosilicate particles, were immunized with L. monocytogenes either before or after exposure. Two additional groups of mice were either immunized or irradiated only. A group of control mice received no irradiation or immunization. The beta radiation dose absorbed by the lungs of each mouse at time of challenge averaged 10,000 rads. Fourteen days after immunization, all mice were challenged with 2 LD/sub 50/ doses ofmore » L. monocytogenes via the respiratory route. Survival of all immunized mice either with or without exposure to /sup 90/Y varied from 90 to 100% as compared to 10 to 20% for the mice irradiated only and for control mice through 14 days after challenge. Pulmonary clearance of inhaled L. monocytogenes during the first 4 hr after challenge was suppressed in the mice irradiated only but not in those immunized only, or in the immunized and irradiated groups, and control mice. There appeared to be a suppression of proliferation of L. monocytogenes in lungs and spleen in the immunized groups 72 hr after challenge, whereas the lungs and spleens of the mice irradiated only and the control mice had extensive bacterial invasion. It was concluded that the 10,000 rads of beta radiation absorbed by the lungs did not suppress the immune mechanisms of the immunized mice.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

M.A. Wasiolek

Inhalation exposure pathway modeling has recently been investigated as one of the tasks of the BIOPROTA Project (BIOPROTA 2005). BIOPROTA was set up to address the key uncertainties in long term assessments of contaminant releases into the environment arising from radioactive waste disposal. Participants of this international Project include national authorities and agencies, both regulators and operators, with responsibility for achieving safe and acceptable radioactive waste management. The objective of the inhalation task was to investigate the calculation of doses arising from inhalation of particles suspended from soils within which long-lived radionuclides, particularly alpha emitters, had accumulated. It was recognizedmore » that site-specific conditions influence the choice of conceptual model and input parameter values. Therefore, one of the goals of the task was to identify the circumstances in which different processes included in specific inhalation exposure pathway models were important. This paper discusses evaluation of processes and modeling assumptions specific to the proposed repository at Yucca Mountain as compared to the typical approaches and other models developed for different assessments and project specific contexts. Inhalation of suspended particulates that originate from contaminated soil is an important exposure pathway, particularly for exposure to actinides such as uranium, neptunium and plutonium. Radionuclide accumulation in surface soil arises from irrigation of soil with contaminated water over many years. The level of radionuclide concentration in surface soil depends on the assumed duration of irrigation. Irrigation duration is one of the parameters used on biosphere models and it depends on a specific assessment context. It is one of the parameters addressed in this paper from the point of view of assessment context for the proposed repository at Yucca Mountain. The preferred model for the assessment of inhalation exposure uses atmospheric mass loading approach, which is based on the mass of airborne particulates per unit volume of air that is inhaled by the receptor. This type of model was used by the majority of the BIOPROTA inhalation task participants and is also used in the Yucca Mountain model. Although the mass loading model is conceptually straightforward, there are some considerations that need to be included when using this model. Small particles have larger surface to volume ratio than large particles and this ratio increases in inverse proportion to the particle size. This is particularly important for elements such as plutonium, which have high sorption coefficients, and thus are preferentially attached to small particles of soil. Suspended particulates originating from soil are composed of particles smaller than average soil particles and thus, on average, have larger available surface area, and consequently activity, per unit mass than that of soil. The increase of radionuclide concentration of suspended particulates compared with that of underlying soil is quantified in terms of the enhancement factor, which is included in the inhalation model for the Yucca Mountain repository. In this paper, the use of the enhancement factor in the inhalation exposure models is discussed. Then, enhancement factor values used in the Yucca Mountain model are discussed from the perspective of site-specific conditions as well as the microenvironmental approach to modeling inhalation exposure of the receptor: The receptor can spend specified time in several environments, each of them characterized by an occupancy time, suspended particulate level, enhancement factor and breathing rate. The environment where inhalation exposure is the highest is associated with the receptor being active outdoors and involved in activities that generate high levels of dust by using farm equipment, walking, or conducting other outdoor activities. I n summary, it is important to recognize that site-specific conditions play an important role in constructing conceptual and mathematical models of inhalation exposure.« less

Physiologic underpinnings of negative BOLD cerebrovascular reactivity in brain ventricles.

PubMed

Thomas, Binu P; Liu, Peiying; Aslan, Sina; King, Kevin S; van Osch, Matthias J P; Lu, Hanzhang

2013-12-01

With a growing need for specific biomarkers in vascular diseases, there has been a surging interest in mapping cerebrovascular reactivity (CVR) of the brain. This index can be measured by conducting a hypercapnia challenge while acquiring blood-oxygenation-level-dependent (BOLD) signals. A BOLD signal increase with hypercapnia is the expected outcome and represents the majority of literature reports; in this work we report an intriguing observation of an apparently negative BOLD CVR response at 3T, during inhalation of 5% CO2 with balance medical air. These "negative-CVR" clusters were specifically located in the ventricular regions of the brain, where CSF is abundant and results in an intense baseline signal. The amplitude of the CVR response was -0.51±0.44% (N=14, age 26±4 years). We hypothesized that this observation might not be due to a decrease in oxygenation but rather a volume effect in which bright CSF signal is replaced by a less intensive blood signal as a result of vasodilation. To test this, we performed an inversion-recovery (IR) experiment to suppress the CSF signal (N=10, age 27±5 years). This maneuver in imaging sequence reversed the sign of the signal response (to 0.66±0.25%), suggesting that the volume change was the predominant reason for the apparently negative CVR in the BOLD experiment. Further support of this hypothesis was provided by a BOLD hyperoxia experiment, in which no voxels showed a negative response, presumably because vasodilation is not usually associated with this challenge. Absolute CBF response to hypercapnia was measured in a new group of subjects (N=8, age 29±7 years) and it was found that CBF in ventricular regions increased by 48% upon CO2 inhalation, suggesting that blood oxygenation most likely increased rather than decreased. The findings from this study suggest that CO2 inhalation results in the dilation of ventricular vessels accompanied by shrinkage in CSF space, which is responsible for the apparently negative CVR in brain ventricles. © 2013.

Inhaled Antibiotics for Ventilator-Associated Infections.

PubMed

Palmer, Lucy B

2017-09-01

Multidrug-resistant organisms are creating a challenge for physicians treating the critically ill. As new antibiotics lag behind the emergence of worsening resistance, intensivists in countries with high rates of extensively drug-resistant bacteria are turning to inhaled antibiotics as adjunctive therapy. These drugs can provide high concentrations of drug in the lung that could not be achieved with intravenous antibiotics without significant systemic toxicity. This article summarizes current evidence describing the use of inhaled antibiotics for the treatment of bacterial ventilator-associated pneumonia and ventilator-associated tracheobronchitis. Preliminary data suggest aerosolized antimicrobials may effectively treat resistant pathogens with high minimum inhibitory concentrations. Copyright © 2017 Elsevier Inc. All rights reserved.

Assessing fullness of asthma patients' aerosol inhalers.

PubMed Central

Rickenbach, M A; Julious, S A

1994-01-01

BACKGROUND. The importance of regular medication in order to control asthma symptoms is recognized. However, there is no accurate mechanism for assessing the fullness of aerosol inhalers. The contribution to asthma morbidity of unexpectedly running out of inhaled medication is unknown. AIM. A study was undertaken to determine how patients assess inhaler fullness and the accuracy of their assessments, and to evaluate the floatation method of assessing inhaler fullness. METHOD. An interview survey of 98 patients (51% of those invited to take part), using 289 inhalers, was completed at one general practice in Hampshire. RESULTS. One third of participants said they had difficulty assessing aerosol inhaler fullness and those aged 60 years and over were found to be more inaccurate in assessing fullness than younger participants. Shaking the inhaler to feel the contents move was the commonest method of assessment. When placed in water, an inhaler canister floating on its side with a corner of the canister valve exposed to air indicates that the canister is less than 15% full (sensitivity 90%, specificity 99%). CONCLUSION. Floating a canister in water provides an objective measurement of aerosol inhaler fullness. Providing the method is recommended by the aerosol inhaler manufacturer, general practitioners should demonstrate the floatation method to patients experiencing difficulty in assessing inhaler fullness. PMID:7619099

Inhalation device options for the management of chronic obstructive pulmonary disease.

PubMed

DePietro, Michael; Gilbert, Ileen; Millette, Lauren A; Riebe, Michael

2018-01-01

Chronic obstructive pulmonary disease (COPD) is characterized by chronic respiratory symptoms and airflow limitation, resulting from abnormalities in the airway and/or damage to the alveoli. Primary care physicians manage the healthcare of a large proportion of patients with COPD. In addition to determining the most appropriate medication regimen, which usually includes inhaled bronchodilators with or without inhaled corticosteroids, physicians are charged with optimizing inhalation device selection to facilitate effective drug delivery and patient adherence. The large variety of inhalation devices currently available present numerous challenges for physicians that include: (1) gaining knowledge of and proficiency with operating different device classes; (2) identifying the most appropriate inhalation device for the patient; and (3) providing the necessary education and training for patients on device use. This review provides an overview of the inhalation device types currently available in the United States for delivery of COPD medications, including information on their successful operation and respective advantages and disadvantages, factors to consider in matching a device to an individual patient, the need for device training for patients and physicians, and guidance for improving treatment adherence. Finally, the review will discuss established and novel tools and technology that may aid physicians in improving education and promoting better adherence to therapy.

Occupational asthma due to tetrachlorophthalic anhydride.

PubMed

Schlueter, D P; Banaszak, E F; Fink, J N; Barboriak, J

1978-03-01

The plastics industry utilizes a number of organic chemicals which have the potential of producing pulmonary reactions, particularly in susceptible individuals. Five workers are reported who were involved in the production of epoxy resins and developed recurrent respiratory symptoms and physiologic abnormalities following exposure to tetrachlorophthalic anhydride (TCPA). Inhalation challenge with TCPA reproduced their symptoms and demonstrated both an immediate and late (4-6 hours) physiologic response. Although the clinical picture strongly suggested a hypersensitivity reaction, immunologic studies failed to demonstrate precipitating or specific IgE antibody. Avoidance of exposure resulted in resolution of symptoms; however, three of the five individuals had residual functional impairment.

Bringing stability to the COPD patient: clinical and pharmacological considerations for frequent exacerbators

PubMed Central

Gulati, Swati

2017-01-01

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are critical events associated with accelerated loss of lung function, increased morbidity, and excess mortality. AECOPD are heterogeneous in nature and this may directly impact clinical decision making, specifically in patients with frequent exacerbations. A “frequent exacerbator” is a sub-phenotype of COPD that is defined as an individual who experiences ≥2 moderate to severe exacerbations per year. This distinct subgroup has higher mortality and account for more than half of COPD-related hospitalizations annually. Thus, it is imperative to identify individuals at risk for frequent exacerbations and choose optimal strategies to minimize risk for these events. New paradigms for utilizing combination inhalers and the introduction of novel oral compounds provide expanded treatment options to reduce the risk and frequency of exacerbations. The goals of managing frequent exacerbators or patients at risk for AECOPD are: 1) maximizing bronchodilation, 2) reducing inflammation, and 3) targeting specific molecular pathways implicated in COPD and AECOPD pathogenesis. Novel inhaler therapies include combination long acting muscarinic agents (LAMA) plus long acting beta agonists (LABA) show promising results compared to monotherapy or LABA inhaled corticosteroid (ICS) combination in reducing exacerbation risk among individuals at risk for exacerbations and among frequent exacerbators. Likewise, oral medications including macrolides and phosphodiesterase (PDE4) inhibitors reduce the risk for AECOPD in select groups of individuals at high risk for exacerbation. Future direction in COPD management is based on identification of various subtypes or “endotypes” and targeting therapies based on their pathophysiology. This review aims to describe the impact of AECOPD, challenges posed by frequent exacerbators, and explores the rationale for different pharmacologic approaches to preventing AECOPD in these individuals. PMID:28255962

Endothelial Inflammatory Transcriptional Responses Induced by Plasma Following Inhalation of Diesel Emissions

PubMed Central

Schisler, Jonathan C.; Ronnebaum, Sarah M.; Madden, Michael; Channell, Meghan M.; Campen, Matthew J.; Willis, Monte S.

2016-01-01

Background Air pollution, especially emissions derived from traffic sources, is associated with adverse cardiovascular outcomes. However, it remains unclear how inhaled factors drive extrapulmonary pathology. Objectives Previously, we found that canonical inflammatory response transcripts were elevated in cultured endothelial cells treated with plasma obtained after exposure compared with pre-exposure samples or filtered air (sham) exposures. While the findings confirmed the presence of bioactive factor(s) in the plasma after diesel inhalation, we wanted to better examine the complete genomic response to investigate 1) major responsive transcripts and 2) collected response pathways and ontogeny that may help to refine this method and inform the pathogenesis. Methods We assayed endothelial RNA with gene expression microarrays, examining the responses of cultured endothelial cells to plasma obtained from 6 healthy human subjects exposed to 100 μg/m3 diesel exhaust or filtered air for 2 h on separate occasions. In addition to pre-exposure baseline samples, we investigated samples obtained immediately-post and 24h-post exposure. Results Microarray analysis of the coronary artery endothelial cells challenged with plasma identified 855 probes that changed over time following diesel exhaust exposure. Over-representation analysis identified inflammatory cytokine pathways were upregulated both at the 2 and 24 h condition. Novel pathways related to FOX transcription factors and secreted extracellular factors were also identified in the microarray analysis. Conclusions These outcomes are consistent with our recent findings that plasma contains bioactive and inflammatory factors following pollutant inhalation. The specific study design implicates a novel pathway related to inflammatory blood borne components that may drive the extrapulmonary toxicity of ambient air pollutants. PMID:25942053

Eosinophilic airway disease in a patient with a negative skin prick test, but a positive patch test with platinum salts--implications for medical surveillance.

PubMed

Merget, Rolf; Fartasch, Manigé; Sander, Ingrid; Van Kampen, Vera; Raulf, Monika; Brüning, Thomas

2015-09-01

We present the case of a 52-year-old woman with a topic dermatitis since adolescence who developed work-related hand eczema, cough and runny nose 12 years after she had started working as a laboratory technician at a precious metals refinery. While skin prick test with sodium hexachloroplatinate (SPTPt ) was negative, patch testing with ammonium tetrachloroplatinate was positive after 24, 48, 72, and 96 hr. Inhalation challenge with sodium hexachloroplatinate yielded cough, mild shortness of breath, and a maximal decrease of FEV1 of 8% from baseline 24 hr after the challenge. Significant increases of bronchial hyperresponsiveness, exhaled nitric monoxide and sputum eosinophils were documented after the challenge. We conclude that eosinophilic airway disease due to platinum salts may occur in SPTPt negative subjects. Both, patch testing and inhalation challenge with platinum salts should be considered in SPT negative subjects with occupational exposure to precious metal salts and work-related allergic symptoms. © 2015 Wiley Periodicals, Inc.

STIR Version 1.0 User's Guide for Pesticide Inhalation Risk

EPA Pesticide Factsheets

STIR estimates inhalation-type exposure based on pesticide-specific information. It also estimates spray droplet exposure using the application method and rate and then compares these exposure estimates to avian and mammalian toxicity data.

The effect of an inhaled neutral endopeptidase inhibitor, thiorphan, on airway responses to neurokinin A in normal humans in vivo.

PubMed

Cheung, D; Bel, E H; Den Hartigh, J; Dijkman, J H; Sterk, P J

1992-06-01

Neuropeptides such as neurokinin A (NKA) have been proposed as important mediators of bronchoconstriction and airway hyperresponsiveness in asthma. Inhaled NKA causes bronchoconstriction in patients with asthma, but not in normal subjects. This is possibly due to the activity of an endogenous neuropeptide-degrading enzyme: neutral endopeptidase (NEP). We investigated whether a NEP-inhibitor, thiorphan, reveals bronchoconstriction to NKA or NKA-induced changes in airway responsiveness to methacholine in normal humans in vivo. Eight normal male subjects participated in a double-blind crossover study, using thiorphan as pretreatment to NKA challenge. Dose-response curves to inhaled NKA (8 to 1,000 micrograms/ml, 0.5 ml/dose) were recorded on 2 randomized days 1 wk apart, and methacholine tests were performed 48 h before and 24 h after the NKA challenge. Ten minutes prior to NKA challenge the subjects inhaled either thiorphan (2.5 mg/ml, 0.5 ml) or placebo. To detect a possible nonspecific effect of thiorphan, we investigated the effect of the same pretreatment with thiorphan or placebo on the dose-response curve to methacholine in a separate set of experiments. The response was measured by the flow from standardized partial expiratory flow-volume curves (V40p), expressed in percent fall from baseline. NKA log dose-response curves were analyzed using the area under the curve (AUC) and the response to the highest dose of 1,000 micrograms/ml (V40p,1000). The methacholine dose-response curves were characterized by their position (PC40V40p) and the maximal-response plateau (MV40p). Baseline V40p was not affected by either pretreatment (p greater than 0.15).(ABSTRACT TRUNCATED AT 250 WORDS)

Intrauterine sensitization of allergen-specific IgE analyzed by a highly sensitive new allergen microarray.

PubMed

Kamemura, Norio; Tada, Hitomi; Shimojo, Naoki; Morita, Yoshinori; Kohno, Yoichi; Ichioka, Takao; Suzuki, Koichi; Kubota, Kenji; Hiyoshi, Mineyoshi; Kido, Hiroshi

2012-07-01

To design a rational allergy prevention program, it is important to determine whether allergic sensitization starts in utero under the maternal immune system. To investigate the origin of allergen-specific IgE antibodies in cord blood (CB) and maternofetal transfer of immunoglobulins. The levels of food and inhalant allergen-specific IgE, IgA, IgG, and IgG(4) antibodies in CB and maternal blood (MB) from 92 paired neonates and mothers were measured by using a novel allergen microarray of diamond-like-carbon-coated chip, with high-sensitivity detection of allergen-specific antibodies and allergen profiles. The levels of allergen-specific IgE antibodies against food and inhalant allergens and allergen profiles were identical in CB and newborn blood, but the levels and profiles, specifically against inhalant allergens, were different from those in MB. The level of allergen-specific IgA antibodies was below the detection levels in CB despite clear detection in MB. Therefore, contamination with MB in CB was excluded on the basis of extremely low levels of IgA antibodies in CB and the obvious mismatch of the allergen-specific IgE and IgA profiles between CB and MB. However, the levels of allergen-specific IgG and IgG(4) antibodies and their allergen profiles were almost identical in both MB and CB. Allergen-specific levels of IgE and IgA antibodies and their allergen profiles analyzed by the diamond-like-carbon allergen chip indicate that IgE antibodies in CB are of fetal origin. Food-allergen specific IgE antibodies were detected more often than inhalant-allergen specific IgE antibodies in CB, the reason of which remains unclarified. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Optimizing inhalation technique using web-based videos in obstructive lung diseases.

PubMed

Müller, Tobias; Müller, Annegret; Hübel, Christian; Knipel, Verena; Windisch, Wolfram; Cornelissen, Christian Gabriel; Dreher, Michael

2017-08-01

Inhaled agents are widely used in the treatment of chronic airway diseases. Correct technique is required to ensure appropriate drug deposition, but poor technique is common. This study investigated whether inhalation technique could be improved by patient training using short videos from the German Airway League. Outpatients from a university hospital respiratory clinic who had incorrect inhalation technique were asked to demonstrate this again immediately after viewing the training videos, and after 4-8 weeks' follow-up. Inhalation technique was rated by a study nurse using specific checklists. One hundred and twelve patients with obstructive lung disease treated with inhaled bronchodilators or corticosteroids were included. More than half (51.8%) had at least one mistake in inhalation technique at baseline. Of these, most (88%) understood the training videos, 76% demonstrated correct device use immediately after training, and 72% were still able to demonstrate correct inhalation technique at follow-up (p = 0.0008 for trend). In addition, the number of mistakes decreased significantly after video training (by 1.82 [95% confidence interval 1.39-2.25]; p < 0.0001 vs. baseline). German Airway League inhalation technique training videos were easy to understand and effectively improved inhalation technique in patients with airway diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Nitrous Oxide and the Inhalation Anesthetics

PubMed Central

Becker, Daniel E; Rosenberg, Morton

2008-01-01

Nitrous oxide is the most commonly used inhalation anesthetic in dentistry and is commonly used in emergency centers and ambulatory surgery centers as well. When used alone, it is incapable of producing general anesthesia reliably, but it may be combined with other inhalation and/or intravenous agents in deep sedative/general anesthestic techniques. However, as a single agent, it has impressive safety and is excellent for providing minimal and moderate sedation for apprehensive dental patients. To gain a full appreciation of the pharmacology, physiologic influences, and proper use of nitrous oxide, one must compare it with other inhalation anesthetics. The purpose of this CE article is to provide an overview of inhalation anesthetics in general and to address nitrous oxide more specifically in comparison. PMID:19108597

AIR Louisville: Addressing Asthma With Technology, Crowdsourcing, Cross-Sector Collaboration, And Policy.

PubMed

Barrett, Meredith; Combs, Veronica; Su, Jason G; Henderson, Kelly; Tuffli, Michael

2018-04-01

Cross-sector partnerships benefit public health by leveraging ideas, resources, and expertise from a wide range of partners. In this study we documented the process and impact of AIR Louisville (a collaboration forged among the Louisville Metro Government, a nonprofit institute, and a technology company) in successfully tackling a complex public health challenge: asthma. We enrolled residents of Louisville, Kentucky, with asthma and used electronic inhaler sensors to monitor where and when they used medication. We found that the use of the digital health platform achieved positive clinical outcomes, including a 78 percent reduction in rescue inhaler use and a 48 percent improvement in symptom-free days. Moreover, the crowdsourced real-world data on inhaler use, combined with environmental data, led to policy recommendations including enhancing tree canopy, tree removal mitigation, zoning for air pollution emission buffers, recommended truck routes, and developing a community asthma notification system. AIR Louisville represents a model that can be replicated to address many public health challenges by simultaneously guiding individual, clinical, and policy decisions.

U.S. EPA'S ACUTE REFERENCE EXPOSURE METHODOLOGY FOR ACUTE INHALATION EXPOSURES

EPA Science Inventory

The US EPA National Center for Environmental Assessment has developed a methodology to derive acute inhalation toxicity benchmarks, called acute reference exposures (AREs), for noncancer effects. The methodology provides guidance for the derivation of chemical-specific benchmark...

Development of Protective Immunity in New Zealand White Rabbits Challenged with Bacillus anthracis Spores and Treated with Antibiotics and Obiltoxaximab, a Monoclonal Antibody against Protective Antigen.

PubMed

Henning, Lisa N; Carpenter, Sarah; Stark, Gregory V; Serbina, Natalya V

2018-02-01

The recommended management of inhalational anthrax, a high-priority bioterrorist threat, includes antibiotics and antitoxins. Obiltoxaximab, a chimeric monoclonal antibody against anthrax protective antigen (PA), is licensed under the U.S. Food and Drug Administration's (FDA's) Animal Rule for the treatment of inhalational anthrax. Because of spore latency, disease reemergence after treatment cessation is a concern, and there is a need to understand the development of endogenous protective immune responses following antitoxin-containing anthrax treatment regimens. Here, acquired protective immunity was examined in New Zealand White (NZW) rabbits challenged with a targeted lethal dose of Bacillus anthracis spores and treated with antibiotics, obiltoxaximab, or a combination of both. Survivors of the primary challenge were rechallenged 9 months later and monitored for survival. Survival rates after primary and rechallenge for controls and animals treated with obiltoxaximab, levofloxacin, or a combination of both were 0, 65, 100, and 95%, and 0, 100, 95, and 89%, respectively. All surviving immune animals had circulating antibodies to PA and serum toxin-neutralizing titers prior to rechallenge. Following rechallenge, systemic bacteremia and toxemia were not detected in most animals, and the levels of circulating anti-PA IgG titers increased starting at 5 days postrechallenge. We conclude that treatment with obiltoxaximab, alone or combined with antibiotics, significantly improves the survival of rabbits that received a lethal inhalation B. anthracis spore challenge dose and does not interfere with the development of immunity. Survivors of primary challenge are protected against reexposure, have rare incidents of systemic bacteremia and toxemia, and have evidence of an anamnestic response. Copyright © 2018 Henning et al.

42 CFR 84.177 - Inhalation and exhalation valves; minimum requirements.

Code of Federal Regulations, 2011 CFR

2011-10-01

... air from adversely affecting filters, except where filters are specifically designed to resist... DEVICES Non-Powered Air-Purifying Particulate Respirators § 84.177 Inhalation and exhalation valves... external influence; and (3) Designed and constructed to prevent inward leakage of contaminated air. ...

42 CFR 84.177 - Inhalation and exhalation valves; minimum requirements.

Code of Federal Regulations, 2010 CFR

2010-10-01

... air from adversely affecting filters, except where filters are specifically designed to resist... DEVICES Non-Powered Air-Purifying Particulate Respirators § 84.177 Inhalation and exhalation valves... external influence; and (3) Designed and constructed to prevent inward leakage of contaminated air. ...

Ambient ultrafine particles provide a strong adjuvant effect in the secondary immune response: implication for traffic-related asthma flares

PubMed Central

Li, Ning; Harkema, Jack R.; Lewandowski, Ryan P.; Wang, Meiying; Bramble, Lori A.; Gookin, Glenn R.; Ning, Zhi; Kleinman, Michael T.; Sioutas, Constantinos

2010-01-01

We have previously demonstrated that intranasal administration of ambient ultrafine particles (UFP) acts as an adjuvant for primary allergic sensitization to ovalbumin (OVA) in Balb/c mice. It is important to find out whether inhaled UFP exert the same effect on the secondary immune response as a way of explaining asthma flares in already-sensitized individuals due to traffic exposure near a freeway. The objective of this study is to determine whether inhalation exposure to ambient UFP near an urban freeway could enhance the secondary immune response to OVA in already-sensitized mice. Prior OVA-sensitized animals were exposed to concentrated ambient UFP at the time of secondary OVA challenge in our mobile animal laboratory in Los Angeles. OVA-specific antibody production, airway morphometry, allergic airway inflammation, cytokine gene expression, and oxidative stress marker were assessed. As few as five ambient UFP exposures were sufficient to promote the OVA recall immune response, including generating allergic airway inflammation in smaller and more distal airways compared with the adjuvant effect of intranasally instilled UFP on the primary immune response. The secondary immune response was characterized by the T helper 2 and IL-17 cytokine gene expression in the lung. In summary, our results demonstrated that inhalation of prooxidative ambient UFP could effectively boost the secondary immune response to an experimental allergen, indicating that vehicular traffic exposure could exacerbate allergic inflammation in already-sensitized subjects. PMID:20562226

Assessing exposure risk for dust storm events-associated lung function decrement in asthmatics and implications for control

NASA Astrophysics Data System (ADS)

Hsieh, Nan-Hung; Liao, Chung-Min

2013-04-01

Asian dust storms (ADS) events are seasonally-based meteorological phenomena that exacerbate chronic respiratory diseases. The purpose of this study was to assess human health risk from airborne dust exposure during ADS events in Taiwan. A probabilistic risk assessment framework was developed based on exposure and experimental data to quantify ADS events induced lung function decrement. The study reanalyzed experimental data from aerosol challenge in asthmatic individuals to construct the dose-response relationship between inhaled dust aerosol dose and decreasing percentage of forced expiratory volume in 1 s (%FEV1). An empirical lung deposition model was used to predict deposition fraction for size specific dust aerosols in pulmonary regions. The toxicokinetic and toxicodynamic models were used to simulate dust aerosols binding kinetics in lung airway in that %FEV1 change was also predicted. The mask respirators were applied to control the inhaled dose under dust aerosols exposure. Our results found that only 2% probability the mild ADS events were likely to cause %FEV1 decrement higher than 5%. There were 50% probability of decreasing %FEV1 exceeding 16.9, 18.9, and 7.1% in north, center, and south Taiwan under severe ADS events, respectively. Our result implicates that the use of activated carbon of mask respirators has the best efficacy for reducing inhaled dust aerosol dose, by which the %FEV1 decrement can be reduced up to less than 1%.

Effect of a 5-lipoxygenase inhibitor and leukotriene antagonist (PF 5901) on antigen-induced airway responses in neonatally immunized rabbits.

PubMed Central

Herd, C. M.; Donigi-Gale, D.; Shoupe, T. S.; Burroughs, D. A.; Yeadon, M.; Page, C. P.

1994-01-01

1. The effect of a single intratracheal dose (10 mg) of PF 5901 (2-[3(1-hydroxyhexyl) phenoxymethyl] quinoline hydrochloride, a specific inhibitor of the 5-lipoxygenase pathway of arachidonic acid metabolism and a leukotriene D4 antagonist) on airway changes induced in response to Alternaria tenuis aerosol challenge was assessed in adult rabbits neonatally immunized. Leukotriene generation was determined in vivo by measuring leukotriene B4 (LTB4) levels in bronchoalveolar lavage (BAL) fluid and ex vivo by measuring calcium ionophore-stimulated production of LTB4 in whole blood. 2. While PF 5901 (10 mg) had no significant effect on the acute bronchoconstriction induced by antigen, this dose was sufficient to inhibit significantly the increase in airway responsiveness to inhaled histamine 24 h following antigen challenge (P < 0.05). 3. Total leucocyte infiltration into the airways induced by antigen, as assessed by bronchoalveolar lavage, was significantly inhibited by pretreatment with PF 5901 (10 mg). However, the pulmonary infiltration of neutrophils and eosinophils induced by antigen was unaltered by prior treatment with PF 5901 (10 mg). 4. PF 5901 (10 mg) had no effect on ex vivo LTB4 synthesis in whole blood. However, the antigen-induced increase in LTB4 levels in BAL 24 h following challenge was significantly inhibited (P < 0.05). 5. We suggest from the results of the present study that the antigen-induced airway hyperresponsiveness to inhaled histamine in immunized rabbits is mediated, at least in part, by products of the 5-lipoxygenase metabolic pathway, and is not dependent on the extent of eosinophil or neutrophil influx into the airway lumen. PMID:8032653

Paradigms and mechanisms of inhalational anesthetics mediated neuroprotection against cerebral ischemic stroke.

PubMed

Wang, Hailian; Li, Peiying; Xu, Na; Zhu, Ling; Cai, Mengfei; Yu, Weifeng; Gao, Yanqin

2016-01-01

Cerebral ischemic stroke is a leading cause of serious long-term disability and cognitive dysfunction. The high mortality and disability of cerebral ischemic stroke is urging the health providers, including anesthesiologists and other perioperative professioners, to seek effective protective strategies, which are extremely limited, especially for those perioperative patients. Intriguingly, several commonly used inhalational anesthetics are recently suggested to possess neuroprotective effects against cerebral ischemia. This review introduces multiple paradigms of inhalational anesthetic treatments that have been investigated in the setting of cerebral ischemia, such as preconditioning, proconditioning and postconditioning with a variety of inhalational anesthetics. The pleiotropic mechanisms underlying these inhalational anesthetics-afforded neuroprotection against stroke are also discussed in detail, including the common pathways shared by most of the inhalational anesthetic paradigms, such as anti-excitotoxicity, anti-apoptosis and anti-inflammation. There are also distinct mechanisms involved in specific paradigms, such as preserving blood brain barrier integrity, regulating cerebral blood flow and catecholamine release. The ready availability of these inhalational anesthetics bedside and renders them a potentially translatable stroke therapy attracting great efforts for understanding of the underlying mechanisms.

Paradigms and mechanisms of inhalational anesthetics mediated neuroprotection against cerebral ischemic stroke

PubMed Central

Wang, Hailian; Li, Peiying; Xu, Na; Zhu, Ling; Cai, Mengfei; Yu, Weifeng; Gao, Yanqin

2016-01-01

Cerebral ischemic stroke is a leading cause of serious long-term disability and cognitive dysfunction. The high mortality and disability of cerebral ischemic stroke is urging the health providers, including anesthesiologists and other perioperative professioners, to seek effective protective strategies, which are extremely limited, especially for those perioperative patients. Intriguingly, several commonly used inhalational anesthetics are recently suggested to possess neuroprotective effects against cerebral ischemia. This review introduces multiple paradigms of inhalational anesthetic treatments that have been investigated in the setting of cerebral ischemia, such as preconditioning, proconditioning and postconditioning with a variety of inhalational anesthetics. The pleiotropic mechanisms underlying these inhalational anesthetics-afforded neuroprotection against stroke are also discussed in detail, including the common pathways shared by most of the inhalational anesthetic paradigms, such as anti-excitotoxicity, anti-apoptosis and anti-inflammation. There are also distinct mechanisms involved in specific paradigms, such as preserving blood brain barrier integrity, regulating cerebral blood flow and catecholamine release. The ready availability of these inhalational anesthetics bedside and renders them a potentially translatable stroke therapy attracting great efforts for understanding of the underlying mechanisms. PMID:28217291

Host Soluble Mediators: Defying the Immunological Inertness of Aspergillus fumigatus Conidia.

PubMed

Wong, Sarah Sze Wah; Aimanianda, Vishukumar

2017-12-24

Aspergillus fumigatus produce airborne spores (conidia), which are inhaled in abundant quantity. In an immunocompromised population, the host immune system fails to clear the inhaled conidia, which then germinate and invade, leading to pulmonary aspergillosis. In an immunocompetent population, the inhaled conidia are efficiently cleared by the host immune system. Soluble mediators of the innate immunity, that involve the complement system, acute-phase proteins, antimicrobial peptides and cytokines, are often considered to play a complementary role in the defense of the fungal pathogen. In fact, the soluble mediators are essential in achieving an efficient clearance of the dormant conidia, which is the morphotype of the fungus upon inhalation by the host. Importantly, harnessing the host soluble mediators challenges the immunological inertness of the dormant conidia due to the presence of the rodlet and melanin layers. In the review, we summarized the major soluble mediators in the lung that are involved in the recognition of the dormant conidia. This knowledge is essential in the complete understanding of the immune defense against A. fumigatus .

Inhalation of 7.5% carbon dioxide increases threat processing in humans.

PubMed

Garner, Matthew; Attwood, Angela; Baldwin, David S; James, Alexandra; Munafò, Marcus R

2011-07-01

Inhalation of 7.5% CO(2) increases anxiety and autonomic arousal in humans, and elicits fear behavior in animals. However, it is not known whether CO(2) challenge in humans induces dysfunction in neurocognitive processes that characterize generalized anxiety, notably selective attention to environmental threat. Healthy volunteers completed an emotional antisaccade task in which they looked toward or away from (inhibited) negative and neutral stimuli during inhalation of 7.5% CO(2) and air. CO(2) inhalation increased anxiety, autonomic arousal, and erroneous eye movements toward threat on antisaccade trials. Autonomic response to CO(2) correlated with hypervigilance to threat (speed to initiate prosaccades) and reduced threat inhibition (increased orienting toward and slower orienting away from threat on antisaccade trials) independent of change in mood. Findings extend evidence that CO(2) triggers fear behavior in animals via direct innervation of a distributed fear network that mobilizes the detection of and allocation of processing resources toward environmental threat in humans.

ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests.

PubMed

Coates, Allan L; Wanger, Jack; Cockcroft, Donald W; Culver, Bruce H; Diamant, Zuzana; Gauvreau, Gail; Hall, Graham L; Hallstrand, Teal S; Horvath, Ildiko; de Jongh, Frans H C; Joos, Guy; Kaminsky, David A; Laube, Beth L; Leuppi, Joerg D; Sterk, Peter J

2017-05-01

This international task force report updates general considerations for bronchial challenge testing and the performance of the methacholine challenge test. There are notable changes from prior recommendations in order to accommodate newer delivery devices. Rather than basing the test result upon a methacholine concentration (provocative concentration (PC 20 ) causing a 20% fall in forced expiratory volume in 1 s (FEV 1 )), the new recommendations base the result upon the delivered dose of methacholine causing a 20% fall in FEV 1 (provocative dose (PD 20 )). This end-point allows comparable results from different devices or protocols, thus any suitable nebuliser or dosimeter may be used, so long as the delivery characteristics are known. Inhalation may be by tidal breathing using a breath-actuated or continuous nebuliser for 1 min (or more), or by a dosimeter with a suitable breath count. Tests requiring maximal inhalations to total lung capacity are not recommended because the bronchoprotective effect of a deep breath reduces the sensitivity of the test. Copyright ©ERS 2017.

Dry powder antibiotic aerosol product development: inhaled therapy for tuberculosis.

PubMed

Hickey, Anthony J; Misra, Amit; Fourie, P Bernard

2013-11-01

Inhaled therapies offer a unique approach to the treatment of tuberculosis (TB) using a relevant target organ system as a route of administration. The number of research reports on this topic has been increasing exponentially in the last decade but studies of clinical efficacy have been rare in recent times. The challenge is to take many research findings and translate them into a strategy for product development. Dry powder inhalers are the dominant drug product under consideration by those interested in the inhaled therapy for TB. A range of factors including candidate drug, formulation, device selection, drug product testing for proof of concept, and preclinical and clinical purposes all demand different considerations. The following review is intended to raise awareness of a growing body of evidence, suggesting that inhaled therapy for TB is possible and desirable. In addition, it is intended to outline key elements of the product-development activity for this particular application that has not been discussed elsewhere in the literature. Hopefully, this will encourage those with development expertise to seriously contemplate the steps required to bring such products forward. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Behavioral effects of subchronic inhalation of toluene in adult rats.

PubMed

Beasley, Tracey E; Evansky, Paul A; Gilbert, Mary E; Bushnell, Philip J

2010-01-01

Whereas the acute neurobehavioral effects of toluene are robust and well characterized, evidence for persistent effects of repeated exposure to this industrial solvent is less compelling. The present experiment sought to determine whether subchronic inhalation of toluene caused persistent behavioral changes in rats. Adult male Long-Evans rats inhaled toluene vapor (0, 10, 100, or 1000 ppm) for 6h/day, 5 days/week for 13 weeks and were evaluated on a series of behavioral tests beginning 3 days after the end of exposure. Toluene delayed appetitively-motivated acquisition of a lever-press response, but did not affect motor activity, anxiety-related behavior in the elevated plus maze, trace fear conditioning, acquisition of an appetitively-motivated visual discrimination, or performance of a visual signal detection task. Challenges with acute inhalation of toluene vapor (1200-2400 ppm for 1 h) and injections of quinpirole (0.01-0.03 mg/kg) and raclopride (0.03-0.10 mg/kg) revealed no toluene-induced latent impairments in visual signal detection. These results are consistent with a pattern of subtle and inconsistent long-term effects of daily exposure to toluene vapor, in contrast to robust and reliable effects of acute inhalation of the solvent. Published by Elsevier Inc.

The innate immune response to Aspergillus fumigatus at the alveolar surface.

PubMed

Margalit, Anatte; Kavanagh, Kevin

2015-09-01

Aspergillus fumigatus is an ubiquitous, saprophytic mould that forms and releases airborne conidia which are inhaled by humans on a daily basis. When the immune system is compromised (e.g. immunosuppressive therapy prior to organ transplantation) or there is pre-existing pulmonary malfunction (e.g. asthma, cystic fibrosis, TB lesions), A. fumigatus exploits weaknesses in the host defenses which can result in the development of saphrophytic, allergic or invasive aspergillosis. If not effectively eliminated by the innate immune response, conidia germinate and form invasive hyphae which can penetrate pulmonary tissues. The innate immune response to A. fumigatus is stage-specific and various components of the host's defenses are recruited to challenge the different cellular forms of the pathogen. In immunocompetent hosts, anatomical barriers (e.g. the mucociliary elevator) and professional phagocytes such as alveolar macrophages (AM) and neutrophils prevent the development of aspergillosis by inhibiting the growth of conidia and hyphae. The recognition of inhaled conidia by AM leads to the intracellular degradation of the spores and the secretion of proinflammatory mediators which recruit neutrophils to assist in fungal clearance. During the later stages of infection, dendritic cells activate a protective A. fumigatus-specific adaptive immune response which is driven by Th1 CD4(+) T cells. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Addressing Emerging Risks: Scientific and Regulatory Challenges Associated with Environmentally Persistent Free Radicals.

PubMed

Dugas, Tammy R; Lomnicki, Slawomir; Cormier, Stephania A; Dellinger, Barry; Reams, Margaret

2016-06-08

Airborne fine and ultrafine particulate matter (PM) are often generated through widely-used thermal processes such as the combustion of fuels or the thermal decomposition of waste. Residents near Superfund sites are exposed to PM through the inhalation of windblown dust, ingestion of soil and sediments, and inhalation of emissions from the on-site thermal treatment of contaminated soils. Epidemiological evidence supports a link between exposure to airborne PM and an increased risk of cardiovascular and pulmonary diseases. It is well-known that during combustion processes, incomplete combustion can lead to the production of organic pollutants that can adsorb to the surface of PM. Recent studies have demonstrated that their interaction with metal centers can lead to the generation of a surface stabilized metal-radical complex capable of redox cycling to produce ROS. Moreover, these free radicals can persist in the environment, hence their designation as Environmentally Persistent Free Radicals (EPFR). EPFR has been demonstrated in both ambient air PM2.5 (diameter < 2.5 µm) and in PM from a variety of combustion sources. Thus, low-temperature, thermal treatment of soils can potentially increase the concentration of EPFR in areas in and around Superfund sites. In this review, we will outline the evidence to date supporting EPFR formation and its environmental significance. Furthermore, we will address the lack of methodologies for specifically addressing its risk assessment and challenges associated with regulating this new, emerging contaminant.

Addressing Emerging Risks: Scientific and Regulatory Challenges Associated with Environmentally Persistent Free Radicals

PubMed Central

Dugas, Tammy R.; Lomnicki, Slawomir; Cormier, Stephania A.; Dellinger, Barry; Reams, Margaret

2016-01-01

Airborne fine and ultrafine particulate matter (PM) are often generated through widely-used thermal processes such as the combustion of fuels or the thermal decomposition of waste. Residents near Superfund sites are exposed to PM through the inhalation of windblown dust, ingestion of soil and sediments, and inhalation of emissions from the on-site thermal treatment of contaminated soils. Epidemiological evidence supports a link between exposure to airborne PM and an increased risk of cardiovascular and pulmonary diseases. It is well-known that during combustion processes, incomplete combustion can lead to the production of organic pollutants that can adsorb to the surface of PM. Recent studies have demonstrated that their interaction with metal centers can lead to the generation of a surface stabilized metal-radical complex capable of redox cycling to produce ROS. Moreover, these free radicals can persist in the environment, hence their designation as Environmentally Persistent Free Radicals (EPFR). EPFR has been demonstrated in both ambient air PM2.5 (diameter < 2.5 µm) and in PM from a variety of combustion sources. Thus, low-temperature, thermal treatment of soils can potentially increase the concentration of EPFR in areas in and around Superfund sites. In this review, we will outline the evidence to date supporting EPFR formation and its environmental significance. Furthermore, we will address the lack of methodologies for specifically addressing its risk assessment and challenges associated with regulating this new, emerging contaminant. PMID:27338429

New methodology for specific inhalation challenges with occupational agents

PubMed Central

2010-01-01

Background Inhalation challenges are used for diagnosing occupational asthma (OA). The initial methodology consisted of a "realistic" exposure without monitoring nor controlling exposure. Our aim was to design an equipment, called the GenaSIC, that allows the generation of various agents regardless of the formulation and to assess the feasibility of its use in patients investigated for OA. Results GenaSIC can generate lactose, flour, malt, isocyanates, formaldehyde and N-butyl acetate with precise and fairly stable concentrations. Using N-butyl-acetate as a control agent and real time measurement, we show that normal breathing has a negligible effect on the concentration. We exposed forty-four different subjects to a control agent and/or to a suspected occupational agent. Nineteen of the subjects were only exposed to N-butyl acetate as a control agent without experiencing any significant irritant effect (no significant changes in spirometry thereafter). Eight subjects who were exposed to both N-butyl acetate and formaldehyde did not show significant reactions. Seven subjects were exposed to dry particles (flour in six instances, malt in the other) and five showed immediate asthmatic reactions which changes in FEV1 from 20% to a maximum of 28%. Finally, ten subjects were exposed to isocyanates, four of whom showed a positive reaction, including one subject with immediate maximum changes in FEV1 of 22%. Conclusion GenaSIC offers the possibility of reliable and safe exposures to dry particles, formaldehyde and isocyanates in the investigation of OA. PMID:20534154

Bradykinin-induced lung inflammation and bronchoconstriction: role in parainfluenze-3 virus-induced inflammation and airway hyperreactivity.

PubMed

Broadley, Kenneth J; Blair, Alan E; Kidd, Emma J; Bugert, Joachim J; Ford, William R

2010-12-01

Inhaled bradykinin causes bronchoconstriction in asthmatic subjects but not nonasthmatics. To date, animal studies with inhaled bradykinin have been performed only in anesthetized guinea pigs and rats, where it causes bronchoconstriction through sensory nerve pathways. In the present study, airway function was recorded in conscious guinea pigs by whole-body plethysmography. Inhaled bradykinin (1 mM, 20 s) caused bronchoconstriction and influx of inflammatory cells to the lungs, but only when the enzymatic breakdown of bradykinin by angiotensin-converting enzyme and neutral endopeptidase was inhibited by captopril (1 mg/kg i.p.) and phosphoramidon (10 mM, 20-min inhalation), respectively. The bronchoconstriction and cell influx were antagonized by the B(2) kinin receptor antagonist 4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132) when given by inhalation (1 and 10 μM, 20 min) and are therefore mediated via B(2) kinin receptors. However, neither intraperitioneal MEN16132 nor the peptide B(2) antagonist icatibant, by inhalation, antagonized these bradykinin responses. Sensitization of guinea pigs with ovalbumin was not sufficient to induce airway hyperreactivity (AHR) to the bronchoconstriction by inhaled bradykinin. However, ovalbumin challenge of sensitized guinea pigs caused AHR to bradykinin and histamine. Infection of guinea pigs by nasal instillation of parainfluenza-3 virus produced AHR to inhaled histamine and lung influx of inflammatory cells. These responses were attenuated by the bradykinin B(2) receptor antagonist MEN16132 and H-(4-chloro)DPhe-2'(1-naphthylalanine)-(3-aminopropyl)guanidine (VA999024), an inhibitor of tissue kallikrein, the enzyme responsible for lung synthesis of bradykinin. These results suggest that bradykinin is involved in virus-induced inflammatory cell influx and AHR.

Asthma pathogenesis, diagnosis, and management in the elderly.

PubMed

Pasha, M Asghar; Sundquist, Britta; Townley, Robert

2017-05-01

Due to the aging population, there is an increase in the number of elderly patients with asthma. Although signs and symptoms are similar to those in younger patients, diagnosis can be challenging due to presence of coexisting conditions in this population. The purpose of this review was to highlight the challenges with regards to diagnosis, management, the high rates of medical costs and mortality in elderly asthmatics. Scientific literature regarding asthma in the elderly population was reviewed. When compared to younger patients, elderly asthmatics have different drug responses, higher rates of bronchial hyper reactivity, more severe phenotype, and lower prevalence of atopy. In addition, there are issues with the adverse effects of asthma medications, use of proper inhaler technique and compliance. There is an unmet need for research in elderly patients with asthma, specifically to facilitate diagnosis, and to investigate therapeutic strategies to improve quality of life in this population.

Exposure versus internal dose: Respiratory tract deposition modeling of inhaled asbestos fibers in rats and humans (Presentation Poster)

EPA Science Inventory

Exposure to asbestos is associated with respiratory diseases, including asbestosis, lung cancer and mesothelioma. Internal fiber dose depends on fiber inhalability and orientation, fiber density, length and width, and various deposition mechanisms (DM). Species-specific param...

Systematic Review Protocol for the IRIS Chloroform Assessment (Inhalation) (Preliminary Assessment Materials)

EPA Science Inventory

In January 2018, EPA released the Systematic Review Protocol for the IRIS Chloroform Assessment (Inhalation). As part of developing a draft IRIS assessment, EPA presents a methods document, referred to as the protocol, for conducting a chemical-specific systematic revie...

75 FR 5261 - Waybill Data Reporting for Toxic Inhalation Hazards

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-02

... monitor traffic flows and rate trends in the industry, and to develop evidence in Board proceedings. The... submitted to include all traffic movements designated as a TIH (Toxic Inhalation Hazard). The revised... Board to assess more accurately TIH traffic within the United States, and specifically would be...

Specificity, Size, and Frequency of Spaces That Characterize the Mechanism of Bulk Transepithelial Transport of Prions in the Nasal Cavities of Hamsters and Mice

PubMed Central

Ayers, J. I.; Bartz, J. C.

2016-01-01

ABSTRACT Inhalation of infected brain homogenate results in transepithelial transport of prions across the nasal mucosa of hamsters, some of which occurs rapidly in relatively large amounts between cells (A. E. Kincaid, K. F. Hudson, M. W. Richey, and J. C. Bartz, J. Virol 86:12731–12740, 2012, doi:http://dx.doi.org/10.1128/JVI.01930-12). Bulk transepithelial transport in the nasal cavity has not been studied to date. In the present study, we characterized the frequency, size, and specificity of the intercellular spaces that mediate the bulk transport of inhaled prions between cells of mice or hamsters following extranasal inoculation with mock-infected brain homogenate, different strains of prion-infected brain homogenate, or brain homogenate mixed with India ink. Infected or mock-infected inoculum was identified within lymphatic vessels of the lamina propria and in spaces of >5 μm between a small number of cells of the nasal mucosa in >90% of animals from 5 to 60 min after inhalation. The width of the spaces between cells, the amount of the inoculum within the lumen of lymphatic vessels, and the timing of the transport indicate that this type of transport was taking place through preexisting spaces in the nasal cavity that were orders of magnitude wider than what is normally reported for paracellular transport. The indiscriminate rapid bulk transport of brain homogenate in the nasal cavity results in immediate entry into nasal cavity lymphatics following inhalation. This novel mechanism may underlie the recent report of the early detection of prions in blood following inhalation and has implications for horizontal prion transmission. IMPORTANCE The results of these studies demonstrate that the nasal mucosa of mice and hamsters is not an absolute anatomical barrier to inhaled prion-infected or uninfected brain homogenate. Relatively large amounts of infected and uninfected brain homogenate rapidly cross the nasal mucosa and enter the lumen of lymphatic vessels following inhalation. These bulk transepithelial transport events were relatively rare but present in >90% of animals 5 to 60 min following inhalation. This novel mechanism of bulk transepithelial transport was seen in experimental and control hamsters and mice, indicating that it was not species specific or in response to prion exposure. The indiscriminate bulk intercellular transport of inhaled pathogens across the nasal mucosa followed by entry into the lymphatic system may be a mechanism that underlies the entry and spread of other toxins and pathogens in olfactory system-driven animals. PMID:27384659

Comparison of experimental respiratory tularemia in three nonhuman primate species.

PubMed

Glynn, Audrey R; Alves, Derron A; Frick, Ondraya; Erwin-Cohen, Rebecca; Porter, Aimee; Norris, Sarah; Waag, David; Nalca, Aysegul

2015-04-01

Tularemia is a zoonotic disease caused by Francisella tularensis, which is transmitted to humans most commonly by contact with infected animals, tick bites, or inhalation of aerosolized bacteria. F. tularensis is highly infectious via the aerosol route; inhalation of as few as 10-50 organisms can cause pneumonic tularemia. Left untreated, the pneumonic form has more than >30% case-fatality rate but with early antibiotic intervention can be reduced to 3%. This study compared tularemia disease progression across three species of nonhuman primates [African green monkey (AGM), cynomolgus macaque (CM), and rhesus macaque (RM)] following aerosolized F. tularensis Schu S4 exposure. Groups of the animals exposed to various challenge doses were observed for clinical signs of infection and blood samples were analyzed to characterize the disease pathogenesis. Whereas the AGMs and CMs succumbed to disease following challenge doses of 40 and 32 colony forming units (CFU), respectively, the RM lethal dose was 276,667 CFU. Following all challenge doses that caused disease, the NHPs experienced weight loss, bacteremia, fever as early as 4 days post exposure, and tissue burden. Necrotizing-to-pyogranulomatous lesions were observed most commonly in the lung, lymph nodes, spleen, and bone marrow. Overall, the CM model consistently manifested pathological responses similar to those resulting from inhalation of F. tularensis in humans and thereby most closely emulates human tularemia disease. The RM model displayed a higher tolerance to infection and survived exposures of up to 15,593 CFU of aerosolized F. tularensis. Published by Elsevier Ltd.

Exposure to substances in the workplace and new-onset asthma: an international prospective population-based study (ECRHS-II).

PubMed

Kogevinas, Manolis; Zock, Jan-Paul; Jarvis, Debbie; Kromhout, Hans; Lillienberg, Linnéa; Plana, Estel; Radon, Katja; Torén, Kjell; Alliksoo, Ada; Benke, Geza; Blanc, Paul D; Dahlman-Hoglund, Anna; D'Errico, Angelo; Héry, Michel; Kennedy, Susan; Kunzli, Nino; Leynaert, Bénédicte; Mirabelli, Maria C; Muniozguren, Nerea; Norbäck, Dan; Olivieri, Mario; Payo, Félix; Villani, Simona; van Sprundel, Marc; Urrutia, Isabel; Wieslander, Gunilla; Sunyer, Jordi; Antó, Josep M

2007-07-28

The role of exposure to substances in the workplace in new-onset asthma is not well characterised in population-based studies. We therefore aimed to estimate the relative and attributable risks of new-onset asthma in relation to occupations, work-related exposures, and inhalation accidents. We studied prospectively 6837 participants from 13 countries who previously took part in the European Community Respiratory Health Survey (1990-95) and did not report respiratory symptoms or a history of asthma at the time of the first study. Asthma was assessed by methacholine challenge test and by questionnaire data on asthma symptoms. Exposures were defined by high-risk occupations, an asthma-specific job exposure matrix with additional expert judgment, and through self-report of acute inhalation events. Relative risks for new onset asthma were calculated with log-binomial models adjusted for age, sex, smoking, and study centre. A significant excess asthma risk was seen after exposure to substances known to cause occupational asthma (Relative risk=1.6, 95% CI 1.1-2.3, p=0.017). Risks were highest for asthma defined by bronchial hyper-reactivity in addition to symptoms (2.4, 1.3-4.6, p=0.008). Of common occupations, a significant excess risk of asthma was seen for nursing (2.2, 1.3-4.0, p=0.007). Asthma risk was also increased in participants who reported an acute symptomatic inhalation event such as fire, mixing cleaning products, or chemical spills (RR=3.3, 95% CI 1.0-11.1, p=0.051). The population-attributable risk for adult asthma due to occupational exposures ranged from 10% to 25%, equivalent to an incidence of new-onset occupational asthma of 250-300 cases per million people per year. Occupational exposures account for a substantial proportion of adult asthma incidence. The increased risk of asthma after inhalation accidents suggests that workers who have such accidents should be monitored closely.

Maintenance inhaler preference, attribute importance, and satisfaction in prescribing physicians and patients with asthma, COPD, or asthma–COPD overlap syndrome consulting for routine care

PubMed Central

Ding, Bo; Small, Mark; Scheffel, Gina; Holmgren, Ulf

2018-01-01

Background In respiratory disorders, patient- and physician-perceived satisfaction with the maintenance inhaler device is an important factor driving treatment compliance and outcomes. We examine inhaler preferences in asthma and COPD from patient and physician perspectives, particularly focusing on the relative importance of individual device attributes and patient characteristics guiding inhaler choice. Materials and methods Real-world data from >7,300 patients with asthma, COPD, or asthma–COPD overlap syndrome (ACOS) consulting for routine care were derived from respiratory Disease Specific Programs conducted in Europe, USA, Japan, and China. Outcome variables included current pattern of inhaled maintenance therapy and device type, physician preference, patient-reported device attribute importance, and satisfaction. Results The most commonly prescribed inhalers for maintenance therapy of asthma, COPD, and ACOS were dry powder inhalers (62.8%–88.5% of patients) and pressurized metered dose inhalers (18.9%–35.3% of patients). One-third of physicians stated no preference for maintenance device when prescribing treatment, and less than one-third of patients reported being “extremely satisfied” with any attribute of their device. Instructions being “simple and easy to follow” was the inhaler attribute most commonly selected as important. For approximately one-third of patients across all groups, “ease of use/suitability of inhaler device” was a reason for the prescribing decision, as stated by the physician. Device characteristics were more likely to impact the prescribing decision in older patients (in asthma and COPD; P<0.01) and those with worse disease severity (in COPD; P<0.001). Conclusion A relatively high proportion of physicians had no preference for inhaler type across asthma, COPD, and ACOS. Simplicity of use was the most important inhaler attribute from a patient’s perspective. Physicians appeared to place most importance on ease of use and device suitability when selecting inhalers for older patients and those with more severe disease, particularly in COPD. PMID:29588581

Long-Term Prevalence and Demographic Trends in U.S. Adolescent Inhalant Use: Implications for Clinicians and Prevention Scientists.

PubMed

Halliburton, Amanda Elizabeth; Bray, Bethany Cara

2016-01-01

Inhalant use by adolescents is cause for concern due to the early age of inhalant use initiation and the many short- and long-term health consequences that can occur concurrently with and subsequent to use. However, inhalant use research has been limited relative to the literature available on other drug use. The present research examined long-term trends in inhalant use prevalence, demographic risk factors of inhalant use, and median grade level of first use. Monitoring the Future data from 1991 to 2011, which includes information drawn from United States eighth, tenth, and twelfth graders, were examined. The total sample comprised more than one million participants. Results were examined descriptively with figures and quantitatively with mixed-effects regression models of the effect of time on use rates. Inhalant use prevalence rates generally declined over the selected period. Though rates of use by males and females decreased significantly, the proportion of females among lifetime users increased significantly. Whites, Hispanics, and members of uncategorized "other" ethnicities showed the highest prevalence rates. Although the proportion of Whites among lifetime users decreased significantly, the proportion of Hispanics and "other" ethnicities increased significantly. The median first use was between sixth and ninth grade. Results suggest a need to tailor inhalant use treatment and prevention programs to the needs of specific demographic groups and to target interventions early to prevent youth inhalant use. Strengths, limitations, and directions for future research are discussed.

Prediction of acute inhalation toxicity using in vitro lung surfactant inhibition.

PubMed

Sørli, Jorid B; Huang, Yishi; Da Silva, Emilie; Hansen, Jitka S; Zuo, Yi Y; Frederiksen, Marie; Nørgaard, Asger W; Ebbehøj, Niels E; Larsen, Søren T; Hougaard, Karin S

2018-01-01

Private consumers and professionals may experience acute inhalation toxicity after inhaling aerosolized impregnation products. The distinction between toxic and non-toxic products is difficult to make for producers and product users alike, as there is no clearly described relationship between the chemical composition of the products and induction of toxicity. The currently accepted method for determination of acute inhalation toxicity is based on experiments on animals; it is time-consuming, expensive and causes stress for the animals. Impregnation products are present on the market in large numbers and amounts and exhibit great variety. Therefore, an alternative method to screen for acute inhalation toxicity is needed. The aim of our study was to determine if inhibition of lung surfactant by impregnation products in vitro could accurately predict toxicity in vivo in mice. We tested 21 impregnation products using the constant flow through set-up of the constrained drop surfactometer to determine if the products inhibited surfactant function or not. The same products were tested in a mouse inhalation bioassay to determine their toxicity in vivo. The sensitivity was 100%, i.e., the in vitro method predicted all the products that were toxic for mice to inhale. The specificity of the in vitro test was 63%, i.e., the in vitro method found three false positives in the 21 tested products. Six of the products had been involved in accidental human inhalation where they caused acute inhalation toxicity. All of these six products inhibited lung surfactant function in vitro and were toxic to mice.

Budesonide suppresses pulmonary antibacterial host defense by down-regulating cathelicidin-related antimicrobial peptide in allergic inflammation mice and in lung epithelial cells

PubMed Central

2013-01-01

Background Glucocorticoids are widely regarded as the most effective treatment for asthma. However, the direct impact of glucocorticoids on the innate immune system and antibacterial host defense during asthma remain unclear. Understanding the mechanisms underlying this process is critical to the clinical application of glucocorticoids for asthma therapy. After sensitization and challenge with ovalbumin (OVA), BALB/c mice were treated with inhaled budesonide and infected with Pseudomonas aeruginosa (P. aeruginosa). The number of viable bacteria in enflamed lungs was evaluated, and levels of interleukin-4 (IL-4) and interferon-γ (IFN-γ) in serum were measured. A lung epithelial cell line was pretreated with budesonide. Levels of cathelicidin-related antimicrobial peptide (CRAMP) were measured by immunohistochemistry and western blot analysis. Intracellular bacteria were observed in lung epithelial cells. Results Inhaled budesonide enhanced lung infection in allergic mice exposed to P. aeruginosa and increased the number of viable bacteria in lung tissue. Higher levels of IL-4 and lower levels of IFN-γ were observed in the serum. Budesonide decreased the expression of CRAMP, increased the number of internalized P. aeruginosa in OVA-challenged mice and in lung epithelial cell lines. These data indicate that inhaled budesonide can suppress pulmonary antibacterial host defense by down-regulating CRAMP in allergic inflammation mice and in cells in vitro. Conclusions Inhaled budesonide suppressed pulmonary antibacterial host defense in an asthmatic mouse model and in lung epithelium cells in vitro. This effect was dependent on the down-regulation of CRAMP. PMID:23387852

Exposure to particulate hexavalent chromium exacerbates allergic asthma pathology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schneider, Brent C.; Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037; Constant, Stephanie L.

Airborne hexavalent chromate, Cr(VI), has been identified by the Environmental Protection Agency as a possible health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate chromates are produced in many different industrial settings, with high levels of aerosolized forms historically documented. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in workers exposed to certain inhaled particulate Cr(VI) compounds. However, a direct causal association between Cr(VI) and allergic asthma has not been established. We recently showed that inhaled particulate Cr(VI) induces an innate neutrophilic inflammatory responsemore » in BALB/c mice. In the current studies we investigated how the inflammation induced by inhaled particulate Cr(VI) might alter the pathology of an allergic asthmatic response. We used a well-established mouse model of allergic asthma. Groups of ovalbumin protein (OVA)-primed mice were challenged either with OVA alone, or with a combination of OVA and particulate zinc chromate, and various parameters associated with asthmatic responses were measured. Co-exposure to particulate Cr(VI) and OVA mediated a mixed form of asthma in which both eosinophils and neutrophils are present in airways, tissue pathology is markedly exacerbated, and airway hyperresponsiveness is significantly increased. Taken together these findings suggest that inhalation of particulate forms of Cr(VI) may augment the severity of ongoing allergic asthma, as well as alter its phenotype. Such findings may have implications for asthmatics in settings in which airborne particulate Cr(VI) compounds are present at high levels. -- Highlights: ► Allergic asthma correlated with exposure to certain inhaled particulate chromates. ► Direct causal association between Cr(VI) and allergic asthma not established. ► Cr exacerbated pathology and airway hyperresponsiveness in an OVA-challenged mouse. ► Particulate Cr(VI) may augment severity and alter phenotype of ongoing allergic asthma.« less

Inhalational botulism in rhesus macaques exposed to botulinum neurotoxin complex serotypes A1 and B1.

PubMed

Sanford, Daniel C; Barnewall, Roy E; Vassar, Michelle L; Niemuth, Nancy; Metcalfe, Karen; House, Robert V; Henderson, Ian; Shearer, Jeffry D

2010-09-01

A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD(50)) and to estimate 50% lethal exposure concentrations relative to time (LCt(50)) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD(50) and LCt(50) for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication.

Inhalational Botulism in Rhesus Macaques Exposed to Botulinum Neurotoxin Complex Serotypes A1 and B1▿ †

PubMed Central

Sanford, Daniel C.; Barnewall, Roy E.; Vassar, Michelle L.; Niemuth, Nancy; Metcalfe, Karen; House, Robert V.; Henderson, Ian; Shearer, Jeffry D.

2010-01-01

A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD50) and to estimate 50% lethal exposure concentrations relative to time (LCt50) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD50 and LCt50 for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication. PMID:20660138

Enhanced neutrophil chemotactic activity after bronchial challenge in subjects with grain dust-induced asthma.

PubMed

Park, H S; Jung, K S

1998-03-01

There have been few reports suggesting involvement of neutrophils in induction of bronchoconstriction after inhalation of grain dust. To understand the role of neutrophils in pathogenesis of grain dust-induced asthma. We observed serum neutrophil chemotactic activity during grain dust-bronchoprovocation tests in six asthmatic subjects with positive bronchial challenges (group I). They were compared with those of six symptomatic subjects from the same workplace with negative bronchial challenges (group II). After grain dust inhalation, serum neutrophil chemotactic activity significantly increased at 30 minutes (P = .028), and then decreased to baseline level at 240 minutes (P = .028) in five subjects of group I having isolated early asthmatic responses. Enhanced neutrophil chemotactic activity was persistent for up to 240 minutes in one asthmatic subject having both early and late asthmatic responses. There was, however, no significant change in serum neutrophil chemotactic activity during bronchial challenges in subjects of group II. Pre-incubation of sera with anti-interleukin-8 (IL-8) antibody did not affect the neutrophil chemotactic activity results of group I subjects. These results suggest that enhanced neutrophil chemotactic activity distinct from IL-8 may contribute to significant bronchoconstriction induced by grain dust.

Alterations in vasodilator-stimulated phosphoprotein (VASP) phosphorylation: associations with asthmatic phenotype, airway inflammation and β2-agonist use

PubMed Central

Hastie, Annette T; Wu, Min; Foster, Gayle C; Hawkins, Gregory A; Batra, Vikas; Rybinski, Katherine A; Cirelli, Rosemary; Zangrilli, James G; Peters, Stephen P

2006-01-01

Background Vasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP via cAMP and cGMP dependent protein kinases releases this "brake" on cell motility. Thus, phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation. Two hypotheses were examined: (1) injury from segmental allergen challenge increases VASP phosphorylation in airway epithelium in asthmatic but not nonasthmatic normal subjects, (2) regular in vivo β2-agonist use increases VASP phosphorylation in asthmatic epithelium, altering cell adhesion. Methods Bronchial epithelium was obtained from asthmatic and non-asthmatic normal subjects before and after segmental allergen challenge, and after regularly inhaled albuterol, in three separate protocols. VASP phosphorylation was examined in Western blots of epithelial samples. DNA was obtained for β2-adrenergic receptor haplotype determination. Results Although VASP phosphorylation increased, it was not significantly greater after allergen challenge in asthmatics or normals. However, VASP phosphorylation in epithelium of nonasthmatic normal subjects was double that observed in asthmatic subjects, both at baseline and after challenge. Regularly inhaled albuterol significantly increased VASP phosphorylation in asthmatic subjects in both unchallenged and antigen challenged lung segment epithelium. There was also a significant increase in epithelial cells in the bronchoalveolar lavage of the unchallenged lung segment after regular inhalation of albuterol but not of placebo. The haplotypes of the β2-adrenergic receptor did not appear to associate with increased or decreased phosphorylation of VASP. Conclusion Decreased VASP phosphorylation was observed in epithelial cells of asthmatics compared to nonasthmatic normals, despite response to β-agonist. The decreased phosphorylation does not appear to be associated with a particular β2-adrenergic receptor haplotype. The observed decrease in VASP phosphorylation suggests greater inhibition of actin reorganization which is necessary for altering attachment and migration required during epithelial repair. PMID:16480498

Alterations in vasodilator-stimulated phosphoprotein (VASP) phosphorylation: associations with asthmatic phenotype, airway inflammation and beta2-agonist use.

PubMed

Hastie, Annette T; Wu, Min; Foster, Gayle C; Hawkins, Gregory A; Batra, Vikas; Rybinski, Katherine A; Cirelli, Rosemary; Zangrilli, James G; Peters, Stephen P

2006-02-15

Vasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP via cAMP and cGMP dependent protein kinases releases this "brake" on cell motility. Thus, phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation. Two hypotheses were examined: (1) injury from segmental allergen challenge increases VASP phosphorylation in airway epithelium in asthmatic but not nonasthmatic normal subjects, (2) regular in vivo beta2-agonist use increases VASP phosphorylation in asthmatic epithelium, altering cell adhesion. Bronchial epithelium was obtained from asthmatic and non-asthmatic normal subjects before and after segmental allergen challenge, and after regularly inhaled albuterol, in three separate protocols. VASP phosphorylation was examined in Western blots of epithelial samples. DNA was obtained for beta2-adrenergic receptor haplotype determination. Although VASP phosphorylation increased, it was not significantly greater after allergen challenge in asthmatics or normals. However, VASP phosphorylation in epithelium of nonasthmatic normal subjects was double that observed in asthmatic subjects, both at baseline and after challenge. Regularly inhaled albuterol significantly increased VASP phosphorylation in asthmatic subjects in both unchallenged and antigen challenged lung segment epithelium. There was also a significant increase in epithelial cells in the bronchoalveolar lavage of the unchallenged lung segment after regular inhalation of albuterol but not of placebo. The haplotypes of the beta2-adrenergic receptor did not appear to associate with increased or decreased phosphorylation of VASP. Decreased VASP phosphorylation was observed in epithelial cells of asthmatics compared to nonasthmatic normals, despite response to beta-agonist. The decreased phosphorylation does not appear to be associated with a particular beta2-adrenergic receptor haplotype. The observed decrease in VASP phosphorylation suggests greater inhibition of actin reorganization which is necessary for altering attachment and migration required during epithelial repair.

Comparison of dermal and inhalation routes of entry for organic chemicals

NASA Technical Reports Server (NTRS)

Jepson, Gary W.; Mcdougal, James N.; Clewell, Harvey J., III

1992-01-01

The quantitative comparison of the chemical concentration inside the body as the result of a dermal exposure versus an inhalation exposure is useful for assessing human health risks and deciding on an appropriate protective posture. In order to describe the relationship between dermal and inhalation routes of exposure, a variety of organic chemicals were evaluated. The types of chemicals chosen for the study were halogenated hydrocarbons, aromatic compounds, non-polar hydrocarbons and inhalation anesthetics. Both dermal and inhalation exposures were conducted in rats and the chemicals were in the form of vapors. Prior to the dermal exposure, rat fur was closely clipped and during the exposure rats were provided fresh breathing air through latex masks. Blood samples were taken during 4-hour exposures and analyzed for the chemical of interest. A physiologically based pharmacokinetic model was used to predict permeability constants (cm/hr) consistent with the observed blood concentrations of the chemical. The ratio of dermal exposure to inhalation exposure required to achieve the same internal dose of chemical was calculated for each test chemical. The calculated ratio in humans ranged from 18 for styrene to 1180 for isoflurane. This methodology can be used to estimate the dermal exposure required to reach the internal dose achieved by a specific inhalation exposure. Such extrapolation is important since allowable exposure standards are often set for inhalation exposures, but occupational exposures may be dermal.

An exposure system for measuring nasal and lung uptake of vapors in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dahl, A.R.; Brookins, L.K.; Gerde, P.

1995-12-01

Inhaled gases and vapors often produce biological damage in the nasal cavity and lower respiratory tract. The specific site within the respirator tract at which a gas or vapor is absorbed strongly influences the tissues at risk to potential toxic effects; to predict or to explain tissue or cell specific toxicity of inhaled gases or vapors, the sites at which they are absorbed must be known. The purpose of the work reported here was to develop a system for determining nose and lung absorption of vapors in rats, an animal commonly used in inhalation toxicity studies. In summary, the exposuremore » system described allows us to measure in the rate: (1) nasal absorption and desorption of vapors; (2) net lung uptake of vapors; and (3) the effects of changed breathing parameters on vapor uptake.« less

Effect of novel inhaler technique reminder labels on the retention of inhaler technique skills in asthma: a single-blind randomized controlled trial.

PubMed

Basheti, Iman A; Obeidat, Nathir M; Reddel, Helen K

2017-02-09

Inhaler technique can be corrected with training, but skills drop off quickly without repeated training. The aim of our study was to explore the effect of novel inhaler technique labels on the retention of correct inhaler technique. In this single-blind randomized parallel-group active-controlled study, clinical pharmacists enrolled asthma patients using controller medication by Accuhaler [Diskus] or Turbuhaler. Inhaler technique was assessed using published checklists (score 0-9). Symptom control was assessed by asthma control test. Patients were randomized into active (ACCa; THa) and control (ACCc; THc) groups. All patients received a "Show-and-Tell" inhaler technique counseling service. Active patients also received inhaler labels highlighting their initial errors. Baseline data were available for 95 patients, 68% females, mean age 44.9 (SD 15.2) years. Mean inhaler scores were ACCa:5.3 ± 1.0; THa:4.7 ± 0.9, ACCc:5.5 ± 1.1; THc:4.2 ± 1.0. Asthma was poorly controlled (mean ACT scores ACCa:13.9 ± 4.3; THa:12.1 ± 3.9; ACCc:12.7 ± 3.3; THc:14.3 ± 3.7). After training, all patients had correct technique (score 9/9). After 3 months, there was significantly less decline in inhaler technique scores for active than control groups (mean difference: Accuhaler -1.04 (95% confidence interval -1.92, -0.16, P = 0.022); Turbuhaler -1.61 (-2.63, -0.59, P = 0.003). Symptom control improved significantly, with no significant difference between active and control patients, but active patients used less reliever medication (active 2.19 (SD 1.78) vs. control 3.42 (1.83) puffs/day, P = 0.002). After inhaler training, novel inhaler technique labels improve retention of correct inhaler technique skills with dry powder inhalers. Inhaler technique labels represent a simple, scalable intervention that has the potential to extend the benefit of inhaler training on asthma outcomes. REMINDER LABELS IMPROVE INHALER TECHNIQUE: Personalized labels on asthma inhalers remind patients of correct technique and help improve symptoms over time. Iman Basheti at the Applied Science Private University in Jordan and co-workers trialed the approach of placing patient-specific reminder labels on dry-powder asthma inhalers to improve long-term technique. Poor asthma control is often exacerbated by patients making mistakes when using their inhalers. During the trial, 95 patients received inhaler training before being split into two groups: the control group received no further help, while the other group received individualized labels on their inhalers reminding them of their initial errors. After three months, 67% of patients with reminder labels retained correct technique compared to only 12% of controls. They also required less reliever medication and reported improved symptoms. This represents a simple, cheap way of tackling inhaler technique errors.

"My body breaks. I take solution." Inhalant use in Delhi as pleasure seeking at a cost.

PubMed

Gigengack, Roy

2014-07-01

Inhalant use has existed in India since the 1970s and has increased significantly over the last decades, especially among street-oriented young people. The latter constitute a heterogeneous category: children from street families, children 'of' the street, rag pickers, and part-time street children. There are also inhalant-using schoolchildren and young people in slums. Fieldwork was conducted for 1 year. Team ethnography, multi-sited and comparative research, flexibility of methods and writing field notes were explicit parts of the research design. Most research was undertaken with six groups in four areas of Delhi, exemplifying six generic categories of inhalant-using street-oriented young people. Inhalants in India are branded: Eraz-Ex diluter and whitener, manufactured by Kores, are used throughout Delhi; Omni glue in one specific area. There is a general lack of awareness and societal indifference towards inhalant use, with the exception of the inhalant users themselves, who possess practical knowledge. They conceive of inhalants as nasha, encapsulating the materiality of the substances and the experiential aspects of intoxication and addiction. Fragments of group interviews narrate the sensory appeal of inhalants, and an ethnographic vignette the dynamics of a sniffing session. These inhalant-using street children seek intoxication in a pursuit of pleasure, despite the harm that befalls them as a result. Some find nasha beautiful, notwithstanding the stigmatization, violence and bodily deterioration; others experience it as an overpowering force. A source of attraction and pleasure, inhalants ravage street children's lives. In this mysterious space of lived experience, their self-organization evolves. Distinguishing between hedonic and side effects, addiction helps to understand inhalant use as at once neurobiological, cultural, and involving agency. The implications are that India needs to develop a policy of treatment and employment to deal with the addiction. Copyright © 2014 Elsevier B.V. All rights reserved.

Developments in laboratory diagnostics for isocyanate asthma

PubMed Central

Wisnewski, Adam V.

2011-01-01

Purpose of review Isocyanates, reactive chemicals used to generate polyurethane, are a leading cause of occupational asthma worldwide. Workplace exposure is the best-recognized risk factor for disease development, but is challenging to monitor. Clinical diagnosis and differentiation of isocyanates as the cause of asthma can be difficult. The gold-standard test, specific inhalation challenge, is technically and economically demanding, and is thus only available in a few specialized centers in the world. With the increasing use of isocyanates, efficient laboratory tests for isocyanate asthma and exposure are urgently needed. Recent findings The review focuses on literature published in 2005 and 2006. Over 150 articles, identified by searching PubMed using keywords ‘diphenylmethane’, ‘toluene’ or ‘hexamethylene diisocyanate’, were screened for relevance to isocyanate asthma diagnostics. New advances in understanding isocyanate asthma pathogenesis are described, which help improve conventional radioallergosorbent and enzyme-linked immunosorbent assay approaches for measuring isocyanate-specific IgE and IgG. Newer immunoassays, based on cellular responses and discovery science readouts are also in development. Summary Contemporary laboratory tests that measure isocyanate-specific human IgE and IgG are of utility in diagnosing a subset of workers with isocyanate asthma, and may serve as a biomarker of exposure in a larger proportion of occupationally exposed workers. PMID:17351466

In view of standardization Part 2: Management of challenges in the initial treatment of burn patients in Burn Centers in Germany, Austria and Switzerland.

PubMed

Ziegler, Benjamin; Hirche, Christoph; Horter, Johannes; Kiefer, Jurij; Grützner, Paul Alfred; Kremer, Thomas; Kneser, Ulrich; Münzberg, Matthias

2017-03-01

Initial therapy of severe burns in specialized burn trauma centers is a challenging task faced by the treating multi-professional and interdisciplinary team. A lack of consistent operating procedures and varying structural conditions was recently demonstrated in preliminary data of our group. These results raised the question on how specific treatment measures in acute burn care are met in the absence of standardized guidelines. A specific questionnaire containing 57 multiple-choice questions was sent to all 22 major burn centers in Germany, Austria and Switzerland. The survey included standards of airway management and ventilation, fluid management and circulation, body temperature monitoring and management, topical burn wound treatment and a microbiological surveillance. Additionally, the distribution of standardized course systems was covered. 17 out of 22 questionnaires (77%) were returned completed. Regarding volume resuscitation, results showed a similar approach in estimating initial fluid while discrepancies persisted in the use of colloidal fluid and human albumin. Elective tracheostomy and the need for bronchoscopy with suspected inhalation injury were the most controversial issues revealed by the survey. Topical treatment of burned body surface also followed different principles regarding the use of synthetic epidermal skin substitutes or enzymatic wound debridement. Less discrepancy was found in basic diagnostic measures, body temperature management, estimation of the extent of burns and microbiological surveillance. While many burn-related issues are clearly not questionable and managed in a similar way in most participating facilities, we were able to show that the most contentious issues in burn trauma management involve initial volume resuscitation, management of inhalation trauma and topical burn wound treatment. Further research is required to address these topics and evaluate a potential superiority of a regime in order to increase the level of evidence. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

STATUS REPORT: EVIDENCE BASED ADVANCES IN ...

EPA Pesticide Factsheets

This report summarizes the status of specific inhalation dosimetry procedures for gases as outlined in U.S. EPA’s 1994 Methods for Derivation of Inhalation Reference Concentrations and Applications of Inhalation Dosimetry (U.S. EPA 1994) and reviews recent scientific advances in gas dosimetry related to these procedures. These procedures are used predominately for interspecies extrapolation, typically from laboratory animal inhalation exposures to humans. The specific procedures addressed in this report are those used for the tracheobronchial (TB) and pulmonary (PU) regions of the respiratory tract and the procedure used for the systemic or extrarespiratory (ER) region. In addition, this report presents, reviews and discusses information and data on inhalation dosimetry in children and the adequacy of the procedures in the RfC Methods with regard to children. For the purposes of this report the scientific literature was searched from 1985 (about 10 years prior to the issuance of RfC Methods) to April 30, 2011. The studies identified in this update addressing overall concepts and approaches for portal-of-entry gas dosimetry in the TB and PU regions of the airways support the principles and procedures in RfC Methods. In some cases these studies suggest and provide examples of further refinement within the existing dosimetry modeling framework of the RfC Methods through development and application of mass transfer coefficients as regional measures of gas up

Characterization of pathogenesis of and immune response to Burkholderia pseudomallei K96243 using both inhalational and intraperitoneal infection models in BALB/c and C57BL/6 mice

PubMed Central

Bearss, Jeremy J.; Hunter, Melissa; Dankmeyer, Jennifer L.; Fritts, Kristen A.; Klimko, Christopher P.; Weaver, Chris H.; Shoe, Jennifer L.; Quirk, Avery V.; Toothman, Ronald G.; Webster, Wendy M.; Fetterer, David P.; Bozue, Joel A.; Worsham, Patricia L.; Welkos, Susan L.; Amemiya, Kei; Cote, Christopher K.

2017-01-01

Burkholderia pseudomallei, the etiologic agent of melioidosis, is a Gram negative bacterium designated as a Tier 1 threat. This bacterium is known to be endemic in Southeast Asia and Northern Australia and can infect humans and animals by several routes. Inhalational melioidosis has been associated with monsoonal rains in endemic areas and is also a significant concern in the biodefense community. There are currently no effective vaccines for B. pseudomallei and antibiotic treatment can be hampered by non-specific symptomology and also the high rate of naturally occurring antibiotic resistant strains. Well-characterized animal models will be essential when selecting novel medical countermeasures for evaluation prior to human clinical trials. Here, we further characterize differences between the responses of BALB/c and C57BL/6 mice when challenged with low doses of a low-passage and well-defined stock of B. pseudomallei K96243 via either intraperitoneal or aerosol routes of exposure. Before challenge, mice were implanted with a transponder to collect body temperature readings, and daily body weights were also recorded. Mice were euthanized on select days for pathological analyses and determination of the bacterial burden in selected tissues (blood, lungs, liver, and spleen). Additionally, spleen homogenate and sera samples were analyzed to better characterize the host immune response after infection with aerosolized bacteria. These clinical, pathological, and immunological data highlighted and confirmed important similarities and differences between these murine models and exposure routes. PMID:28235018

Inhalable Antimicrobials for Treatment of Bacterial Biofilm-Associated Sinusitis in Cystic Fibrosis Patients: Challenges and Drug Delivery Approaches

PubMed Central

Kłodzińska, Sylvia Natalie; Priemel, Petra Alexandra; Rades, Thomas; Mørck Nielsen, Hanne

2016-01-01

Bacterial biofilm-associated chronic sinusitis in cystic fibrosis (CF) patients caused by Pseudomonas aeruginosa infections and the lack of available treatments for such infections constitute a critical aspect of CF disease management. Currently, inhalation therapies to combat P. aeruginosa infections in CF patients are focused mainly on the delivery of antimicrobials to the lower respiratory tract, disregarding the sinuses. However, the sinuses constitute a reservoir for P. aeruginosa growth, leading to re-infection of the lungs, even after clearing an initial lung infection. Eradication of P. aeruginosa from the respiratory tract after a first infection has been shown to delay chronic pulmonary infection with the bacteria for up to two years. The challenges with providing a suitable treatment for bacterial sinusitis include: (i) identifying a suitable antimicrobial compound; (ii) selecting a suitable device to deliver the drug to the sinuses and nasal cavities; and (iii) applying a formulation design, which will mediate delivery of a high dose of the antimicrobial directly to the site of infection. This review highlights currently available inhalable antimicrobial formulations for treatment and management of biofilm infections caused by P. aeruginosa and discusses critical issues related to novel antimicrobial drug formulation design approaches. PMID:27735846

Preference, satisfaction and critical errors with Genuair and Breezhaler inhalers in patients with COPD: a randomised, cross-over, multicentre study

PubMed Central

Pascual, Sergi; Feimer, Jan; De Soyza, Anthony; Sauleda Roig, Jaume; Haughney, John; Padullés, Laura; Seoane, Beatriz; Rekeda, Ludmyla; Ribera, Anna; Chrystyn, Henry

2015-01-01

Background: The specific attributes of inhaler devices can influence patient use, satisfaction and treatment compliance, and may ultimately impact on clinical outcomes in patients with chronic obstructive pulmonary disease (COPD). Aims: To assess patient preference, satisfaction and critical inhaler technique errors with Genuair (a multidose inhaler) and Breezhaler (a single-dose inhaler) after 2 weeks of daily use. Methods: Patients with COPD and moderate to severe airflow obstruction were randomised in a cross-over, open-label, multicentre study to consecutive once-daily inhalations of placebo via Genuair and Breezhaler, in addition to current COPD medication. The primary end point was the proportion of patients who preferred Genuair versus Breezhaler after 2 weeks (Patient Satisfaction and Preference Questionnaire). Other end points included overall satisfaction and correct use of the inhalers after 2 weeks, and willingness to continue with each device. Results: Of the 128 patients enrolled, 127 were included in the safety population (male n=91; mean age 67.6 years). Of the 110 of the 123 patients in the intent-to-treat population who indicated an inhaler preference, statistically significantly more patients preferred Genuair than Breezhaler (72.7 vs. 27.3%; P<0.001). Mean overall satisfaction scores were also greater for Genuair than for Breezhaler (5.9 vs. 5.3, respectively; P<0.001). After 2 weeks, there was no statistically significant difference in the number of patients who made ⩾1 critical inhaler technique error with Breezhaler than with Genuair (7.3 vs. 3.3%, respectively). Conclusions: Patient overall preference and satisfaction was significantly higher with Genuair compared with Breezhaler. The proportion of patients making critical inhaler technique errors was low with Genuair and Breezhaler. PMID:25927321

Computational fluid dynamics (CFD) assisted performance evaluation of the Twincer™ disposable high-dose dry powder inhaler.

PubMed

de Boer, Anne H; Hagedoorn, Paul; Woolhouse, Robert; Wynn, Ed

2012-09-01

To use computational fluid dynamics (CFD) for evaluating and understanding the performance of the high-dose disposable Twincer™ dry powder inhaler, as well as to learn the effect of design modifications on dose entrainment, powder dispersion and retention behaviour. Comparison of predicted flow and particle behaviour from CFD computations with experimental data obtained with cascade impactor and laser diffraction analysis. Inhaler resistance, flow split, particle trajectories and particle residence times can well be predicted with CFD for a multiple classifier based inhaler like the Twincer™. CFD computations showed that the flow split of the Twincer™ is independent of the pressure drop across the inhaler and that the total flow rate can be decreased without affecting the dispersion efficacy or retention behaviour. They also showed that classifier symmetry can be improved by reducing the resistance of one of the classifier bypass channels, which for the current concept does not contribute to the swirl in the classifier chamber. CFD is a highly valuable tool for development and optimisation of dry powder inhalers. CFD can assist adapting the inhaler design to specific physico-chemical properties of the drug formulation with respect to dispersion and retention behaviour. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Effects of inhaled citronella oil and related compounds on rat body weight and brown adipose tissue sympathetic nerve.

PubMed

Batubara, Irmanida; Suparto, Irma H; Sa'diah, Siti; Matsuoka, Ryunosuke; Mitsunaga, Tohru

2015-03-12

Citronella oil is one of the most famous Indonesian essential oils, having a distinctive aroma. As with other essential oils, it is crucial to explore the effects of inhalation of this oil. Therefore, the aim of this research was to elucidate the effects of inhalation of citronella oil and its components isolated from Cymbopogon nardus L. (Poaceae), Indonesian local name: "Sereh Wangi" on the body weight, blood lipid profile, and liver function of rats, as well as on the sympathetic nerve activity and temperature of brown adipose tissue. Sprague-Dawley male adult rats fed with high fat diet (HFD) were made to inhale citronella oil, R-(+)-citronellal, and β-citronellol for five weeks, and the observations were compared to those of HFD rats that were not subjected to inhalation treatment. The results showed that inhalation of β-citronellol decreased feed consumption. As a consequence, the percentage of weight gain decreased compared with that in control group and the blood cholesterol level in the β-citronellol group was significantly lowered. Concentration of liver function enzymes were not significantly different among the groups. In conclusion, inhalation of citronella oil, specifically β-citronellol, decreased body weight by decreasing appetite, without any marked changes in liver enzyme concentrations.

Effect of Ganoderma lucidum on pollen-induced biphasic nasal blockage in a guinea pig model of allergic rhinitis.

PubMed

Mizutani, Nobuaki; Nabe, Takeshi; Shimazu, Masaji; Yoshino, Shin; Kohno, Shigekatsu

2012-03-01

Ganoderma lucidum (GL), an oriental medical mushroom, has been used in Asia for the prevention and treatment of a variety of diseases. However, the effect of GL on allergic rhinitis has not been well defined. The current study describes the inhibitory effect of GL on the biphasic nasal blockage and nasal hyperresponsiveness induced by repeated antigen challenge in a guinea pig model of allergic rhinitis. Intranasally sensitized guinea pigs were repeatedly challenged by inhalation of Japanese cedar pollen once every week. Ganoderma lucidum was orally administered once daily for 8 weeks from the time before the first challenge. The treatment with GL dose-dependently inhibited the early and late phase nasal blockage at the fifth to ninth antigen challenges. Furthermore, nasal hyperresponsiveness to intranasally applied leukotriene D₄ on 2 days after the eighth antigen challenge was also inhibited by the treatment with GL. However, Cry j 1-specific IgE antibody production was not affected by the treatment. In conclusion, we demonstrated that the pollen-induced biphasic nasal blockage and nasal hyperresponsiveness were suppressed by the daily treatment with GL in the guinea pig model of allergic rhinitis. These results suggest that GL may be a useful therapeutic drug for treating patients with allergic rhinitis. Copyright © 2011 John Wiley & Sons, Ltd.

Quantification of atopy, lung function and airway hypersensitivity in adults

PubMed Central

2011-01-01

Background Studies in children have shown that concentration of specific serum IgE (sIgE) and size of skin tests to inhalant allergens better predict wheezing and reduced lung function than the information on presence or absence of atopy. However, very few studies in adults have investigated the relationship of quantitative atopy with lung function and airway hyperresponsiveness (AHR). Objective To determine the association between lung function and AHR and quantitative atopy in a large sample of adults from the UK. Methods FEV1 and FVC (% predicted) were measured using spirometry and airway responsiveness by methacholine challenge (5-breath dosimeter protocol) in 983 subjects (random sample of 800 parents of children enrolled in a population-based birth cohort enriched with 183 patients with physician-diagnosed asthma). Atopic status was assessed by skin prick tests (SPT) and measurement of sIgE (common inhalant allergens). We also measured indoor allergen exposure in subjects' homes. Results Spirometry was completed by 792 subjects and 626 underwent methacholine challenge, with 100 (16.0%) having AHR (dose-response slope>25). Using sIgE as a continuous variable in a multiple linear regression analysis, we found that increasing levels of sIgE to mite, cat and dog were significantly associated with lower FEV1 (mite p = 0.001, cat p = 0.0001, dog p = 2.95 × 10-8). Similar findings were observed when using the size of wheal on skin testing as a continuous variable, with significantly poorer lung function with increasing skin test size (mite p = 8.23 × 10-8, cat p = 3.93 × 10-10, dog p = 3.03 × 10-15, grass p = 2.95 × 10-9). The association between quantitative atopy with lung function and AHR remained unchanged when we repeated the analyses amongst subjects defined as sensitised using standard definitions (sIgE>0.35 kUa/l, SPT-3 mm>negative control). Conclusions In the studied population, lung function decreased and AHR increased with increasing sIgE levels or SPT wheal diameter to inhalant allergens, suggesting that atopy may not be a dichotomous outcome influencing lung function and AHR. PMID:22410099

A study of myocardial perfusion in patients with panic disorder and low risk coronary artery disease after 35% CO2 challenge.

PubMed

Fleet, Richard; Foldes-Busque, Guillaume; Grégoire, Jean; Harel, François; Laurin, Catherine; Burelle, Denis; Lavoie, Kim

2014-01-01

We have previously reported that 35% CO2 challenge induced myocardial ischemia in 81% of coronary artery disease (CAD) patients with comorbid panic disorder (PD) and previous positive nuclear exercise stress tests. However, it is yet unclear whether this is the case among CAD patients with PD and normal nuclear exercise stress test results. We hypothesized that a potent mental stressor such as a panic challenge among CAD patients with PD would also induce ischemia in patients with normal exercise stress tests. Forty-one coronary artery disease patients with normal nuclear exercise stress tests (21 patients with PD and 20 without PD) were submitted to a well-established panic challenge test (with 1 vital capacity inhalation of a gas mixture containing 35% CO2 and 65% O2) and injected with Tc-99m-tetrofosmin (Myoview), upon inhalation. Single photon emission computed tomography imaging was used to assess per-panic challenge reversible myocardial ischemia and HR, BP, and a 12 lead ECG was continuously measured during the procedure. Fifty-eight percent of panic disorder patients (12/21) had a panic attack during the panic challenge vs 15% (3/20) of controls (p=0.005). Only 10% of patients in each group displayed myocardial ischemia per panic challenge. These findings suggest that panic attacks among panic disorder patients with lower-risk coronary artery disease may not confer a risk for myocardial ischemia. © 2013.

WORKER INHALATION DOSE COEFFICIENTS FOR RADIONUCLIDES NOT PREVIOUSLY IDENTIFIED IN ICRP PUBLICATION 68

DOE Office of Scientific and Technical Information (OSTI.GOV)

McLaughlin, David A; Schwahn, Scott O

2011-01-01

While inhalation dose coefficients are provided for about 800 radionuclides in International Commission on Radiological Protection (ICRP) Publication 68, many radionuclides of practical dosimetric interest for facilities such as high-energy proton accelerators are not specifically addressed, nor are organ-specific dose coefficients tabulated. The ICRP Publication 68 methodology is used, along with updated radiological decay data and metabolic data, to identify committed equivalent dose coefficients [hT(50)] and committed effective dose coefficients [e(50)] for radionuclides produced at the Oak Ridge National Laboratory s Spallation Neutron Source.

Real-time PCR detection of toxigenic Fusarium in airborne and settled grain dust and associations with trichothecene mycotoxins.

PubMed

Halstensen, Anne Straumfors; Nordby, Karl-Christian; Eduard, Wijnand; Klemsdal, Sonja Sletner

2006-12-01

Inhalation of immunomodulating mycotoxins produced by Fusarium spp. that are commonly found in grain dust may imply health risks for grain farmers. Airborne Fusarium and mycotoxin exposure levels are mainly unknown due to difficulties in identifying Fusarium and mycotoxins in personal aerosol samples. We used a novel real-time PCR method to quantify the fungal trichodiene synthase gene (tri5) and DNA specific to F. langsethiae and F. avenaceum in airborne and settled grain dust, determined the personal inhalant exposure level to toxigenic Fusarium during various activities, and evaluated whether quantitative measurements of Fusarium-DNA could predict trichothecene levels in grain dust. Airborne Fusarium-DNA was detected in personal samples even from short tasks (10-60 min). The median Fusarium-DNA level was significantly higher in settled than in airborne grain dust (p < 0.001), and only the F. langsethiae-DNA levels correlated significantly in settled and airborne dust (r(s) = 0.20, p = 0.003). Both F. langsethiae-DNA and tri5-DNA were associated with HT-2 and T-2 toxins (r(s) = 0.24-0.71, p < 0.05 to p < 00.01) in settled dust, and could thus be suitable as indicators for HT-2 and T-2. The median personal inhalant exposure to specific toxigenic Fusarium spp. was less than 1 genome m(-3), but the exposure ranged from 0-10(5) genomes m(-3). This study is the first to apply real-time PCR on personal samples of inhalable grain dust for the quantification of tri5 and species-specific Fusarium-DNA, which may have potential for risk assessments of inhaled trichothecenes.

Flight assessment in patients with respiratory disease: hypoxic challenge testing vs. predictive equations.

PubMed

Martin, S E; Bradley, J M; Buick, J B; Bradbury, I; Elborn, J S

2007-06-01

Predictive equations have been proposed as a simpler alternative to hypoxic challenge testing (HCT) for determining the risk of in-flight hypoxia. To assess agreement between hypoxic challenge testing (HCT) and predictive equations for assessment of in-flight hypoxia. Retrospective study. Patients with chronic obstructive pulmonary disease (COPD) (n = 15), interstitial lung disease (ILD) (n = 15) and cystic fibrosis (CF) (n = 15) were studied. Spirometry was recorded prior to hypoxic inhalation and oxygen saturations (SpO2) were recorded before, after and during hypoxic inhalation. Blood gases were analysed before and after hypoxic inhalation and when SpO2 = 85%. An HCT was performed using the Ventimask method. The PaO2 at altitude was estimated for each group using four published predictive equations, which use values of PaO2 (ground) and lung function measurements to predict altitude PaO2. Results were interpreted using the BTS recommendations for prescription of in-flight oxygen post HCT. The Stuart Maxwell test of overall homogeneity was used to assess agreement between HCT results and each of the predictive equations. Ground PaO2 was significantly greater in patients with CF than either ILD or COPD (p < 0.05). PaO2 in all three groups significantly decreased following HCT. With the exception of equation 3, significantly fewer patients in each group would require in-flight O2 if prescription was based on HCT, compared to predictive equations (p < 0.05). Predictive equations considerably overestimate the need for in-flight O2, compared to HCT.

Development and evaluation of an innovative model of inter-professional education focused on asthma medication use

PubMed Central

2014-01-01

Background Inter-professional learning has been promoted as the solution to many clinical management issues. One such issue is the correct use of asthma inhaler devices. Up to 80% of people with asthma use their inhaler device incorrectly. The implications of this are poor asthma control and quality of life. Correct inhaler technique can be taught, however these educational instructions need to be repeated if correct technique is to be maintained. It is important to maximise the opportunities to deliver this education in primary care. In light of this, it is important to explore how health care providers, in particular pharmacists and general medical practitioners, can work together in delivering inhaler technique education to patients, over time. Therefore, there is a need to develop and evaluate effective inter-professional education, which will address the need to educate patients in the correct use of their inhalers as well as equip health care professionals with skills to engage in collaborative relationships with each other. Methods This mixed methods study involves the development and evaluation of three modules of continuing education, Model 1, Model 2 and Model 3. A fourth group, Model 4, acting as a control. Model 1 consists of face-to-face continuing professional education on asthma inhaler technique, aimed at pharmacists, general medical practitioners and their practice nurses. Model 2 is an electronic online continuing education module based on Model 1 principles. Model 3 is also based on asthma inhaler technique education but employs a learning intervention targeting health care professional relationships and is based on sociocultural theory. This study took the form of a parallel group, repeated measure design. Following the completion of continuing professional education, health care professionals recruited people with asthma and followed them up for 6 months. During this period, inhaler device technique training was delivered and data on patient inhaler technique, clinical and humanistic outcomes were collected. Outcomes related to professional collaborative relationships were also measured. Discussion Challenges presented included the requirement of significant financial resources for development of study materials and limited availability of validated tools to measure health care professional collaboration over time. PMID:24708800

Development and evaluation of an innovative model of inter-professional education focused on asthma medication use.

PubMed

Bosnic-Anticevich, Sinthia Z; Stuart, Meg; Mackson, Judith; Cvetkovski, Biljana; Sainsbury, Erica; Armour, Carol; Mavritsakis, Sofia; Mendrela, Gosia; Travers-Mason, Pippa; Williamson, Margaret

2014-04-07

Inter-professional learning has been promoted as the solution to many clinical management issues. One such issue is the correct use of asthma inhaler devices. Up to 80% of people with asthma use their inhaler device incorrectly. The implications of this are poor asthma control and quality of life. Correct inhaler technique can be taught, however these educational instructions need to be repeated if correct technique is to be maintained. It is important to maximise the opportunities to deliver this education in primary care. In light of this, it is important to explore how health care providers, in particular pharmacists and general medical practitioners, can work together in delivering inhaler technique education to patients, over time. Therefore, there is a need to develop and evaluate effective inter-professional education, which will address the need to educate patients in the correct use of their inhalers as well as equip health care professionals with skills to engage in collaborative relationships with each other. This mixed methods study involves the development and evaluation of three modules of continuing education, Model 1, Model 2 and Model 3. A fourth group, Model 4, acting as a control.Model 1 consists of face-to-face continuing professional education on asthma inhaler technique, aimed at pharmacists, general medical practitioners and their practice nurses.Model 2 is an electronic online continuing education module based on Model 1 principles.Model 3 is also based on asthma inhaler technique education but employs a learning intervention targeting health care professional relationships and is based on sociocultural theory.This study took the form of a parallel group, repeated measure design. Following the completion of continuing professional education, health care professionals recruited people with asthma and followed them up for 6 months. During this period, inhaler device technique training was delivered and data on patient inhaler technique, clinical and humanistic outcomes were collected. Outcomes related to professional collaborative relationships were also measured. Challenges presented included the requirement of significant financial resources for development of study materials and limited availability of validated tools to measure health care professional collaboration over time.

Asthma caused by potassium aluminium tetrafluoride: a case series.

PubMed

Laštovková, Andrea; Klusáčková, Pavlina; Fenclová, Zdenka; Bonneterre, Vincent; Pelclová, Daniela

2015-01-01

The objective of this study is to describe a case-series of potassium aluminium tetrafluoride (KAlF(4))-induced occupational asthma (OA) and/or occupational rhinitis (OR). The study involves five patients from a heat-exchanger production line who were examined (including specific inhalation challenge tests) for suspected OA and/or OR caused by a flux containing almost 100% KAlF(4) - with fluorides' workplace air concentrations ranging between 1.7 and 2.8 mg/m(3). No subject had a previous history of asthma. All five patients had a positive specific challenge test (three patients were diagnosed with OA alone, one with OR and one with both OR and OA). At the follow-up visit, after three years on average, all patients needed permanent corticosteroid therapy (four topical, one oral). After elimination from the exposure, only one of the observed subjects gave an indication of an improvement, two subjects stabilized and two worsened. Our case series focuses on the correlation between patients' exposure to fluorides in air-conditioner production and the subsequent occurrence of OR/OA. Currently, it is uncertain whether these OR/OA were caused by hypersensitivity or irritation.

Asthma caused by potassium aluminium tetrafluoride: a case series

PubMed Central

LAŠTOVKOVÁ, Andrea; KLUSÁČKOVÁ, Pavlina; FENCLOVÁ, Zdenka; BONNETERRE, Vincent; PELCLOVÁ, Daniela

2015-01-01

The objective of this study is to describe a case-series of potassium aluminium tetrafluoride (KAlF4)-induced occupational asthma (OA) and/or occupational rhinitis (OR). The study involves five patients from a heat-exchanger production line who were examined (including specific inhalation challenge tests) for suspected OA and/or OR caused by a flux containing almost 100% KAlF4 − with fluorides’ workplace air concentrations ranging between 1.7 and 2.8 mg/m3. No subject had a previous history of asthma. All five patients had a positive specific challenge test (three patients were diagnosed with OA alone, one with OR and one with both OR and OA). At the follow-up visit, after three years on average, all patients needed permanent corticosteroid therapy (four topical, one oral). After elimination from the exposure, only one of the observed subjects gave an indication of an improvement, two subjects stabilized and two worsened. Our case series focuses on the correlation between patients’ exposure to fluorides in air-conditioner production and the subsequent occurrence of OR/OA. Currently, it is uncertain whether these OR/OA were caused by hypersensitivity or irritation. PMID:26212411

IRIS Toxicological Review of Ammonia Noncancer Inhalation ...

EPA Pesticide Factsheets

EPA has finalized the Integrated Risk Information System (IRIS) Assessment of Ammonia (Noncancer Inhalation). This assessment addresses the potential noncancer human health effects from long-term inhalation exposure to ammonia. Now final, this assessment will update the current toxicological information on ammonia posted in 1991. EPA’s program and regional offices may use this assessment to inform decisions to protect human health. EPA completed the Integrated Risk Information System (IRIS) health assessment for ammonia. IRIS is an EPA database containing Agency scientific positions on potential adverse human health effects that may result from chronic (or lifetime) exposure to chemicals in the environment. IRIS contains chemical-specific summaries of qualitative and quantitative health information in support of two steps of the risk assessment paradigm, i.e., hazard identification and dose-response evaluation. IRIS assessments are used in combination with specific situational exposure assessment information to evaluate potential public health risk associated with environmental contaminants.

Inhaled glycopyrrolate for the treatment of chronic obstructive pulmonary disease.

PubMed

Tashkin, Donald P; Gross, Nicholas J

2018-01-01

Long-acting muscarinic antagonists (LAMAs), along with long-acting β 2 -agonists (LABAs), are the mainstay for treatment of patients with COPD. Glycopyrrolate, or glycopyrronium bromide, like other LAMAs, inhibits parasympathetic nerve impulses by selectively blocking the binding of acetylcholine to muscarinic receptors. Glycopyrrolate is unusual in that it preferentially binds to M 3 over M 2 muscarinic receptors, thereby specifically targeting the primary muscarinic receptor responsible for bronchoconstriction occurring in COPD. Inhaled glycopyrrolate is slowly absorbed from the lungs and rapidly eliminated from the bloodstream, most likely by renal excretion in its unmetabolized form, limiting the potential for systemic adverse events. Inhaled glycopyrrolate is a fast-acting, efficacious treatment option for patients with moderate-severe COPD. It improves lung function, reduces the risk of exacerbations, and alleviates the symptoms of breathlessness, which in turn may explain the improvement seen in patients' quality of life. Inhaled formulations containing glycopyrrolate are well tolerated, and despite being an anticholinergic, few cardiovascular-related events have been reported. Inhaled glycopyrrolate is thus of value as both monotherapy and in combination with other classes of medication for maintenance treatment of COPD. This review covers the mechanism of action of inhaled glycopyrrolate, including its pharmacokinetic, pharmacodynamic, and safety profiles, and effects on mucus secretion. It also discusses the use of inhaled glycopyrrolate in the treatment of COPD, as monotherapy and in fixed-dose combinations with LABAs and inhaled corticosteroid-LABAs, including a triple therapy recently approved in Europe.

An Acoustic-Based Method to Detect and Quantify the Effect of Exhalation into a Dry Powder Inhaler.

PubMed

Holmes, Martin S; Seheult, Jansen N; O'Connell, Peter; D'Arcy, Shona; Ehrhardt, Carsten; Healy, Anne Marie; Costello, Richard W; Reilly, Richard B

2015-08-01

Dry powder inhaler (DPI) users frequently exhale into their inhaler mouthpiece before the inhalation step. This error in technique compromises the integrity of the drug and results in poor bronchodilation. This study investigated the effect of four exhalation factors (exhalation flow rate, distance from mouth to inhaler, exhalation duration, and relative air humidity) on dry powder dose delivery. Given that acoustic energy can be related to the factors associated with exhalation sounds, we then aimed to develop a method of identifying and quantifying this critical inhaler technique error using acoustic based methods. An in vitro test rig was developed to simulate this critical error. The effect of the four factors on subsequent drug delivery were investigated using multivariate regression models. In a further study we then used an acoustic monitoring device to unobtrusively record the sounds 22 asthmatic patients made whilst using a Diskus(™) DPI. Acoustic energy was employed to automatically detect and analyze exhalation events in the audio files. All exhalation factors had a statistically significant effect on drug delivery (p<0.05); distance from the inhaler mouthpiece had the largest effect size. Humid air exhalations were found to reduce the fine particle fraction (FPF) compared to dry air. In a dataset of 110 audio files from 22 asthmatic patients, the acoustic method detected exhalations with an accuracy of 89.1%. We were able to classify exhalations occurring 5 cm or less in the direction of the inhaler mouthpiece or recording device with a sensitivity of 72.2% and specificity of 85.7%. Exhaling into a DPI has a significant detrimental effect. Acoustic based methods can be employed to objectively detect and analyze exhalations during inhaler use, thus providing a method of remotely monitoring inhaler technique and providing personalized inhaler technique feedback.

Misconceptions regarding the pathogenicity of silicas and silicates.

PubMed

Feigin, D S

1989-01-01

Several inhaled substances, from occupational or other environmental exposure, produce significant pulmonary disease and abnormalities demonstrated by pulmonary imaging. Areas of controversy and misconception relate principally to the extent and nature of both the clinical disease and the imaging abnormalities specific to each substance. The size and shape of the inhaled particles is an important determinant of the nature and severity of the disease produced, with fibrous shapes usually being the most pathogenetic. Fibrogenicity is another important pathogenetic characteristic of talc and kaolin, as well as asbestos. Talc produces four distinct forms of pulmonary disease, depending not only on the other substances with which it is inhaled, but also whether it is inhaled or injected intravenously. When inhaled alone, talc does not appear to produce significant pulmonary fibrosis or malignancy. Kaolin, mica, fuller's earth, zeolite, and fiberglass all vary in disease production according to their shape and fibrogenicity. Silica, diatomaceous earth, and other forms of silica are all highly fibrogenic and thus produce clinically obvious disease with sufficient inhalation. The largest particles usually produce nodular patterns in the upper pulmonary fields, as is typical of silicosis. The fibrous particles are more likely to manifest themselves as interstitial patterns in the lower pulmonary fields.

Inhaler technique: facts and fantasies. A view from the Aerosol Drug Management Improvement Team (ADMIT).

PubMed

Levy, Mark L; Dekhuijzen, P N R; Barnes, P J; Broeders, M; Corrigan, C J; Chawes, B L; Corbetta, L; Dubus, J C; Hausen, Th; Lavorini, F; Roche, N; Sanchis, J; Usmani, Omar S; Viejo, J; Vincken, W; Voshaar, Th; Crompton, G K; Pedersen, Soren

2016-04-21

Health professionals tasked with advising patients with asthma and chronic obstructive pulmonary disease (COPD) how to use inhaler devices properly and what to do about unwanted effects will be aware of a variety of commonly held precepts. The evidence for many of these is, however, lacking or old and therefore in need of re-examination. Few would disagree that facilitating and encouraging regular and proper use of inhaler devices for the treatment of asthma and COPD is critical for successful outcomes. It seems logical that the abandonment of unnecessary or ill-founded practices forms an integral part of this process: the use of inhalers is bewildering enough, particularly with regular introduction of new drugs, devices and ancillary equipment, without unnecessary and pointless adages. We review the evidence, or lack thereof, underlying ten items of inhaler 'lore' commonly passed on by health professionals to each other and thence to patients. The exercise is intended as a pragmatic, evidence-informed review by a group of clinicians with appropriate experience. It is not intended to be an exhaustive review of the literature; rather, we aim to stimulate debate, and to encourage researchers to challenge some of these ideas and to provide new, updated evidence on which to base relevant, meaningful advice in the future. The discussion on each item is followed by a formal, expert opinion by members of the ADMIT Working Group.

Effects of inhalable microparticle of flower of Lonicera japonica in a mouse model of COPD.

PubMed

Park, Yang-Chun; Jin, Mirim; Kim, Seung-Hyung; Kim, Min-Hee; Namgung, Uk; Yeo, Yoon

2014-01-01

Flower of Lonicera japonica (FLJ) is a traditional herbal medicine widely used in East Asia as an anti-inflammatory and anti-oxidative agent. The purpose of this study is to develop an inhalable powder formulation of FLJ and to evaluate its biological effects in a mouse model of chronic obstructive pulmonary disease (COPD). Inhalable dry powder containing FLJ was produced by spray-drying with leucine as an excipient. Its aerodynamic properties and anti-inflammatory activities were evaluated using the Anderson cascade impactor (ACI) and a mouse model of COPD, respectively. FLJ microparticle (FLJmp) had a hollow spherical shape in electron microscopy and showed aerodynamic properties suitable for inhalation (fine particle fraction of 54.0 ± 4.68% and mass median aerodynamic diameter of 4.6 ± 0.34μm). FLJmp decreased TNF-α and IL-6 expression in RAW264.7 cells activated by lipopolysaccharide (LPS). In mice challenged with LPS and cigarette smoke solution (CSS) to develop COPD, FLJmp decreased the levels of TNF-α and IL-6 in bronchoalveolar fluidas well as the number of inflammatory cells including neutrophils in peripheral blood. In addition, FLJmp induced recovery of elastin and collagen distribution, reduction of caspase-3 expression in lung tissues of COPD mice. Inhalational delivery of FLJ using a microparticle system is a promising strategy for the treatment of COPD. © 2013 Elsevier Ireland Ltd. All rights reserved.

Physiological and affective reactivity to a 35% CO₂ inhalation challenge in individuals differing in the 5-HTTLPR genotype and trait neuroticism.

PubMed

Verschoor, Ellen; Markus, C Rob

2012-08-01

The inhalation of 35% carbon dioxide (CO₂) results in an acute stress response in healthy individuals and may accordingly provide a good paradigm to examine potential vulnerability factors for stress reactivity and stress-related psychopathology. It has been proposed that CO₂ reactivity is moderated by genetic (5-HTTLPR) and personality (neuroticism) factors, yet no experimental study has investigated their effects on CO₂ reactivity simultaneously. The current study examined the singular and interactive effects of the 5-HTTLPR genotype and neuroticism in predicting the affective and physiological response to a 35% CO₂ challenge in a healthy sample of male and female students. From a large group of 771 students, 48 carriers of the low/low expressing allele (S/S, S/Lg, Lg/Lg) and 48 carriers of the high/high expressing allele (La/La) with the lowest and the highest neuroticism scores (77 females, 19 males; mean age ± SD: 20.6 ± 2 years) were selected and underwent a 35% CO₂ inhalation. Visual analogue scales for anxiety and discomfort and the Panic Symptom List were used to assess affective symptomatology, while salivary samples and heart rate were assessed to establish the physiological response. A typical pattern of responses to CO₂ was observed, characterised by increases in anxiogenic symptoms and physical panic symptomatology and a reduction in heart rate; however, no effect on salivary cortisol concentration was observed. Additionally, the CO₂ reactivity did not differ between groups divided by the 5-HTTLPR genotype or neuroticism. Findings of the current study do not support a role for singular or interactive effects of the 5-HTTLPR genotype and trait neuroticism on affective and physiological reactivity to a 35% CO₂ inhalation procedure. Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.

The effect of inhaling a dry powder of sodium chloride on the airways of asthmatic subjects.

PubMed

Anderson, S D; Spring, J; Moore, B; Rodwell, L T; Spalding, N; Gonda, I; Chan, K; Walsh, A; Clark, A R

1997-11-01

Wet aerosols of 4.5% sodium chloride (NaCl) are often used to assess the bronchial responsiveness associated with asthma. We questioned whether dry NaCl could be used as an alternative. Dry powder NaCl was inhaled from capsules containing either 5, 10, 20 or 40 mg to a cumulative dose of 635 mg. The powder was delivered via an Inhalator or Halermatic. The airway sensitivity to the dry and wet NaCl was compared in 24 patients with asthma aged 19-39 yrs. All subjects responded to both preparations and the geometric mean (95% confidence intervals) for the provocative dose of NaCl causing forced expiratory volume in one second (FEV1) to fall 20% from baseline (PD[20,NaCl]) for dry NaCl was 103 mg (68-157) versus 172 mg (102-292), p<0.03 for the wet NaCl. The response to dry NaCl was reproducible and on repeat challenge the PD20 was 108 mg (75-153). The mean maximum fall in FEV1 was approximately 25% on each of the two test days. Spontaneous recovery occurred within 60 min after challenge with dry NaCl and within 5 min after bronchodilator. There were no serious side-effects requiring medical attention, however some patients coughed on inhalation of the 40 mg dose and three gagged. Arterial oxygen saturation remained within normal limits. We conclude that a suitably prepared dry powder of sodium chloride could potentially replace wet sodium chloride to assess bronchial responsiveness in patients with asthma, but further studies are required to establish the long-term stability of the dry powder preparation.

ALLERGEN PROVOCATION AUGMENTS ENDOTOXIN-INDUCED NASAL INFLAMMATION IN ATOPIC ASTHMATICS

EPA Science Inventory

Background: Recent epidemiologic and in vivo studies have suggested that inhaled endotoxin plays an important role in asthma pathogenesis.
Objective: The present study examines the effect of nasal allergen provocation on subsequent endotoxin challenges in subjects with atopi...

Inhaled Micro/Nanoparticulate Anticancer Drug Formulations: An Emerging Targeted Drug Delivery Strategy for Lung Cancers.

PubMed

Islam, Nazrul; Richard, Derek

2018-05-24

Local delivery of drug to the target organ via inhalation offers enormous benefits in the management of many diseases. Lung cancer is the most common of all cancers and it is the leading cause of death worldwide. Currently available treatment systems (intravenous or oral drug delivery) are not efficient in accumulating the delivered drug into the target tumor cells and are usually associated with various systemic and dose-related adverse effects. The pulmonary drug delivery technology would enable preferential accumulation of drug within the cancer cell and thus be superior to intravenous and oral delivery in reducing cancer cell proliferation and minimising the systemic adverse effects. Site-specific drug delivery via inhalation for the treatment of lung cancer is both feasible and efficient. The inhaled drug delivery system is non-invasive, produces high bioavailability at low dose and avoids first pass metabolism of the delivered drug. Various anticancer drugs including chemotherapeutics, proteins and genes have been investigated for inhalation in lung cancers with significant outcomes. Pulmonary delivery of drugs from dry powder inhaler (DPI) formulation is stable and has high patient compliance. Herein, we report the potential of pulmonary drug delivery from dry powder inhaler (DPI) formulations inhibiting lung cancer cell proliferation at very low dose with reduced unwanted adverse effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Differential behavioral sensitivity to carbon dioxide (CO2) inhalation in rats

PubMed Central

Winter, Andrew; Ahlbrand, Rebecca; Naik, Devanshi; Sah, Renu

2017-01-01

Inhalation of carbon dioxide (CO2) is frequently employed as a biological challenge to evoke intense fear and anxiety. In individuals with panic disorder, CO2 reliably evokes panic attacks. Sensitivity to CO2 is highly heterogeneous among individuals, and although a genetic component is implicated, underlying mechanisms are not clear. Preclinical models that can simulate differential responsivity to CO2 are therefore relevant. In the current study we investigated CO2-evoked behavioral responses in four different rat strains: Sprague-Dawley (SD), Wistar (W), Long Evans (LE) and Wistar-Kyoto, (WK) rats. We also assessed tryptophan hydroxylase 2 (TPH-2)-positive serotonergic neurons in anxiety/panic regulatory subdivisions of the dorsal raphe nucleus (DR), as well as dopamine β hydroxylase (DβH)-positive noradrenergic neurons in the locus coeruleus, implicated in central CO2-chemosensitivity. Behavioral responsivity to CO2 inhalation varied between strains. CO2-evoked immobility was significantly higher in LE and WK rats as compared with W and SD cohorts. Differences were also observed in CO2-evoked rearing and grooming behaviors. Exposure to CO2 did not produce conditioned behavioral responses upon re-exposure to CO2 context in any strain. Reduced TPH-2 positive cell counts were observed specifically in the panic-regulatory dorsal raphe ventrolateral (DRVL)-ventrolateral periaqueductal grey (VLPAG) subdivision in CO2-sensitive strains. Conversely, DβH positive cell counts within the LC were significantly higher in CO2-sensitive strains. Collectively, our data provide evidence for strain dependent, differential CO2-sensitivity and potential differences in monoaminergic systems regulating panic and anxiety. Comparative studies between CO2-vulnerable and resistant strains may facilitate the mechanistic understanding of differential CO2-sensitivity in the development of panic and anxiety disorders. PMID:28087339

Interest of cyclodextrins in spray-dried microparticles formulation for sustained pulmonary delivery of budesonide.

PubMed

Dufour, Gilles; Bigazzi, William; Wong, Nelson; Boschini, Frederic; de Tullio, Pascal; Piel, Geraldine; Cataldo, Didier; Evrard, Brigitte

2015-11-30

To achieve an efficient lung delivery and efficacy, both active ingredient aerosolisation properties and permeability through the lung need to be optimized. To overcome these challenges, the present studies aim to develop cyclodextrin-based spray-dried microparticles containing a therapeutic corticosteroid (budesonide) that could be used to control airway inflammation associated with asthma. The complexation between budesonide and hydroxypropyl-β-cyclodextrin (HPBCD) has been investigated. Production of inhalation powders was carried out using a bi-fluid nozzle spray dryer and was optimized based on a design of experiments. Spray-dried microparticles display a specific "deflated-ball like shape" associated with an appropriate size for inhalation. Aerodynamic assessment show that the fine particle fraction was increased compared to a classical lactose-based budesonide formulation (44.05 vs 26.24%). Moreover, the budesonide permeability out of the lung was shown to be reduced in the presence of cyclodextrin complexes. The interest of this sustained budesonide release was evaluated in a mouse model of asthma. The anti-inflammatory effect was compared to a non-complexed budesonide formulation at the same concentration and attests the higher anti-inflammatory activity reach with the cyclodextrin-based formulation. This strategy could therefore be of particular interest for improving lung targeting while decreasing systemic side effects associated with high doses of corticosteroids. In conclusion, this works reports that cyclodextrins could be used in powder for inhalation, both for their abilities to improve active ingredient aerosolisation properties and further to their dissolution in lung fluid, to decrease permeability out of the lungs leading to an optimized activity profile. Copyright © 2015 Elsevier B.V. All rights reserved.

Preventive and curative effects of radon inhalation on chronic constriction injury-induced neuropathic pain in mice.

PubMed

Yamato, K; Kataoka, T; Nishiyama, Y; Taguchi, T; Yamaoka, K

2013-04-01

Radon therapy is clinically useful for the treatment of pain-related diseases. However, there have been no studies regarding the effects of radon inhalation on neuropathic pain. In this study, we aimed to determine whether radon inhalation actually induced a remission of neuropathic pain and improved the quality of life. First, we investigated the antinociceptive effects of radon inhalation in the chronic constriction injury (CCI) model of neuropathic pain. We evaluated pain behaviour in mice before and after CCI surgery, using von Frey test. Pretreated mice received CCI surgery immediately after 24-h inhalation of radon at background (BG) concentration (c. 19 Bq/m(3) ), or at a concentration of 1000 or 2000 Bq/m(3) , and post-treated mice inhaled similar levels of radon 2 days after CCI surgery. CCI surgery induced mechanical allodynia and hyperalgesia on a plantar surface of mice, as assessed using von Frey test, and 2000 Bq/m(3) radon inhalation alleviated hyperalgesic conditions 22-37% compared to BG level concentration. Concurrently, CCI surgery increased norepinephrine (NE), tumour necrosis factor-alpha (TNF-α) and nitric oxide (NO) concentrations in plasma, and leukocyte migration in paws. Furthermore, CCI-induced neuropathy reduced superoxide dismutase (SOD) activity. Treatment with radon inhalation, specifically at a concentration of 2000 Bq/m(3) , produced antinociceptive effects, i.e., lowered plasma TNF-α, NE and NO levels and restored SOD activity, as well as pain-related behaviour. This study showed that inhalation of 2000 Bq/m(3) radon prevented and alleviated CCI-induced neuropathic pain in mice. © 2012 European Federation of International Association for the Study of Pain Chapters.

History of aerosol therapy: liquid nebulization to MDIs to DPIs.

PubMed

Anderson, Paula J

2005-09-01

Inhaled therapies have been used since ancient times and may have had their origins with the smoking of datura preparations in India 4,000 years ago. In the late 18th and in the 19th century, earthenware inhalers were popular for the inhalation of air drawn through infusions of plants and other ingredients. Atomizers and nebulizers were developed in the mid-1800s in France and were thought to be an outgrowth of the perfume industry as well as a response to the fashion of inhaling thermal waters at spas. Around the turn of the 20th century, combustible powders and cigarettes containing stramonium were popular for asthma and other lung complaints. Following the discovery of the utility of epinephrine for treating asthma, hand-bulb nebulizers were developed, as well as early compressor nebulizers. The marketing of the first pressurized metered-dose inhaler for epinephrine and isoproterenol, by Riker Laboratories in 1956, was a milestone in the development of inhaled drugs. There have been remarkable advances in the technology of devices and formulations for inhaled drugs in the past 50 years. These have been influenced greatly by scientific developments in several areas: theoretical modeling and indirect measures of lung deposition, particle sizing techniques and in vitro deposition studies, scintigraphic deposition studies, pharmacokinetics and pharmacodynamics, and the 1987 Montreal Protocol, which banned chlorofluorocarbon propellants. We are now in an era of rapid technologic progress in inhaled drug delivery and applications of aerosol science, with the use of the aerosolized route for drugs for systemic therapy and for gene replacement therapy, use of aerosolized antimicrobials and immunosuppressants, and interest in specific targeting of inhaled drugs.

The accuracy of burn diagnosis codes in health administrative data: A validation study.

PubMed

Mason, Stephanie A; Nathens, Avery B; Byrne, James P; Fowler, Rob; Gonzalez, Alejandro; Karanicolas, Paul J; Moineddin, Rahim; Jeschke, Marc G

2017-03-01

Health administrative databases may provide rich sources of data for the study of outcomes following burn. We aimed to determine the accuracy of International Classification of Diseases diagnoses codes for burn in a population-based administrative database. Data from a regional burn center's clinical registry of patients admitted between 2006-2013 were linked to administrative databases. Burn total body surface area (TBSA), depth, mechanism, and inhalation injury were compared between the registry and administrative records. The sensitivity, specificity, and positive and negative predictive values were determined, and coding agreement was assessed with the kappa statistic. 1215 burn center patients were linked to administrative records. TBSA codes were highly sensitive and specific for ≥10 and ≥20% TBSA (89/93% sensitive and 95/97% specific), with excellent agreement (κ, 0.85/κ, 0.88). Codes were weakly sensitive (68%) in identifying ≥10% TBSA full-thickness burn, though highly specific (86%) with moderate agreement (κ, 0.46). Codes for inhalation injury had limited sensitivity (43%) but high specificity (99%) with moderate agreement (κ, 0.54). Burn mechanism had excellent coding agreement (κ, 0.84). Administrative data diagnosis codes accurately identify burn by burn size and mechanism, while identification of inhalation injury or full-thickness burns is less sensitive but highly specific. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

Defining thresholds of specific IgE levels to grass pollen and birch pollen allergens improves clinical interpretation.

PubMed

Van Hoeyveld, Erna; Nickmans, Silvie; Ceuppens, Jan L; Bossuyt, Xavier

2015-10-23

Cut-off values and predictive values are used for the clinical interpretation of specific IgE antibody results. However, cut-off levels are not well defined, and predictive values are dependent on the prevalence of disease. The objective of this study was to document clinically relevant diagnostic accuracy of specific IgE for inhalant allergens (grass pollen and birch pollen) based on test result interval-specific likelihood ratios. Likelihood ratios are independent of the prevalence and allow to provide diagnostic accuracy information for test result intervals. In a prospective study we included consecutive adult patients presenting at an allergy clinic with complaints of rhinitis or rhinoconjunctivitis. The standard for diagnosis was a suggestive clinical history of grass or birch pollen allergy and a positive skin test. Specific IgE was determined with the ImmunoCAP Fluorescence Enzyme Immuno-Assay. We established specific IgE test result interval related likelihood ratios for clinical allergy to inhalant allergens (grass pollen, rPhl p 1,5, birch pollen, rBet v 1). The likelihood ratios for allergy increased with increasing specific IgE antibody levels. The likelihood ratio was <0.03 for specific IgE <0.1 kU/L, between 0.1 and 1.4 for specific IgE between 0.1 kU/L and 0.35 kU/L, between 1.4 and 4.2 for specific IgE between 0.35 kU/L and 3.5 kU/L, >6.3 for specific IgE>0.7, and very high (∞) for specific IgE >3.5 kU/L. Test result interval specific likelihood ratios provide a useful tool for the interpretation of specific IgE test results for inhalant allergens. Copyright © 2015 Elsevier B.V. All rights reserved.

Small-molecule anti-inflammatory drug compositions for the treatment of asthma: a patent review (2013 - 2014).

PubMed

Glossop, Paul; Whitlock, Gavin; Gibson, Karl

2015-07-01

Asthma is a chronic condition affecting 235 million people worldwide, with prevalence continuing to increase. A significant number of patients have poorly controlled asthma but despite this, a new mechanistic class of small-molecule asthma therapy has not emerged over the past 15 years. In this article, the authors review the published patent literature from 2013 to 2014 that describes the discovery of novel small-molecule anti-inflammatory agents for the treatment of asthma. This patent analysis was performed using multiple search engines including SciFinder and Free Patents Online. This review highlights that significant research is still directed towards the development of novel anti-inflammatory agents for the treatment of asthma. Current standard-of-care therapies are given topically to the lung via an inhaled dose, which the authors believe can offer significant advantages in terms of efficacy and therapeutic index, compared with an oral dose. Several of the patents reviewed disclose preferred compounds and data that suggest an inhaled approach is being specifically pursued. The patents reviewed target a wide range of inflammatory pathways, although none have yet delivered an approved novel medicine for asthma; this gives an indication of both the opportunity and challenge involved in such an endeavor.

Airway responsiveness to mannitol 24 h after allergen challenge in atopic asthmatics.

PubMed

Davis, B E; Amakye, D O; Cockcroft, D W

2015-06-01

Airway responsiveness to indirect stimuli correlates positively with airway inflammation. In atopic asthmatics, allergen inhalation is associated with an influx of inflammatory cells and increased responsiveness to the direct-acting stimuli methacholine at 3 and 24 h after exposure. We have shown mannitol responsiveness decreases 3 h after allergen inhalation. The current investigation assessed mannitol responsiveness 24 h after allergen challenge. Eleven mild atopic asthmatics completed allergen challenges on two separate occasions. In random order, methacholine or mannitol challenges were performed 24 h pre- and post-allergen challenge. Levels of fractional exhaled nitric oxide were also measured. Allergen challenge increased airway responsiveness to methacholine 24 h postchallenge; the geometric mean (95% CI) methacholine PC20 decreased from 5.9 mg/ml (1.8-19.4) to 2.2 mg/ml (0.81-5.89); P = 0.01. This coincided with a significant increase (P = 0.02) in FeNO levels. Conversely, allergen challenge decreased airway responsiveness to mannitol; geometric mean (95% CI) dose-response ratio was significantly higher after allergen exposure (57 mg/% FEV1 fall [27-121] to 147 mg/% FEV1 fall [57-379]; P = 0.03), and FeNO levels were not significantly increased (P = 0.054). Allergen-induced changes in airway responsiveness to direct and indirect stimuli are markedly different. The loss in responsiveness to mannitol is likely not explainable by a refractory state. The effect(s) of allergen exposure on airway responsiveness to indirect-acting stimuli require further investigation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

EOSINOPHIL INFLUX TO THE NASAL AIRWAY FOLLOWING LOCAL, LOW-LEVEL LPS CHALLENGE IN HUMANS

EPA Science Inventory

Background: Recent obervations show that atopic asthmatic subjects have increased sensitivity to respirable endotoxin (or LPS) compared with normal persons. In vitro studies demonstrate that LPS enchances eosinophil survival. These obervations suggest that the effects of inhal...

Sequestration of mitochondrial iron by silica particles initiates a biological effect.

EPA Science Inventory

Summary Inhalation of particulate matter has presented a challenge to human health for thousands of years. The underlying mechanism for biological effect following particle exposure is incompletely understood. We tested the postulate that particle sequestration of cell and mit...

Effects of helium and air inhalation on the innate and early adaptive immune system in healthy volunteers ex vivo.

PubMed

Oei, Gezina T M L; Smit, Kirsten F; vd Vondervoort, Djai; Brevoord, Daniel; Hoogendijk, Arjan; Wieland, Catharina W; Hollmann, Markus W; Preckel, Benedikt; Weber, Nina C

2012-09-24

Helium inhalation protects myocardium, brain and endothelium against ischemia/reperfusion injury in animals and humans, when applied according to specific "conditioning" protocols. Before widespread use of this "conditioning" agent in clinical practice, negative side effects have to be ruled out. We investigated the effect of prolonged helium inhalation on the responsiveness of the human immune response in whole blood ex vivo. Male healthy volunteers inhaled 30 minutes heliox (79%He/21%O(2)) or air in a cross over design, with two weeks between measurements. Blood was withdrawn at T0 (baseline), T1 (25 min inhalation) and T2-T5 (1, 2, 6, 24 h after inhalation) and incubated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), T-cell stimuli anti-CD3/ anti-CD28 (TCS) or RPMI (as control) for 2, 4 and 24 hours or not incubated (0 h). An additional group of six volunteers inhaled 60 minutes of heliox or air, followed by blood incubation with LPS and RPMI. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interferon-γ (IFN-γ) and interleukin-2 (IL-2) was analyzed by cytometric bead array. Statistical analysis was performed by the Wilcoxon test for matched samples. Incubation with LPS, LTA or TCS significantly increased TNF-α, IL-1β, IL-6, IL-8, IFN-γ and IL-2 in comparison to incubation with RPMI alone. Thirty min of helium inhalation did not influence the amounts of TNF-α, IL-1β, IL-6, IL-8, IFN-γ and IL-2 in comparison to air. Sixty min of helium inhalation did not affect cytokine production after LPS stimulation. We conclude that 79% helium inhalation does not affect the responsiveness of the human immune system in healthy volunteers. Dutch Trial Register: http://www.trialregister.nl/ NTR2152.

Effect of inhaled nitric oxide on pulmonary hemodynamics after acute lung injury in dogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Romand, J.A.; Pinsky, M.R.; Firestone, L.

Increased pulmonary vascular resistance (PVR) and mismatch in ventilation-to-perfusion ratio characterize acute lung injury (ALI). Pulmonary arterial pressure (Ppa) decreases when nitric oxide (NO) is inhaled during hypoxic pulmonary vasoconstriction (HPV); thus NO inhalation may reduce PVR and improve gas exchange in ALI. The authors studied the hemodynamic and gas exchange effects of NO inhalation during HPV and then ALI in eight anesthetized open-chest mechanically ventilated dogs. Right atrial pressure, Ppa, and left ventricular and arterial pressures were measured, and cardiac output was estimated by an aortic flow probe. Shunt and dead space were also estimated. The effect of 5-minmore » exposures to 0, 17, 28, 47, and 0 ppm inhaled NO was recorded during hyperoxia, hypoxia, and oleic acid-induced ALI. During ALI, partial [beta]-adrenergic blockage (propanolol, 0.15 mg/kg iv) was induced and 74 ppm NO was inhaled. Nitrosylhemoglobin (NO-Hb) and methemoglobin (MetHb) levels were measured. During hyperoxia, NO inhalation had no measurable effects. Hypoxia increased Ppa and calculated PVR, both of which decreased with 17 ppm NO. ALI decreased arterial Po[sub 2] and increased airway pressure, shunt, and dead space ventilation. Ppa and PVR were greater during ALI than during hyperoxia. NO inhalation had no measurable effect during ALI before or after [beta]-adrenergic blockage. MetHb remained low, and NO-Hb was unmeasurable. Bolus infusion of nitroglycerin (15 [mu]g) induced an immediate decrease in Ppa and PVR during ALI. Short-term NO inhalation does not affect PVR or gas exchange in dogs with oleic acid-induced ALI, nor does it increase NO-Hb or MetHb. In contrast, NO can diminish hypoxia-induced elevations in pulmonary vascular tone. These data suggest that NO inhalation selectively dilates the pulmonary circulation and specifically reduces HPV but not oleic acid-induced increases in pulmonary vasomotor tone. 28 refs., 3 figs., 2 tabs.« less

Effect of Inhalation of Aromatherapy Oil on Patients with Perennial Allergic Rhinitis: A Randomized Controlled Trial.

PubMed

Choi, Seo Yeon; Park, Kyungsook

2016-01-01

This study aimed to investigate the effects of aromatherapy oil inhalation on symptoms, quality of life, sleep quality, and fatigue level among adults with perennial allergic rhinitis (PAR). Fifty-four men and women aged between 20 and 60 were randomized to inhale aromatherapy oil containing essential oil from sandalwood, geranium, and Ravensara or almond oil (the placebo) for 5 minutes twice daily for 7 days. PAR symptoms determined by Total Nasal Symptom Score (TNSS), the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), sleep quality by Verran Synder-Halpern (VSH) scale, and fatigue level by Chalder Fatigue Scale (CFS) were assessed before and after intervention period. Compared with the placebo, the experimental group showed significant improvement in TNSS, especially in nasal obstruction. The aromatherapy group also showed significantly higher improvements in total score of RQLQ and CFS. These findings indicate that inhalation of certain aromatherapy oil helps relieve PAR symptoms, improve rhinitis-specific quality of life, and reduce fatigue in patients with PAR. In conclusion, inhalation of aromatherapy essential oil may have potential as an effective intervention to alleviate PAR.

Effect of Inhalation of Aromatherapy Oil on Patients with Perennial Allergic Rhinitis: A Randomized Controlled Trial

PubMed Central

Choi, Seo Yeon

2016-01-01

This study aimed to investigate the effects of aromatherapy oil inhalation on symptoms, quality of life, sleep quality, and fatigue level among adults with perennial allergic rhinitis (PAR). Fifty-four men and women aged between 20 and 60 were randomized to inhale aromatherapy oil containing essential oil from sandalwood, geranium, and Ravensara or almond oil (the placebo) for 5 minutes twice daily for 7 days. PAR symptoms determined by Total Nasal Symptom Score (TNSS), the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), sleep quality by Verran Synder-Halpern (VSH) scale, and fatigue level by Chalder Fatigue Scale (CFS) were assessed before and after intervention period. Compared with the placebo, the experimental group showed significant improvement in TNSS, especially in nasal obstruction. The aromatherapy group also showed significantly higher improvements in total score of RQLQ and CFS. These findings indicate that inhalation of certain aromatherapy oil helps relieve PAR symptoms, improve rhinitis-specific quality of life, and reduce fatigue in patients with PAR. In conclusion, inhalation of aromatherapy essential oil may have potential as an effective intervention to alleviate PAR. PMID:27034695

Zinc toxicology following particulate inhalation

PubMed Central

Cooper, Ross G.

2008-01-01

The current mini-review describes the toxic effects of zinc inhalation principally in the workplace and associated complications with breathing and respiration. The International Classification of Functioning, Disability and Health Criteria were used to specifically select articles. Most of the commercial production of zinc involves the galvanizing of iron and the manufacture of brass. The recommended daily allowance for adults is 15 mg zinc/day. Metal fume fever associated with inhalation of fumes of ZnO is characterized by fatigue, chills, fever, myalgias, cough, dyspnea, leukocytosis, thirst, metallic taste and salivation. ZnCl2 inhalation results in edema in the alveolar surface and the protein therein the lavage fluid is elevated. Particular pathological changes associated with zinc intoxication include: pale mucous membranes; jaundice; numerous Heinz bodies; and marked anemia. Adequate ambient air monitors for permissible exposure limits, excellent ventilation and extraction systems, and approved respirators are all important in providing adequate protection. PMID:20040991

Proposed standards for acute exposure to low enrichment uranium for compliance with 10 CFR 70.61.

PubMed

Kathren, Ronald L; Burklin, Richard K

2008-08-01

Title 10, Code of Federal Regulations Part 70, puts forth requirements for licensure of special nuclear material including specific risk criteria for acute intakes based on biological effects. Standards for acute oral and inhalation intakes of soluble low enrichment are proposed for the three levels of biological effects given in the regulations. These levels were developed largely from available human data and have a large measure of conservatism. The proposed threshold for life endangerment was 500 mg for acute inhalation intakes and 2,500 mg for acute ingestion intakes. Acute intakes of 1,400 mg for ingestion and 100 mg for inhalation are proposed as thresholds for irreversible or serious long lasting health effects. For minor transient health effects, the proposed levels are 410 and 30 mg, respectively, for acute ingestion and inhalation intakes. For acute intakes below these levels, no demonstrable toxicological effects are anticipated.

Inhibition of artificially induced cough in man by bronchodilators.

PubMed Central

Lowry, R; Higenbottam, T; Johnson, T; Godden, D

1987-01-01

1. The antitussive properties of bronchodilators were evaluated in a total of 47 normal volunteers. 2. Cough was induced by inhalation of ultrasonically nebulized solutions of distilled water and hypotonic saline. 3. Inhaled fenoterol hydrobromide (360 micrograms; 20 volunteers) and inhaled ipratropium bromide (72 micrograms; 14 volunteers) both significantly reduced couch compared with placebo (P less than 0.01). Oral salbutamol sulphate (4 mg; 11 volunteers) and oral pirenzepine hydrochloride (50 mg; 14 volunteers) had lesser effects. 4. Cough inhibition correlated with a small but statistically significant degree of bronchodilatation as measured by specific airway conductance (sGaw) and forced expiratory volume in one second (FEV1) in six normal subjects studied with each treatment in a placebo controlled, double blind study (r = 0.67, P less than 0.001). 5. Small reductions in airway tone are associated with a reduced cough response elicited by inhaled ultrasonically nebulized distilled water. PMID:3689630

Recombinant anthrax toxin receptor-Fc fusion proteins produced in plants protect rabbits against inhalational anthrax.

PubMed

Wycoff, Keith L; Belle, Archana; Deppe, Dorothée; Schaefer, Leah; Maclean, James M; Haase, Simone; Trilling, Anke K; Liu, Shihui; Leppla, Stephen H; Geren, Isin N; Pawlik, Jennifer; Peterson, Johnny W

2011-01-01

Inhalational anthrax, a zoonotic disease caused by the inhalation of Bacillus anthracis spores, has a ∼50% fatality rate even when treated with antibiotics. Pathogenesis is dependent on the activity of two toxic noncovalent complexes: edema toxin (EdTx) and lethal toxin (LeTx). Protective antigen (PA), an essential component of both complexes, binds with high affinity to the major receptor mediating the lethality of anthrax toxin in vivo, capillary morphogenesis protein 2 (CMG2). Certain antibodies against PA have been shown to protect against anthrax in vivo. As an alternative to anti-PA antibodies, we produced a fusion of the extracellular domain of human CMG2 and human IgG Fc, using both transient and stable tobacco plant expression systems. Optimized expression led to the CMG2-Fc fusion protein being produced at high levels: 730 mg/kg fresh leaf weight in Nicotiana benthamiana and 65 mg/kg in N. tabacum. CMG2-Fc, purified from tobacco plants, fully protected rabbits against a lethal challenge with B. anthracis spores at a dose of 2 mg/kg body weight administered at the time of challenge. Treatment with CMG2-Fc did not interfere with the development of the animals' own immunity to anthrax, as treated animals that survived an initial challenge also survived a rechallenge 30 days later. The glycosylation of the Fc (or lack thereof) had no significant effect on the protective potency of CMG2-Fc in rabbits or on its serum half-life, which was about 5 days. Significantly, CMG2-Fc effectively neutralized, in vitro, LeTx-containing mutant forms of PA that were not neutralized by anti-PA monoclonal antibodies.

Evaluating psychological interventions in a novel experimental human model of anxiety

PubMed Central

Ainsworth, Ben; Marshall, Jemma E.; Meron, Daniel; Baldwin, David S.; Chadwick, Paul; Munafò, Marcus R.; Garner, Matthew

2015-01-01

Inhalation of 7.5% carbon dioxide increases anxiety and autonomic arousal and provides a novel experimental model of anxiety with which to evaluate pharmacological and psychological treatments for anxiety. To date several psychotropic drugs including benzodiazepines, SSRIs and SNRIs have been evaluated using the 7.5% CO2 model; however, it has yet to be used to evaluate psychological interventions. We compared the effects of two core psychological components of mindfulness-meditation (open monitoring and focused attention) against general relaxation, on subjective, autonomic and neuropsychological outcomes in the 7.5% CO2 experimental model. 32 healthy screened adults were randomized to complete 10 min of guided open monitoring, focused attention or relaxation, immediately before inhaling 7.5% CO2 for 20 min. During CO2-challenge participants completed an eye-tracking measure of attention control and selective attention. Measures of subjective anxiety, blood pressure and heart rate were taken at baseline and immediately following intervention and CO2-challenge. OM and FA practice reduced subjective feelings of anxiety during 20-min inhalation of 7.5% CO2 compared to relaxation control. OM practice produced a strong anxiolytic effect, whereas the effect of FA was more modest. Anxiolytic OM and FA effects occurred in the absence of group differences in autonomic arousal and eye-movement measures of attention. Our findings are consistent with neuropsychological models of mindfulness-meditation that propose OM and FA activate prefrontal mechanisms that support emotion regulation during periods of anxiety and physiological hyper-arousal. Our findings complement those from pharmacological treatment studies, further supporting the use of CO2 challenge to evaluate future therapeutic interventions for anxiety. PMID:25765144

The effect of pH on citric acid cough challenge: A randomised control trial in chronic cough and healthy volunteers.

PubMed

Rai, Z L; Fowles, H E; Wright, C; Howard, Joseph; Morice, A H

2018-03-06

Citric acid has been used for over six decades to induce cough; however the mechanism of its pro-tussive effect is still not fully understood. We assessed the response to inhalation of citric acid at varying levels of acidity to determine if the pH of the solution plays a role in the induction of cough. Data was collected from both healthy volunteers and patients with chronic cough. 20 chronic cough patients and 20 healthy volunteers were recruited and underwent three cough challenges on separate days. Each visit involved 5 repeated one second inhalations of 300 mM citric acid solution. The concentration of the citrate cation remained constant, but the pH of the solution altered by the addition of sodium bicarbonate to 3, 5 and 6, representing the pK a values of the individual acid moieties. The total number of coughs elicited was recorded for each inhalation. Two subjects withdrew and were not included in the analysis. Participants were gender matched, each group consisting of 12 females. 74% of chronic coughers coughed at pH 3 (mean coughs 16), 89% coughed at pH 5 (18) and 63% coughed at pH 6 (7). In healthy volunteers, 60% of subjects coughed at pH 3 (9), 30% of subjects coughed at pH 5 (3), and 10% of subjects coughed at pH 6 (0). Thus chronic cough patients coughed more than healthy volunteers and did not exhibit a clear pH concentration response. There was also a greater variability in their response to individual challenges. Copyright © 2018 Elsevier B.V. All rights reserved.

Studies on the role of routes of allergen exposure in high IgE-producing beagle dogs sensitized to house dust mites.

PubMed

Marsella, R; Nicklin, C; Lopez, J

2006-10-01

The current study aimed to investigate the role played by oral, epicutaneous, and inhalation routes of exposure to house dust mites (HDM). The colony of high IgE-producing beagle dogs has been shown to develop pruritic dermatitis compatible with atopic dermatitis following environmental exposure (EE) to HDM. In crossover experiments, the response to EE was compared to two modified challenges, oral exposure (OE) and snood and muzzle exposure (SME). For OE, HDM were fed daily for 3 days. For SME, ingestion of allergen was prevented but there was inhalation and epicutaneous exposure to all body regions except to one ear. In all experiments, dogs were challenged for three consecutive days, and evaluated before, 6 h after exposure and daily thereafter, for 5 days. After a wash-out period, groups were crossed-over so that each dog was randomly challenged to all three protocols. Clinical scores were analysed using least squares analysis of variance. All dogs developed pruritic dermatitis regardless of the protocol. With OE, lesions developed in the same body regions as with EE although scores were lower. This difference became more evident after the first 3 days when OE scores decreased and EE scores continued to increase. The scores of covered and uncovered ears did not differ with SME. Scores for the remainder of the body were significantly lower than for EE. The development of lesions on covered ears supports the importance of inhalation or a systemic reaction to epicutaneous exposure in other areas. It is concluded that all routes are important and have additive effects, that route of exposure does not determine the distribution of lesions and that continuous epicutaneous exposure probably plays the most important role.

An evaluation of children's metered-dose inhaler technique for asthma medications.

PubMed

Burkhart, Patricia V; Rayens, Mary Kay; Bowman, Roxanne K

2005-03-01

Regardless of the medication delivery system, health care providers need to teach accurate medication administration techniques to their patients, educate them about the particular nuances of the prescribed delivery system (eg, proper storage), and reinforce these issues at each health encounter. A single instruction session is not sufficient to maintain appropriate inhaler techniques for patients who require continued use. Providing written steps for the administration technique is helpful so that the patient can refer to them later when using the medication. The National Heart, Lung, and Blood Institute's "Practical Guide for the Diagnosis and Management of Asthma" recommends that practitioners follow these steps for effective inhaler technique training when first prescribing an inhaler: 1. Teach patients the steps and give written instruction handouts. 2. Demonstrate how to use the inhaler step-by-step. 3. Ask patients to demonstrate how to use the inhaler. Let the patient refer to the handout on the first training. Then use the handout asa checklist to assess the patient's future technique. 4. Provide feedback to patients about what they did right and what they need to improve. Have patients demonstrate their technique again, if necessary. The last two steps should be performed (ie, demonstration and providing feedback on what patients did right and what they need to improve) at every subsequent visit. If the patient makes multiple errors, it is advisable to focus on improving one or two key steps at a time. With improvements in drug delivery come challenges, necessitating that practitioners stay current with new medication administration techniques. Teaching and reinforcing accurate technique at each health care encounter are critical to help ensure medication efficacy for patients with asthma. Since one fifth of children in the study performed incorrect medication technique even after education, checklists of steps for the correct use of inhalation devices, such as those provided in this article, should be given to patients for home use and for use by clinicians to evaluate patient technique at each health encounter.

An official American Thoracic Society Workshop Report: presentations and discussion of the fifth Jack Pepys Workshop on Asthma in the Workplace. Comparisons between asthma in the workplace and non-work-related asthma.

PubMed

Malo, Jean-Luc; Tarlo, Susan M; Sastre, Joaquin; Martin, James; Jeebhay, Mohamed F; Le Moual, Nicole; Heederik, Dick; Platts-Mills, Thomas; Blanc, Paul D; Vandenplas, Olivier; Moscato, Gianna; de Blay, Frédéric; Cartier, André

2015-07-01

The fifth Jack Pepys Workshop on Asthma in the Workplace focused on the similarities and differences of work-related asthma (WRA) and non-work-related asthma (non-WRA). WRA includes occupational asthma (OA) and work-exacerbated asthma (WEA). There are few biological differences in the mechanisms of sensitization to environmental and occupational allergens. Non-WRA and OA, when due to high-molecular-weight agents, are both IgE mediated; it is uncertain whether OA due to low-molecular-weight agents is also IgE mediated. Risk factors for OA include female sex, a history of upper airway symptoms, and a history of bronchial hyperresponsiveness. Atopy is a risk factor for OA due to high-molecular-weight agents, and exposure to cleaning agents is a risk factor for both OA and non-WRA. WEA is important among workers with preexisting asthma and may overlap with irritant-induced asthma, a type of OA. Induced sputum cytology can confirm airway inflammation, but specific inhalation challenge is the reference standard diagnostic test. Inhalation challenges are relatively safe, with the most severe reactions occurring with low-molecular-weight agents. Indirect health care costs account for about 50% of total asthma costs. Workers with poor asthma control (WRA or non-WRA) are less likely to be employed. Income loss is a major contributor to the indirect costs of WRA. Overall, asthma outcomes probably are worse for adult-onset than for childhood-onset asthma but better for OA than adult-onset non-WRA. Important aspects of management of OA are rapid and proper confirmation of the diagnosis and reduction of exposure to sensitizers or irritants at work and home.

An Official American Thoracic Society Workshop Report: Presentations and Discussion of the Fifth Jack Pepys Workshop on Asthma in the Workplace. Comparisons between Asthma in the Workplace and Non–Work-related Asthma

PubMed Central

Malo, Jean-Luc; Sastre, Joaquin; Martin, James; Jeebhay, Mohamed F.; Le Moual, Nicole; Heederik, Dick; Platts-Mills, Thomas; Blanc, Paul D.; Vandenplas, Olivier; Moscato, Gianna; de Blay, Frédéric; Cartier, André

2015-01-01

The fifth Jack Pepys Workshop on Asthma in the Workplace focused on the similarities and differences of work-related asthma (WRA) and non–work-related asthma (non-WRA). WRA includes occupational asthma (OA) and work-exacerbated asthma (WEA). There are few biological differences in the mechanisms of sensitization to environmental and occupational allergens. Non-WRA and OA, when due to high-molecular-weight agents, are both IgE mediated; it is uncertain whether OA due to low-molecular-weight agents is also IgE mediated. Risk factors for OA include female sex, a history of upper airway symptoms, and a history of bronchial hyperresponsiveness. Atopy is a risk factor for OA due to high-molecular-weight agents, and exposure to cleaning agents is a risk factor for both OA and non-WRA. WEA is important among workers with preexisting asthma and may overlap with irritant-induced asthma, a type of OA. Induced sputum cytology can confirm airway inflammation, but specific inhalation challenge is the reference standard diagnostic test. Inhalation challenges are relatively safe, with the most severe reactions occurring with low-molecular-weight agents. Indirect health care costs account for about 50% of total asthma costs. Workers with poor asthma control (WRA or non-WRA) are less likely to be employed. Income loss is a major contributor to the indirect costs of WRA. Overall, asthma outcomes probably are worse for adult-onset than for childhood-onset asthma but better for OA than adult-onset non-WRA. Important aspects of management of OA are rapid and proper confirmation of the diagnosis and reduction of exposure to sensitizers or irritants at work and home. PMID:26203621

An overview of animal models for assessing synthetic vitreous fibers (SVFs) safety.

PubMed

Johnson, N F

1994-12-01

Synthetic vitreous fibers (SVFs) are materials with many important commercial applications. The fibrous nature of the SVFs raises concerns about their potential human health hazards. However, sufficient epidemiological data do not exist to establish the hazardous nature of all SVFs. In addition, the cellular and molecular mechanisms underlying the induction of pulmonary lesions are only partially understood. Without sufficient evidence to associate fiber exposure and lung disease, animal bioassays have been used to identify specific hazardous fibers. These bioassays include inhalation exposures, intratracheal instillation, and intracavitary injection (intrapleural and intraperitoneal). Inhalation exposures of animals most closely represent the human experience, but these exposures are costly and time-consuming to conduct. Intratracheal and intracavitary administrations of fiber are alternatives to inhalation exposures; however, they do not represent human exposures and can give false positive results. The limitations of the noninhalation approaches must be considered when addressing the potential for a respirable fiber to induce human lung disease. In addition, when the results from inhalation exposures do not agree with the alternative animal assays, most weight should be given to the animal inhalation assays because of the limitations of the alternative approaches. To determine the safety of SVFs, both the inhalation and noninhalation approaches are suggested.

Comparison of non-invasive measures of cholinergic and allergic airway responsiveness in rats.

PubMed

Glaab, T; Hecker, H; Stephan, M; Baelder, R; Braun, A; Korolewitz, R; Krug, N; Hoymann, H G

2006-04-01

Non-invasive analysis of tidal expiratory flow parameters such as Tme/TE (time needed to reach peak expiratory flow divided by total expiratory time) or midexpiratory tidal flow (EF50) has been shown useful for phenotypic characterization of lung function in humans and animal models. In this study, we aimed to compare the utility of two non-invasive measures, EF50 and Tme/TE, to monitor bronchoconstriction to inhaled cholinergic and allergic challenges in Brown-Norway rats. Non-invasive measurements of Tme/TE and EF50 were paralleled by invasive recordings of Tme/TE, EF50 and pulmonary conductance (GL). First, dose-response studies with acetylcholine were performed in naive rats, showing that EF50 better than Tme/TE reflected the dose-related changes as observed with the classical invasive outcome parameter GL. The subsequent determination of allergen-specific early airway responsiveness (EAR) showed that ovalbumin-sensitized and -challenged rats exhibited airway inflammation and allergen-specific EAR. Again, EF50 was more sensitive than Tme/TE in detecting the allergen-specific EAR recorded with invasive and non-invasive lung function methods and agreed well with classical GL measurements. We conclude that non-invasive assessment of EF50 is significantly superior to Tme/TE and serves as a suitable and valid tool for phenotypic screening of cholinergic and allergic airway responsiveness in rats.

Triclosan Exposure and Allergic Sensitization in Norwegian Children

PubMed Central

Bertelsen, Randi J.; Longnecker, Matthew P.; Løvik, Martinus; Calafat, Antonia M.; Carlsen, Kai-Håkon; London, Stephanie J.; Carlsen, Karin C. Lødrup

2012-01-01

Background Exposure to the synthetic antimicrobial chemical, triclosan, used in personal care products, has been hypothesized to lead to allergic disease. We investigated whether triclosan exposure was associated with allergic sensitization and symptoms in 10-year old Norwegian children. Methods Urinary concentrations of triclosan were measured in one first morning void from 623 children, collected 2001– 2004. Logistic regression models, controlling for urine specific gravity, parental allergic disease, maternal education, and household income, were fitted for allergic sensitization (either skin prick test positivity or serum specific IgE ≥0.35 kU/L to at least one of 15 evaluated inhalant and food allergens), current rhinitis, and current asthma (questionnaire and exercise challenge test). Results The adjusted odds ratio (aOR) for allergic sensitization among those in the fourth quartile of triclosan concentration was 2.0 (95% confidence interval (CI): 1.1, 3.4) compared with the reference group (< the limit of detection) and the aOR per log10 unit increase in triclosan was 1.2 (95% CI: 1.0, 1.4). The aOR for current rhinitis was 1.9 (95% CI: 1.1, 3.4) for the fourth quartile and 1.2 (95% CI:0.97, 1.4) per log10 unit increase in triclosan. Conclusion Triclosan concentrations were associated with allergic sensitization, especially inhalant and seasonal allergens rather thanfood allergens. Current rhinitis was associated with the highest levels of triclosan, whereas no association was seen for current asthma. These results are consistent with recent findings in other studies and provide additional evidence for an association between triclosan and allergy. PMID:23146048

Methamphetamine and Amphetamine Isomer Concentrations in Human Urine Following Controlled Vicks VapoInhaler Administration

PubMed Central

Smith, Michael L.; Nichols, Daniel C.; Underwood, Paula; Fuller, Zachary; Moser, Matthew A.; Flegel, Ron; Gorelick, David A.; Newmeyer, Matthew N.; Concheiro, Marta; Huestis, Marilyn A.

2014-01-01

Legitimate use of legal intranasal decongestants containing l-methamphetamine may complicate interpretation of urine drug tests positive for amphetamines. Our study hypotheses were that commonly used immunoassays would produce no false-positive results and a recently developed enantiomer-specific gas chromatography–mass spectrometry (GC–MS) procedure would find no d-amphetamine or d-methamphetamine in urine following controlled Vicks VapoInhaler administration at manufacturer's recommended doses. To evaluate these hypotheses, 22 healthy adults were each administered one dose (two inhalations in each nostril) of a Vicks VapoInhaler every 2 h for 10 h on Day 1 (six doses), followed by a single dose on Day 2. Every urine specimen was collected as an individual void for 32 h after the first dose and assayed for d- and l-amphetamines specific isomers with a GC–MS method with >99% purity of R-(−)-α-methoxy-α-(trifluoromethyl)phenylacetyl derivatives and 10 µg/L lower limits of quantification. No d-methamphetamine or d-amphetamine was detected in any urine specimen by GC–MS. The median l-methamphetamine maximum concentration was 62.8 µg/L (range: 11.0–1,440). Only two subjects had detectable l-amphetamine, with maximum concentrations coinciding with l-methamphetamine peak levels, and always ≤4% of the parent's maximum. Three commercial immunoassays for amphetamines EMIT® II Plus, KIMS® II and DRI® had sensitivities, specificities and efficiencies of 100, 97.8, 97.8; 100, 99.6, 99.6 and 100, 100, 100%, respectively. The immunoassays had high efficiencies, but our first hypothesis was not affirmed. The EMIT® II Plus assay produced 2.2% false-positive results, requiring an enantiomer-specific confirmation. PMID:25217541

The Dynamic Characteristics of Silver Nanoparticles in Physiological Fluids: Toxicological Implications

DTIC Science & Technology

2014-11-19

and polysaccharide (Ag-PS) coated silver NM. As inhalation is a common route of exposure, an alveolar macrophage cell model with deposition dosages... polysaccharide -coated (Ag− PS) silver NMs. As inhalation is a common route of exposure, an alveolar macrophage cell model with deposition dosages...bioeffects, we evaluated fluid-specific influences on 25 nm Ag NPs with either a hydrocarbon or polysaccharide coating. Our data demonstrated that

Nitrogen Dioxide Exposure and Airway Responsiveness in Individuals with Asthma

EPA Science Inventory

Controlled human exposure studies evaluating the effect of inhaled NO2 on the inherent responsiveness of the airways to challenge by bronchoconstricting agents have had mixed results. In general, existing meta-analyses show statistically significant effects of NO2 on the airway r...

Comparative airway inflammatory response of normal volunteers to ozone and lipopolysaccharide challenge

EPA Science Inventory

Ozone and lipopolysaccharide (LPS) are environmental pollutants with adverse heatth effects noted in both healthy and asthmatic individuals. The authors and others have shown that inhalation of ozone and LPS both induce airway neutrophilia. Based on these similarities, the author...

Inhalant use, inhalant-use disorders, and antisocial behavior: findings from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

PubMed

Howard, Matthew O; Perron, Brian E; Vaughn, Michael G; Bender, Kimberly A; Garland, Eric

2010-03-01

Few studies have explored the topography of antisocial behavior in a nationally representative sample of inhalant users. We examined (a) the lifetime prevalence of 20 childhood and adult antisocial behaviors in inhalant users with inhalant-use disorders (IUD+) and without IUDs (IUD-); (b) the nature and strength of associations between inhalant use, IUDs, and specific antisocial behaviors in multivariate analyses; and (c) the relationships between inhalant use, IUDs, and antisocial behaviors in a national sample of adults with antisocial personality disorder. The National Epidemiologic Survey on Alcohol and Related Conditions was a multistage national survey of 43,093 U.S. residents. Respondents completed a structured psychiatric interview. IUD+ and IUD- respondents were significantly younger and more likely to be unemployed, to be male, to have never married, and to report family and personal histories of alcohol and drug problems than inhalant nonusers. Family histories of alcohol problems and personal histories of drug problems were significantly more prevalent among IUD+ respondents, compared with IUD- respondents. In bivariate analyses, IUD+ and IUD- respondents evidenced significantly higher lifetime levels of all childhood and adult antisocial behaviors than inhalant nonusers. IUD+ respondents were significantly more likely than their IUD- counterparts to report bullying behavior, starting physical fights, using dangerous weapons, physical cruelty to people, staying out all night without permission, running away, and frequent truancy in childhood, as well as greater deceitfulness, impulsivity, irritability/aggressiveness, recklessness, and irresponsibility in adulthood. Multivariate analyses indicated that IUD+ respondents had a significantly elevated risk for childhood and adult antisocial behaviors, compared with inhalant nonusers, with the strongest effects for using dangerous weapons, physical cruelty to animals, and physical cruelty to people. Similarly, IUD+ respondents differed significantly from their IUD- counterparts primarily across measures of interpersonal violence. Among persons with antisocial personality disorder, inhalant use and IUDs were associated with greater antisocial behavior, albeit with fewer and weaker effects. Respondents with IUDs had pervasively elevated levels of antisocial conduct, including diverse forms of early-onset and interpersonally violent behavior.

Inhalant Use, Inhalant-Use Disorders, and Antisocial Behavior: Findings From the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)*

PubMed Central

Howard, Matthew O.; Perron, Brian E.; Vaughn, Michael G.; Bender, Kimberly A.; Garland, Eric

2010-01-01

Objective: Few studies have explored the topography of antisocial behavior in a nationally representative sample of inhalant users. We examined (a) the lifetime prevalence of 20 childhood and adult antisocial behaviors in inhalant users with inhalant-use disorders (IUD+) and without IUDs (IUD−); (b) the nature and strength of associations between inhalant use, IUDs, and specific antisocial behaviors in multi-variate analyses; and (c) the relationships between inhalant use, IUDs, and antisocial behaviors in a national sample of adults with antisocial personality disorder. Method: The National Epidemiologic Survey on Alcohol and Related Conditions was a multistage national survey of 43,093 U.S. residents. Respondents completed a structured psychiatric interview. Results: IUD+ and IUD− respondents were significantly younger and more likely to be unemployed, to be male, to have never married, and to report family and personal histories of alcohol and drug problems than inhalant nonusers. Family histories of alcohol problems and personal histories of drug problems were significantly more prevalent among IUD+ respondents, compared with IUD− respondents. In bivariate analyses, IUD+ and IUD− respondents evidenced significantly higher lifetime levels of all childhood and adult antisocial behaviors than inhalant nonusers. IUD+ respondents were significantly more likely than their IUD− counterparts to report bullying behavior, starting physical fights, using dangerous weapons, physical cruelty to people, staying out all night without permission, running away, and frequent truancy in childhood, as well as greater deceitfulness, impulsivity, irritability/aggressiveness, recklessness, and irresponsibility in adulthood. Multivari-ate analyses indicated that IUD+ respondents had a significantly elevated risk for childhood and adult antisocial behaviors, compared with inhalant nonusers, with the strongest effects for using dangerous weapons, physical cruelty to animals, and physical cruelty to people. Similarly, IUD+ respondents differed significantly from their IUD− counterparts primarily across measures of interpersonal violence. Among persons with antisocial personality disorder, inhalant use and IUDs were associated with greater antisocial behavior, albeit with fewer and weaker effects. Conclusions: Respondents with IUDs had pervasively elevated levels of antisocial conduct, including diverse forms of early-onset and inter-personally violent behavior. PMID:20230717

Anti-Aspergillus Activities of the Respiratory Epithelium in Health and Disease.

PubMed

Bertuzzi, Margherita; Hayes, Gemma E; Icheoku, Uju J; van Rhijn, Norman; Denning, David W; Osherov, Nir; Bignell, Elaine M

2018-01-08

Respiratory epithelia fulfil multiple roles beyond that of gaseous exchange, also acting as primary custodians of lung sterility and inflammatory homeostasis. Inhaled fungal spores pose a continual antigenic, and potentially pathogenic, challenge to lung integrity against which the human respiratory mucosa has developed various tolerance and defence strategies. However, respiratory disease and immune dysfunction frequently render the human lung susceptible to fungal diseases, the most common of which are the aspergilloses, a group of syndromes caused by inhaled spores of Aspergillus fumigatus . Inhaled Aspergillus spores enter into a multiplicity of interactions with respiratory epithelia, the mechanistic bases of which are only just becoming recognized as important drivers of disease, as well as possible therapeutic targets. In this mini-review we examine current understanding of Aspergillus -epithelial interactions and, based upon the very latest developments in the field, we explore two apparently opposing schools of thought which view epithelial uptake of Aspergillus spores as either a curative or disease-exacerbating event.

INHALATION EXPOSURE TO CARBON NANOTUBES (CNT) AND CARBON NANOFIBERS (CNF): METHODOLOGY AND DOSIMETRY

PubMed Central

Oberdörster, Günter; Castranova, Vincent; Asgharian, Bahman; Sayre, Phil

2015-01-01

Carbon nanotubes (CNT) and nanofibers (CNF) are used increasingly in a broad array of commercial products. Given current understandings, the most significant life-cycle exposures to CNT/CNF occur from inhalation when they become airborne at different stages of their life cycle, including workplace, use, and disposal. Increasing awareness of the importance of physicochemical properties as determinants of toxicity of CNT/CNF and existing difficulties in interpreting results of mostly acute rodent inhalation studies to date necessitate a reexamination of standardized inhalation testing guidelines. The current literature on pulmonary exposure to CNT/CNF and associated effects is summarized; recommendations and conclusions are provided that address test guideline modifications for rodent inhalation studies that will improve dosimetric extrapolation modeling for hazard and risk characterization based on the analysis of exposure-dose-response relationships. Several physicochemical parameters for CNT/CNF, including shape, state of agglomeration/aggregation, surface properties, impurities, and density, influence toxicity. This requires an evaluation of the correlation between structure and pulmonary responses. Inhalation, using whole-body exposures of rodents, is recommended for acute to chronic pulmonary exposure studies. Dry powder generator methods for producing CNT/CNF aerosols are preferred, and specific instrumentation to measure mass, particle size and number distribution, and morphology in the exposure chambers are identified. Methods are discussed for establishing experimental exposure concentrations that correlate with realistic human exposures, such that unrealistically high experimental concentrations need to be identified that induce effects under mechanisms that are not relevant for workplace exposures. Recommendations for anchoring data to results seen for positive and negative benchmark materials are included, as well as periods for postexposure observation. A minimum data set of specific bronchoalveolar lavage parameters is recommended. Retained lung burden data need to be gathered such that exposure-dose-response correlations may be analyzed and potency comparisons between materials and mammalian species are obtained considering dose metric parameters for interpretation of results. Finally, a list of research needs is presented to fill data gaps for further improving design, analysis, and interpretation and extrapolation of results of rodent inhalation studies to refine meaningful risk assessments for humans. PMID:26361791

Spiromax, a New Dry Powder Inhaler: Dose Consistency under Simulated Real-World Conditions.

PubMed

Canonica, Giorgio Walter; Arp, Jan; Keegstra, Johan René; Chrystyn, Henry

2015-10-01

Spiromax(®) is a novel dry powder inhaler for patients with asthma or chronic obstructive pulmonary disease (COPD). The studies presented here provide further data on attributes (in vitro dosing consistency with budesonide-formoterol (DuoResp) Spiromax; flow rates through empty versions of the Spiromax and Turbuhaler inhaler) of importance to patients with asthma or COPD. Dose-delivery studies were performed using low-, middle-, and high-strength DuoResp Spiromax. Dose consistency was assessed over inhaler life. Total emitted doses (TEDs) were measured at various flow rates, after exposure to high and low temperature or humidity, at different inhaler orientations, and after dropping the inhaler. The criterion for evaluating dose uniformity was whether mean TEDs were within the product specification limits. In separate studies, flow rates were measured after training, using the patient information leaflets, and again after enhanced training as part of a randomized, open-label, cross-over study. Mean values for both budesonide and formoterol were within 85%-115% of the label claim for each strength of DuoResp Spiromax for initial dose uniformity and for the other investigated conditions (temperature, humidity, orientation, dropping, knocking), with the exception of approximately an 80% increase in first dose after dropping the inhaler (subsequent doses not affected). In the flow rate patient study, two patients' inhalations with Spiromax and six with Turbuhaler were <30 L/min. The majority of asthma patients [91% (Spiromax) versus 82% (Turbuhaler)] achieved the preferred flow rate of >60 L/min. DuoResp Spiromax consistently meets dose uniformity criteria, under controlled laboratory conditions and with variations intended to mimic real-world use. Following enhanced training, all patients in the flow study were able to achieve the minimal inspiratory flow rate of >30 L/min, which is required for effective treatment.

Ideal Particle Sizes for Inhaled Steroids Targeting Vocal Granulomas: Preliminary Study Using Computational Fluid Dynamics.

PubMed

Perkins, Elizabeth L; Basu, Saikat; Garcia, Guilherme J M; Buckmire, Robert A; Shah, Rupali N; Kimbell, Julia S

2018-03-01

Objectives Vocal fold granulomas are benign lesions of the larynx commonly caused by gastroesophageal reflux, intubation, and phonotrauma. Current medical therapy includes inhaled corticosteroids to target inflammation that leads to granuloma formation. Particle sizes of commonly prescribed inhalers range over 1 to 4 µm. The study objective was to use computational fluid dynamics to investigate deposition patterns over a range of particle sizes of inhaled corticosteroids targeting the larynx and vocal fold granulomas. Study Design Retrospective, case-specific computational study. Setting Tertiary academic center. Subjects/Methods A 3-dimensional anatomically realistic computational model of a normal adult airway from mouth to trachea was constructed from 3 computed tomography scans. Virtual granulomas of varying sizes and positions along the vocal fold were incorporated into the base model. Assuming steady-state, inspiratory, turbulent airflow at 30 L/min, computational fluid dynamics was used to simulate respiratory transport and deposition of inhaled corticosteroid particles ranging over 1 to 20 µm. Results Laryngeal deposition in the base model peaked for particle sizes 8 to 10 µm (2.8%-3.5%). Ideal sizes ranged over 6 to 10, 7 to 13, and 7 to 14 µm for small, medium, and large granuloma sizes, respectively. Glottic deposition was maximal at 10.8% for 9-µm-sized particles for the large posterior granuloma, 3 times the normal model (3.5%). Conclusion As the virtual granuloma size increased and the location became more posterior, glottic deposition and ideal particle size generally increased. This preliminary study suggests that inhalers with larger particle sizes, such as fluticasone propionate dry-powder inhaler, may improve laryngeal drug deposition. Most commercially available inhalers have smaller particles than suggested here.

Early pulmonary response is critical for extra-pulmonary carbon nanoparticle mediated effects: comparison of inhalation versus intra-arterial infusion exposures in mice.

PubMed

Ganguly, Koustav; Ettehadieh, Dariusch; Upadhyay, Swapna; Takenaka, Shinji; Adler, Thure; Karg, Erwin; Krombach, Fritz; Kreyling, Wolfgang G; Schulz, Holger; Schmid, Otmar; Stoeger, Tobias

2017-06-20

The death toll associated with inhaled ambient particulate matter (PM) is attributed mainly to cardio-vascular rather than pulmonary effects. However, it is unclear whether the key event for cardiovascular impairment is particle translocation from lung to circulation (direct effect) or indirect effects due to pulmonary particle-cell interactions. In this work, we addressed this issue by exposing healthy mice via inhalation and intra-arterial infusion (IAI) to carbon nanoparticles (CNP) as surrogate for soot, a major constituent of (ultrafine) urban PM. Equivalent surface area CNP doses in the blood (30mm 2 per animal) were applied by IAI or inhalation (lung-deposited dose 10,000mm 2 ; accounting for 0.3% of lung-to-blood CNP translocation). Mice were analyzed for changes in hematology and molecular markers of endothelial/epithelial dysfunction, pro-inflammatory reactions, oxidative stress, and coagulation in lungs and extra-pulmonary organs after CNP inhalation (4 h and 24 h) and CNP infusion (4 h). For methodological reasons, we used two different CNP types (spark-discharge and Printex90), with very similar physicochemical properties [≥98 and ≥95% elemental carbon; 10 and 14 nm primary particle diameter; and 800 and 300 m 2 /g specific surface area] for inhalation and IAI respectively. Mild pulmonary inflammatory responses and significant systemic effects were observed following 4 h and 24 h CNP inhalation. Increased retention of activated leukocytes, secondary thrombocytosis, and pro-inflammatory responses in secondary organs were detected following 4 h and 24 h of CNP inhalation only. Interestingly, among the investigated extra-pulmonary tissues (i.e. aorta, heart, and liver); aorta revealed as the most susceptible extra-pulmonary target following inhalation exposure. Bypassing the lungs by IAI however did not induce any extra-pulmonary effects at 4 h as compared to inhalation. Our findings indicate that extra-pulmonary effects due to CNP inhalation are dominated by indirect effects (particle-cell interactions in the lung) rather than direct effects (translocated CNPs) within the first hours after exposure. Hence, CNP translocation may not be the key event inducing early cardiovascular impairment following air pollution episodes. The considerable response detected in the aorta after CNP inhalation warrants more emphasis on this tissue in future studies.

Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial.

PubMed

Wechsler, Michael E; Kunselman, Susan J; Chinchilli, Vernon M; Bleecker, Eugene; Boushey, Homer A; Calhoun, William J; Ameredes, Bill T; Castro, Mario; Craig, Timothy J; Denlinger, Loren; Fahy, John V; Jarjour, Nizar; Kazani, Shamsah; Kim, Sophia; Kraft, Monica; Lazarus, Stephen C; Lemanske, Robert F; Markezich, Amy; Martin, Richard J; Permaul, Perdita; Peters, Stephen P; Ramsdell, Joe; Sorkness, Christine A; Sutherland, E Rand; Szefler, Stanley J; Walter, Michael J; Wasserman, Stephen I; Israel, Elliot

2009-11-21

Some studies suggest that patients with asthma who are homozygous for arginine at the 16th amino acid position of the beta2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting beta2 agonists and inhaled corticosteroids than do those homozygous for glycine (B16 Gly/Gly). We investigated whether there is a genotype-specific response to treatment with a longacting beta2 agonist in combination with inhaled corticosteroid. In this multicentre, randomised, double-blind, placebo-controlled trial, adult patients with moderate asthma were enrolled in pairs matched for forced expiratory volume in 1 s and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were randomly assigned by computer-generated randomisation sequence to receive inhaled longacting beta2 agonist (salmeterol 50 microg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 microg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00200967. After 18 weeks of treatment, mean morning PEF in Arg/Arg participants was 21.4 L/min (95% CI 11.8-31.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). In Gly/Gly participants, morning PEF was 21.5 L/min (11.0-32.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). The improvement in PEF did not differ between genotypes (difference [Arg/Arg-Gly/Gly] -0.1, -14.4 to 14.2; p=0.99). In Gly/Gly participants, methacholine PC20 (20% reduction in forced expiratory volume in 1 s; a prespecified secondary outcome) was 2.4 times higher when participants were assigned to salmeterol than when assigned to placebo (p<0.0001). Responsiveness to methacholine did not differ between salmeterol and placebo in Arg/Arg participants (p=0.87). The 2.5 times higher genotype-specific difference in responsiveness to methacholine was significant (1.32 doubling dose difference between genotypes, 0.43-2.21, p=0.0038). Seven Arg/Arg participants (placebo, n=5; salmeterol, n=2) and six Gly/Gly participants (placebo, n=3; salmeterol, n=3) had an asthma exacerbation. Five serious adverse events were reported, one each during the pre-match and run-in phases on open-label inhaled corticosteroid, two during double-blind treatment with salmeterol/inhaled corticosteroid, and one during double-blind treatment with placebo/inhaled corticosteroid. None of the serious events was asthma-related or related to study drugs or procedures. In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone. These findings suggest that patients should continue to be treated with longacting beta2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine. National Institutes of Health.

Guinea pigs inbred for studies of respiratory anaphylaxis.

PubMed

Lundberg, L

1979-02-01

A selective inbreeding of approximately 24 generations of albino guinea pigs by brother x sister mating has resulted in two strains, registered IMM/S and IMM/R, with high and low responsiveness, respectively, to ovalbumin-induced respiratory anaphylaxis. The two guinea pig strains differed in their ability to be immunized by the inhalation of antigen and produce antibodies, as well as to develop respiratory anaphylaxis. A correlation between the strength of the anaphylactic reactions and the amount of hemagglutinating antibodies produced was observed. When immunization was carried out by an intradermal injection of ovalbumin (OA), even in small doses incorporated in FCA, guinea pigs from both strains produced hemagglutinating antibodies in nearly the same amount. These antibodies do not influence the ability of the animals to react with a high respectively low anaphylactic response on subsequent challenge by inhalation of OA, neither in the actively sensitized animals nor in passively sensitized animals. However, with repeated inhalations of OA, desensitization occurred in the intradermally immunized high-responders, while the passively immunized high-responders could be provoked several times without any signs of desensitization. No systematical differences between the two strains with regard to sensitivity to inhalations of histamine were demonstrated. The low responders were found to be less resistant to infections than high-responders.

Anthrax vaccine recipients lack antibody against the loop neutralizing determinant: A protective neutralizing epitope from Bacillus anthracis protective antigen.

PubMed

Oscherwitz, Jon; Quinn, Conrad P; Cease, Kemp B

2015-05-11

Epitope-focused immunogens can elicit antibody against the loop neutralizing determinant (LND), a neutralizing epitope found within the 2β2-2β3 loop of protective antigen (PA), which can protect rabbits from high-dose inhalation challenge with Bacillus anthracis Ames strain. Interestingly, data suggests that this epitope is relatively immunosilent in rabbits and non-human primates immunized with full length PA. To determine whether the LND is immunosilent among humans vaccinated with PA, we screened antisera from AVA- or placebo-vaccinees from a clinical trial for antibody reactive with the LND. AVA-vaccinee sera had significant PA-specific antibody compared to placebo-vaccinee sera; however, sera from the two cohorts were indistinguishable with regard to the frequency of individuals with antibody specific for the LND. AVA-vaccinees have a low frequency of antibody reactive with the LND. As with rabbits and non-human primates, the elicitation of LND-specific antibody in humans appears to require immunization with an epitope-focused vaccine. Copyright © 2015 Elsevier Ltd. All rights reserved.

A specific and sensitive HPLC-MS/MS micromethod for milrinone plasma levels determination after inhalation in cardiac patients.

PubMed

Gavra, Paul; Nguyen, Anne Q-N; Theoret, Yves; Litalien, Catherine; Denault, André Y; Varin, France

2014-10-01

Milrinone administered through inhalation is an emerging method aimed at specifically reducing pulmonary hypertension without affecting systemic pressures. Its administration has been shown to be useful both in patients undergoing cardiac surgery and for persistent pulmonary hypertension of the newborn. These populations are prone to receive many concomitant medications and/or blood sampling may require a low volume quantification method. To address these issues in view of pharmacokinetic studies, this article aims to develop and validate a specific and sensitive analytical assay using high performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS) detection for the quantification of milrinone plasma concentrations after inhalation in patients undergoing cardiac surgery. Plasma samples (50 μL) were extracted using ethyl acetate. Milrinone was separated on a C18 analytical column at 50°C. The mobile phase consisted of methanol and 10 mM ammonium acetate (45:55 vol/vol). The electrospray was operated in the negative ionization mode and monitored the following mass transitions: m/z 212.1 → 140.0 at 36 eV for milrinone and m/z 252.1 → 156.1 at 32 eV for olprinone. Calibration curves followed a quadratic regression in the concentration range of 0.3125-640 ng/mL. The lower limit of quantification is 0.3125 ng/mL and is based on a low plasma volume of 50 μL. Mean drug recovery and accuracy were ≥72.3% and 96.0%, respectively. Intraday and interday precision coefficient of variation (%) was ≤7.4% and ≤11.5%, respectively. The specificity allowed milrinone quantification in the multidrug administration conditions of cardiopulmonary bypass. This validated micromethod proved to be highly sensitive and specific while using a low volume of plasma. Its low volume and its lower limit of quantification indicate that this approach is suitable for further characterization of milrinone pharmacokinetics in both adults (inhalation) and neonates.

Mathematical Modeling of Physical and Cognitive Performance Decrement from Mechanical and Inhalation Insults

DTIC Science & Technology

2006-12-01

on specific short term problems. 1.1.1 Dynamic Physiological Modeling The oxygenation of the blood by the lung through respiration is a critical...tests as apnea , reduced arterial saturation, and may even be linked to long term CNS deficits. Inhalation of toxic gases can dramatically affect the...of TGAS model the respiration , circulation, and metabolic processes and include models of the ventilation and cardiac output control due to 3

Occupational asthma caused by exposure to asparagus: detection of allergens by immunoblotting.

PubMed

Lopez-Rubio, A; Rodriguez, J; Crespo, J F; Vives, R; Daroca, P; Reaño, M

1998-12-01

Vegetables of the Liliaceae family, such as garlic or onion, have been reported to cause occupational asthma. However, there are few data on adverse reactions to asparagus. We evaluated the role of asparagus as a cause of asthma in a patient with respiratory symptoms occurring at work (horticulture) and studied relevant allergens. A 28-year-old man complained of rhinoconjunctivitis and asthma when harvesting asparagus at work. Eating cooked asparagus did not provoke symptoms. A positive skin test reaction was observed with raw asparagus, Alternaria alternata, and grass-pollen extracts. The methacholine test demonstrated mild bronchial hyperresponsiveness. The patient had an immediate asthmatic response after challenge with raw asparagus extract. Bronchial provocation tests with boiled asparagus, A. alternata, and control extracts were negative. Two unexposed subjects with seasonal allergic asthma did not react to the raw asparagus extract. The double-blind, placebo-controlled food challenge with raw asparagus was negative. Serum asparagus-specific IgE was 13.9 kU(A)/l. By SDS-PAGE immunoblot, at least six IgE-binding components, ranging from 22 to 73 kDa, were detected only in raw asparagus. We report a case of occupational asthma caused by asparagus inhalation, confirmed by specific bronchoprovocation. Immunoblot analysis showed that asparagus allergens are very labile and quite sensitive to heat denaturation.

The small airway epithelium as a target for the adverse pulmonary effects of silver nanoparticle inhalation.

PubMed

Guo, Chang; Buckley, Alison; Marczylo, Tim; Seiffert, Joanna; Römer, Isabella; Warren, James; Hodgson, Alan; Chung, Kian Fan; Gant, Timothy W; Smith, Rachel; Leonard, Martin O

2018-05-11

Experimental modeling to identify specific inhalation hazards for nanomaterials has in the main focused on in vivo approaches. However, these models suffer from uncertainties surrounding species-specific differences and cellular targets for biologic response. In terms of pulmonary exposure, approaches which combine 'inhalation-like' nanoparticulate aerosol deposition with relevant human cell and tissue air-liquid interface cultures are considered an important complement to in vivo work. In this study, we utilized such a model system to build on previous results from in vivo exposures, which highlighted the small airway epithelium as a target for silver nanoparticle (AgNP) deposition. RNA-SEQ was used to characterize alterations in mRNA and miRNA within the lung. Organotypic-reconstituted 3D human primary small airway epithelial cell cultures (SmallAir) were exposed to the same spark-generated AgNP and at the same dose used in vivo, in an aerosol-exposure air-liquid interface (AE-ALI) system. Adverse effects were characterized using lactate, LDH release and alterations in mRNA and miRNA. Modest toxicological effects were paralleled by significant regulation in gene expression, reflective mainly of specific inflammatory events. Importantly, there was a level of concordance between gene expression changes observed in vitro and in vivo. We also observed a significant correlation between AgNP and mass equivalent silver ion (Ag + ) induced transcriptional changes in SmallAir cultures. In addition to key mechanistic information relevant for our understanding of the potential health risks associated with AgNP inhalation exposure, this work further highlights the small airway epithelium as an important target for adverse effects.

A recombinant 63-kDa form of Bacillus anthracis protective antigen produced in the yeast Saccharomyces cerevisiae provides protection in rabbit and primate inhalational challenge models of anthrax infection.

PubMed

Hepler, Robert W; Kelly, Rosemarie; McNeely, Tessie B; Fan, Hongxia; Losada, Maria C; George, Hugh A; Woods, Andrea; Cope, Leslie D; Bansal, Alka; Cook, James C; Zang, Gina; Cohen, Steven L; Wei, Xiaorong; Keller, Paul M; Leffel, Elizabeth; Joyce, Joseph G; Pitt, Louise; Schultz, Loren D; Jansen, Kathrin U; Kurtz, Myra

2006-03-06

Infection by Bacillus anthracis is preventable by prophylactic vaccination with several naturally derived and recombinant vaccine preparations. Existing data suggests that protection is mediated by antibodies directed against the protective antigen (PA) component of the anthrax toxin complex. PA is an 83-kDa protein cleaved in vivo to yield a biologically active 63-kDa protein. In an effort to evaluate the potential of yeast as an expression system for the production of recombinant PA, and to determine if the yeast-purified rPA63 can protect from a lethal inhalational challenge, the sequence of the 63-kDa form of PA was codon-optimized and expressed in the yeast Saccharomyces cerevisiae. Highly purified rPA63 isolated from Saccharomyces under denaturing conditions demonstrated reduced biological activity in a macrophage-killing assay compared to non-denatured rPA83 purified from Escherichia coli. Rabbits and non-human primates (NHP) immunized with rPA63 and later challenged with a lethal dose of B. anthracis spores were generally protected from infection. These results indicate that epitopes present in the 63-kDa from of PA can protect rabbits and non-human primates from a lethal spore challenge, and further suggest that a fully functional rPA63 is not required in order to provide these epitopes.

Alveolar macrophages have a dual role in a rat model for trimellitic anhydride-induced occupational asthma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valstar, Dingena L.; Schijf, Marcel A.; Nijkamp, Frans P.

2006-02-15

Occupational exposure to low molecular weight chemicals, like trimellitic anhydride (TMA), can result in occupational asthma. Alveolar macrophages (AMs) are among the first cells to encounter inhaled compounds. These cells can produce many different mediators that have a putative role in asthma. In this study, we examined the role of AMs in lung function and airway inflammation of rats exposed to TMA. Female Brown Norway rats were sensitized by dermal application of TMA or received vehicle alone on days 0 and 7. One day before challenge, rats received intratracheally either empty or clodronate-containing liposomes to deplete the lungs of AMs.more » On day 21, all rats were challenged by inhalation of TMA in air. Lung function parameters were measured before, during, within 1 h after, and 24 h after challenge. IgE levels and parameters of inflammation and tissue damage were assessed 24 h after challenge. Sensitization with TMA led to decreased lung function parameters during and within 1 h after challenge as compared to non-sensitized rats. AM depletion alleviated the TMA-induced drop in lung function parameters and induced a faster recovery compared to sham-depleted TMA-sensitized rats. It also decreased the levels of serum IgE 24 h after challenge, but did not affect the sensitization-dependent increase in lung lavage fluid IL-6 and tissue TNF-{alpha} levels. In contrast, AM depletion augmented the TMA-induced tissue damage and inflammation 24 h after challenge. AMs seem to have a dual role in this model for TMA-induced occupational asthma since they potentiate the immediate TMA-induced decrease in lung function but tended to dampen the TMA-induced inflammatory reaction 24 h later.« less

Investigation of electrostatic behavior of a lactose carrier for dry powder inhalers.

PubMed

Chow, Keat Theng; Zhu, Kewu; Tan, Reginald B H; Heng, Paul W S

2008-12-01

This study aims to elucidate the electrostatic behavior of a model lactose carrier used in dry powder inhaler formulations by examining the effects of ambient relative humidity (RH), aerosolization air flow rate, repeated inhaler use, gelatin capsule and tapping on the specific charge (nC/g) of bulk and aerosolized lactose. Static and dynamic electrostatic charge measurements were performed using a Faraday cage connected to an electrometer. Experiments were conducted inside a walk-in environmental chamber at 25 degrees C and RHs of 20% to 80%. Aerosolization was achieved using air flow rates of 30, 45, 60 and 75 L/min. The initial charges of the bulk and capsulated lactose were a magnitude lower than the charges of tapped or aerosolized lactose. Dynamic charge increased linearly with aerosolization air flow rate and RH. Greater frictional forces at higher air flow rate induced higher electrostatic charges. Increased RH enhanced charge generation. Repeated inhaler use significantly influenced electrostatic charge due to repeated usage. This study demonstrated the significance of interacting influences by variables commonly encountered in the use DPI such as variation in patient's inspiratory flow rate, ambient RH and repeated inhaler use on the electrostatic behavior of a lactose DPI carrier.

Workflow and Proof of Concept for Non-Targeted Analysis of Environmental Samples by LC-MS/MS

EPA Science Inventory

The human exposure includes thousands of chemicals acquired through various routes of exposure such as inhalation, ingestion, dermal contact, and indirect ingestion. Rapid assessment and screening of these chemicals is a difficult challenge facing EPA in its mission to protect pu...

Inhaled Mannitol as a Laryngeal and Bronchial Provocation Test.

PubMed

Tay, Tunn Ren; Hoy, Ryan; Richards, Amanda L; Paddle, Paul; Hew, Mark

2017-03-01

Timely diagnosis of vocal cord dysfunction (VCD), more recently termed "inducible laryngeal obstruction," is important because VCD is often misdiagnosed as asthma, resulting in delayed diagnosis and inappropriate treatment. Visualization of paradoxical vocal cord movement on laryngoscopy is the gold standard for diagnosis, but is limited by poor test sensitivity. Provocation tests may improve the diagnosis of VCD, but the diagnostic performance of current tests is less than ideal. Alternative provocation tests are required. This pilot study demonstrates the feasibility of using inhaled mannitol for concurrent investigation of laryngeal and bronchial hyperresponsiveness. Consecutive patients with suspected VCD seen at our institution's asthma clinic underwent flexible laryngoscopy at baseline and following mannitol challenge. VCD was diagnosed on laryngoscopy based on inspiratory adduction, or >50% expiratory adduction of the vocal cords. Bronchial hyperresponsiveness after mannitol challenge was also assessed. We evaluated the interrater agreement of postmannitol laryngoscopy between respiratory specialists and laryngologists. Fourteen patients with suspected VCD in the context of asthma evaluation were included in the study. Mannitol provocation demonstrated VCD in three of the seven patients with normal baseline laryngoscopy (42.9%). Only two patients had bronchial hyperresponsiveness. There was substantial interrater agreement between respiratory specialists and laryngologists, kappa = 0.696 (95% confidence interval: 0.324-1) (P = 0.006). Inhaled mannitol can be used to induce VCD. It is well tolerated and can evaluate laryngeal and bronchial hyperresponsiveness at the same setting. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

The effect of smoking status on burn inhalation injury mortality.

PubMed

Knowlin, Laquanda; Stanford, Lindsay; Cairns, Bruce; Charles, Anthony

2017-05-01

Three factors that effect burn mortality are age, total body surface of burn (TBSA), and inhalation injury. Of the three, inhalation injury is the strongest predictor of mortality thus its inclusion in the revised Baux score (age+TBSA+17* (inhalation injury, 1=yes, 0=no)). However, the weighted contribution of specific comorbidities such as smoker status on mortality has traditionally not been accounted for nor studied in this subset of burn patients. We therefore sought to examine the impact of current tobacco and/or marijuana smoking in patients with inhalation injury. A retrospective analysis of patients admitted to a regional burn center from 2002 to 2012. Independent variables analyzed included basic demographics, burn mechanism, presence of inhalation injury, TBSA, pre-existing comorbidities, and smoker status. Bivariate analysis was performed and logistic regression modeling using significant variables was utilized to estimate odds of mortality. There were a total of 7640 patients over the study period. 7% (n=580) of the burn cohort with inhalation injury were included in this study. In-hospital burn mortality for inhalation injury patients was 23%. Current smokers (20%) included cigarette smokers and marijuana users, 19% and 3%, respectively. Preexisting respiratory disease (17%) was present in 36% of smokers compared to 13% of non-smokers (p<0.001). Smokers had significantly lower mortality rate (9%) compared to non-smokers (26%, p<0.01). The logistic regression model for mortality outcomes identified statistically four significant variables: age, TBSA, ethnicity, and smoker status (OR=0.41, 95% CI=0.18-0.93). Presence of comorbidities, including preexisting respiratory disease, was not significant. In the sub group of burn patients with inhalation injury, the odds of mortality significantly decreased in pre-existing smokers after adjusting for significant covariates. We postulate that an immune tolerance mechanism that modulates and diminishes the pro-inflammatory response confers a survival advantage in smokers after exposure to acute smoke inhalation injury. Future prospective studies in human and/or animal models are needed to confirm these findings. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

Nitrite inhalant use among young gay and bisexual men in Vancouver during a period of increasing HIV incidence

PubMed Central

Lampinen, Thomas M; Mattheis, Kelly; Chan, Keith; Hogg, Robert S

2007-01-01

Background Nitrite inhalants ("poppers") are peripheral vasodilators which, since the beginning of the epidemic, have been known to increase risk for acquiring HIV infection among men who have sex with men (MSM). However, few studies in recent years have characterized use. From 1999 to 2004, new HIV diagnoses among MSM in British Columbia increased 78%, prompting us to examine the prevalence and correlates of this modifiable HIV risk factor. Methods Self-administered questionnaires were completed between October 2002 and May 2004 as part of an open cohort study of HIV-seronegative young MSM. We measured nitrite inhalant use during the previous year and use during sexual encounters with casual partners specifically. Correlates of use were identified using odds ratios. Results Among 354 MSM surveyed, 31.6% reported any use during the previous year. Nitrite inhalant use during sexual encounters was reported by 22.9% of men and was strongly associated with having casual partners, with greater numbers of casual partners (including those with positive or unknown serostatus) and with anal intercourse with casual partners. Nitrite inhalant use was not associated with non-use of condoms with casual sexual partners per se. Conclusion Contemporary use of nitrite inhalants amongst young MSM is common and a strong indicator of anal intercourse with casual sexual partners. Since use appears to increase the probability of infection following exposure to HIV, efforts to reduce the use of nitrite inhalants among MSM should be a very high priority among HIV prevention strategies. PMID:17362516

Towards soft robotic devices for site-specific drug delivery.

PubMed

Alici, Gursel

2015-01-01

Considerable research efforts have recently been dedicated to the establishment of various drug delivery systems (DDS) that are mechanical/physical, chemical and biological/molecular DDS. In this paper, we report on the recent advances in site-specific drug delivery (site-specific, controlled, targeted or smart drug delivery are terms used interchangeably in the literature, to mean to transport a drug or a therapeutic agent to a desired location within the body and release it as desired with negligibly small toxicity and side effect compared to classical drug administration means such as peroral, parenteral, transmucosal, topical and inhalation) based on mechanical/physical systems consisting of implantable and robotic drug delivery systems. While we specifically focus on the robotic or autonomous DDS, which can be reprogrammable and provide multiple doses of a drug at a required time and rate, we briefly cover the implanted DDS, which are well-developed relative to the robotic DDS, to highlight the design and performance requirements, and investigate issues associated with the robotic DDS. Critical research issues associated with both DDSs are presented to describe the research challenges ahead of us in order to establish soft robotic devices for clinical and biomedical applications.

Fluticasone propionate in clinically suspected asthma patients with negative methacholine challenge test.

PubMed

Peiman, Soheil; Abtahi, Hamidreza; Akhondzadeh, Shahin; Safavi, Enayat; Moin, Mostafa; Rahimi Foroushani, Abbas

2017-07-01

Despite reports of response to steroid inhaler in some clinically suspected asthma patients with negative methacholine challenge test (CSA/MCT-), treatment in these patients has not been prospectively studied. We studied the role of a 12 week high dose inhaled fluticasone trial in CSA/MCT- patients. After a 2 week run-in period, CSA/MCT-patients were treated with 12 weeks of Fluticasone propionate 1000 µg/day. The Asthma Control Test (ACT), numeric cough score (NCS) and bronchodilator use were compared with their pretreatment values. Thirty-four of 42 CSA/MCT-patients completed the study. Mean pretreatment ACT score (pACT) was significantly increased after treatment (14.7 ± 3.37 to 20.9 ± 3.1, P < 0.001). Posttreatment values of daytime (1.0 ± 1.0) and night-time (0.6 ± 0.9) NCS decreased compared to their pretreatment values (2.8 ± 1.1 and 1.9 ± 1.3, respectively; P < 0.001). ACT score change (ΔACT) were significantly greater in those with pACT < 15 than in those ≥15 (P < 0.001) . Fifteen of 21 patients with ΔACT > 5 did not need to use bronchodilator for their symptom relief. Wheeze disappeared in all six patients with ΔACT > 5 after the trial. Six months after the study, steroid inhaler continued to be used by 72.2% of patients. A significant portion of CSA/MCT- (especially those with pretreatment ACT score <15) respond to high dose fluticasone inhaler in terms of symptoms relief, disappearance of wheeze and need to bronchodilator use. ΔACT could not be predicted with any individual symptoms or signs before MCT, % FEV1 decline or symptoms during MCT and exhaled nitric oxide. © 2015 John Wiley & Sons Ltd.

Effects of acute inhalation of aerosols generated during resistance spot welding with mild-steel on pulmonary, vascular and immune responses in rats

PubMed Central

Zeidler-Erdely, Patti C.; Meighan, Terence G.; Erdely, Aaron; Fedan, Jeffrey S.; Thompson, Janet A.; Bilgesu, Suzan; Waugh, Stacey; Anderson, Stacey; Marshall, Nikki B.; Afshari, Aliakbar; McKinney, Walter; Frazer, David G.; Antonini, James M.

2015-01-01

Spot welding is used in the automotive and aircraft industries, where high-speed, repetitive welding is needed to join thin sections of metal. Epoxy adhesives are applied as sealers to the metal seams. Pulmonary function abnormalities and airway irritation have been reported in spot welders, but no animal toxicology studies exist. Therefore, the goal of this study was to investigate vascular, immune and lung toxicity measures after exposure to these metal fumes in an animal model. Male Sprague-Dawley rats were exposed by inhalation to 25 mg/m3 to either mild-steel spot welding aerosols with sparking (high metal, HM) or without sparking (low metal, LM) for 4 h/d for 3, 8 and 13 d. Shams were exposed to filtered air. Bronchoalveolar lavage (BAL), lung gene expression and ex vivo BAL cell challenge were performed to assess lung toxicity. Lung resistance (RL) was evaluated before and after challenge with inhaled methacholine (MCh). Functional assessment of the vascular endothelium in isolated rat tail arteries and leukocyte differentiation in the spleen and lymph nodes via flow cytometry was also done. Immediately after exposure, baseline RL was significantly elevated in the LM spot welding aerosols, but returned to control level by 24 h postexposure. Airway reactivity to MCh was unaffected. Lung inflammation and cytotoxicity were mild and transient. Lung epithelial permeability was significantly increased after 3 and 8 d, but not after 13 d of exposure to the HM aerosol. HM aerosols also caused vascular endothelial dysfunction and increased CD4+, CD8+ and B cells in the spleen. Only LM aerosols caused increased IL-6 and MCP-1 levels compared with sham after ex vivo LPS stimulation in BAL macrophages. Acute inhalation of mild-steel spot welding fumes at occupationally relevant concentrations may act as an irritant as evidenced by the increased RL and result in endothelial dysfunction, but otherwise had minor effects on the lung. PMID:25140454

Orange-Pigmented Sputum as a Manifestation of Smoke Grenade Inhalation Injury.

PubMed

Chatzivasiloglou, Fotini; Katsenos, Stamatis; Psara, Anthoula; Tsintiris, Konstantinos

2016-01-01

A 34-year-old man presented with scanty hemoptysis, orange-colored expectoration, and mild dyspnea. He was in an enclosed building taking part in a military training exercise inhaling an orange-colored smoke from a smoke grenade ignition. His symptoms developed immediately after the initial exposure but he sought medical assistance 20 hours later because of their persistence. Fiberoptic bronchoscopy was performed revealing diffuse inflammatory tracheobronchial tree with streaky orange-pigmented secretions in the trachea and both main-stem bronchi. Acute tracheobronchitis was diagnosed and the patient was treated with nebulized bronchodilators and intravenous corticosteroids showing complete recovery. To our knowledge, this is the first well-documented report of inhalation injury induced by a smoke bomb explosion including potassium chlorate oxidizer and Sudan I and presenting with orange-pigmented sputum production. Smoke inhalation injury is associated with significant morbidity and mortality. The heterogeneity of the smoke and the large variety of the resulting symptoms may be the reason why a definition, specific diagnostic criteria, and therapeutic guidelines are still lacking.

Lung deposition analyses of inhaled toxic aerosols in conventional and less harmful cigarette smoke: a review.

PubMed

Kleinstreuer, Clement; Feng, Yu

2013-09-23

Inhaled toxic aerosols of conventional cigarette smoke may impact not only the health of smokers, but also those exposed to second-stream smoke, especially children. Thus, less harmful cigarettes (LHCs), also called potential reduced exposure products (PREPs), or modified risk tobacco products (MRTP) have been designed by tobacco manufacturers to focus on the reduction of the concentration of carcinogenic components and toxicants in tobacco. However, some studies have pointed out that the new cigarette products may be actually more harmful than the conventional ones due to variations in puffing or post-puffing behavior, different physical and chemical characteristics of inhaled toxic aerosols, and longer exposure conditions. In order to understand the toxicological impact of tobacco smoke, it is essential for scientists, engineers and manufacturers to develop experiments, clinical investigations, and predictive numerical models for tracking the intake and deposition of toxicants of both LHCs and conventional cigarettes. Furthermore, to link inhaled toxicants to lung and other diseases, it is necessary to determine the physical mechanisms and parameters that have significant impacts on droplet/vapor transport and deposition. Complex mechanisms include droplet coagulation, hygroscopic growth, condensation and evaporation, vapor formation and changes in composition. Of interest are also different puffing behavior, smoke inlet conditions, subject geometries, and mass transfer of deposited material into systemic regions. This review article is intended to serve as an overview of contributions mainly published between 2009 and 2013, focusing on the potential health risks of toxicants in cigarette smoke, progress made in different approaches of impact analyses for inhaled toxic aerosols, as well as challenges and future directions.

Ultrafine particles affect the balance of endogenous pro- and anti-inflammatory lipid mediators in the lung: in-vitro and in-vivo studies

PubMed Central

2012-01-01

Background Exposure to ultrafine particles exerts diverse harmful effects including aggravation of pulmonary diseases like asthma. Recently we demonstrated in a mouse model for allergic airway inflammation that particle-derived oxidative stress plays a crucial role during augmentation of allergen-induced lung inflammation by ultrafine carbon particle (UfCP) inhalation. The mechanisms how particle inhalation might change the inflammatory balance in the lungs, leading to accelerated inflammatory reactions, remain unclear. Lipid mediators, known to be immediately generated in response to tissue injury, might be strong candidates for priming this particle-triggered change of the inflammatory balance. Methods We hypothesize that inhalation of UfCP may disturb the balance of pro- and anti-inflammatory lipid mediators in: i) a model for acute allergic pulmonary inflammation, exposing mice for 24 h before allergen challenge to UfCP inhalation (51.7 nm, 507 μg/m3), and ii) an in-vitro model with primary rat alveolar macrophages (AM) incubated with UfCP (10 μg/1 x 106 cells/ml) for 1 h. Lungs and AM were analysed for pro- and anti-inflammatory lipid mediators, namely leukotriene B4 (LTB4), prostaglandin E2 (PGE2), 15(S)-hydroxy-eicosatetraenoic acid (15(S)-HETE), lipoxin A4 (LXA4) and oxidative stress marker 8-isoprostane by enzyme immunoassays and immunohistochemistry. Results In non-sensitized mice UfCP exposure induced a light non-significant increase of all lipid mediators. Similarly but significantly in rat AM all lipid mediators were induced already within 1 h of UfCP stimulation. Also sensitized and challenge mice exposed to filtered air showed a partially significant increase in all lipid mediators. In sensitized and challenged mice UfCP exposure induced highest significant levels of all lipid mediators in the lungs together with the peak of allergic airway inflammation on day 7 after UfCP inhalation. The levels of LTB4, 8-isoprostane and PGE2 were significantly increased also one day after UfCP exposure. Immunohistochemistry localized highest concentrations of PGE2 especially in AM one day after UfCP exposure. Conclusion Our results suggest that UfCP exposure affects the balance between pro- and anti-inflammatory lipid mediators. In allergic mice, where the endogenous balance of pro- and anti-inflammatory mediators is already altered, UfCP exposure aggravates the inflammation and the increase in anti-inflammatory, pro-resolving lipid mediators is insufficient to counterbalance the extensive inflammatory response. This may be a contributing mechanism that explains the increased susceptibility of asthmatic patients towards particle exposure. PMID:22809365

Gold nanoparticle aerosols for rodent inhalation and translocation studies

NASA Astrophysics Data System (ADS)

Möller, Winfried; Gibson, Neil; Geiser, Marianne; Pokhrel, Suman; Wenk, Alexander; Takenaka, Shinji; Schmid, Otmar; Bulgheroni, Antonio; Simonelli, Federica; Kozempel, Jan; Holzwarth, Uwe; Wigge, Christoph; Eigeldinger-Berthou, Sylvie; Mädler, Lutz; Kreyling, Wolfgang G.

2013-04-01

The intensive use of nano-sized particles in many different applications necessitates studies on their risk assessment as there are still open questions on their safe handling and utilization. For reliable risk assessment, the interaction of nanoparticles (NP) with biological systems after various routes of exposure needs to be investigated using well-characterized NP. We report here on the generation of gold-NP (Au-NP) aerosols for inhalation studies with the spark ignition technique, and their characterization in terms of chemical composition, physical structure, morphology, and specific surface area, and on interaction with lung tissues and lung cells after 1 h inhalation by mice. The originally generated agglomerated Au-NP were converted into compact spherical Au-NP by thermal annealing at 600 °C, providing particles of similar mass, but different size and specific surface area. Since there are currently no translocation data available on inhaled Au-NP in the 10-50 nm diameter range, the emphasis was to generate NP as small as 20 nm for inhalation in rodents. For anticipated in vivo systemic translocation and dosimetry analyses, radiolabeled Au-NP were created by proton irradiating the gold electrodes of the spark generator, thus forming gamma ray emitting 195Au with 186 days half-life, allowing long-term biokinetic studies. The dissolution rate of 195Au from the NP was below detection limits. The highly concentrated, polydisperse Au-NP aerosol (1-2 × 107 NP/cm3) proved to be constant over several hours in terms of its count median mobility diameter, its geometric standard deviation and number concentration. After collection on filters particles can be re-suspended and used for instillation or ingestion studies.

A Review of the Comparative Anatomy, Histology, Physiology and Pathology of the Nasal Cavity of Rats, Mice, Dogs and Non-human Primates. Relevance to Inhalation Toxicology and Human Health Risk Assessment.

PubMed

Chamanza, R; Wright, J A

2015-11-01

There are many significant differences in the structural and functional anatomy of the nasal cavity of man and laboratory animals. Some of the differences may be responsible for the species-specific nasal lesions that are often observed in response to inhaled toxicants. This paper reviews the comparative anatomy, physiology and pathology of the nasal cavity of the rat, mouse, dog, monkey and man, highlighting factors that may influence the distribution of nasal lesions. Gross anatomical variations such as turbinate structure, folds or grooves on nasal walls, or presence or absence of accessory structures, may influence nasal airflow and species-specific uptake and deposition of inhaled material. In addition, interspecies variations in the morphological and biochemical composition and distribution of the nasal epithelium may affect the local tissue susceptibility and play a role in the development of species-specific nasal lesions. It is concluded that, while the nasal cavity of the monkey might be more similar to that of man, each laboratory animal species provides a model that responds in a characteristic and species-specific manner. Therefore for human risk assessment, careful consideration must be given to the anatomical differences between a given animal model and man. Copyright © 2015 Elsevier Ltd. All rights reserved.

Positive "alveolar" responses to antigen inhalation provocation tests: their validity and recognition.

PubMed Central

Hendrick, D J; Marshall, R; Faux, J A; Krall, J M

1980-01-01

The validity of inhalation tests in the investigation of extrinsic allergic alveolitis was assessed from the results of 144 antigen and control tests in 31 subjects. A definitive pattern of positive late responses was observed. Reactions to nebulised bird serum and droppings in subjects with bird fancier's lung were identical to reactions after "natural" exposures in aviaries or lofts, and to reactions after "occupational" challenges in subjects with farmer's lung and mushroom worker's lung. In general, positive tests were easily recognised subjectively from symptoms and signs appropriate to an influenza-like illness and undue respiratory effort on exercise. They were associated with significant changes in six readily available objective monitoring measurements--exercise minute ventilation (greater than or equal to +15%), body temperature (> 37.2 degrees C), circulating neutrophils (greater than or equal to +2500/mm3), exercise respiratory frequency (greater than or equal to +25%), circulating lymphocytes (greater than ore equal to -500/mm3 with lymphopenia), and forced vital capacity (greater than or equal to -15%). These confirmatory monitoring tests had specificities of approximately 95% and sensitivities of 85-48%. Measurement of diffusing capacity, lung volume subdivisions, or resting minute ventilation/respiratory frequency proved to be too insensitive to be useful, as did auscultation and chest radiography. We conclude that responses that do provoke significant changes in these less sensitive tests are unnecessarily distressing and, presumable, unnecessarily hazardous. PMID:7434297

Role of alveolar topology on acinar flows and convective mixing.

PubMed

Hofemeier, Philipp; Sznitman, Josué

2014-06-01

Due to experimental challenges, computational simulations are often sought to quantify inhaled aerosol transport in the pulmonary acinus. Commonly, these are performed using generic alveolar topologies, including spheres, toroids, and polyhedra, to mimic the complex acinar morphology. Yet, local acinar flows and ensuing particle transport are anticipated to be influenced by the specific morphological structures. We have assessed a range of acinar models under self-similar breathing conditions with respect to alveolar flow patterns, convective flow mixing, and deposition of fine particles (1.3 μm diameter). By tracking passive tracers over cumulative breathing cycles, we find that irreversible flow mixing correlates with the location and strength of the recirculating vortex inside the cavity. Such effects are strongest in proximal acinar generations where the ratio of alveolar to ductal flow rates is low and interalveolar disparities are most apparent. Our results for multi-alveolated acinar ducts highlight that fine 1 μm inhaled particles subject to alveolar flows are sensitive to the alveolar topology, underlining interalveolar disparities in particle deposition patterns. Despite the simplicity of the acinar models investigated, our findings suggest that alveolar topologies influence more significantly local flow patterns and deposition sites of fine particles for upper generations emphasizing the importance of the selected acinar model. In distal acinar generations, however, the alveolar geometry primarily needs to mimic the space-filling alveolar arrangement dictated by lung morphology.

First evidence of occupational asthma to argan powder in a cosmetic factory.

PubMed

Paris, C; Herin, F; Penven, E; Thaon, I; Richard, C; Jacquenet, S; Barbaud, A; Poussel, M

2016-04-01

Argan is used worldwide in numerous cosmetic products, as this fruit is supposed to have many beneficial properties on health. New cases of allergy can be expected with the growing use of argan. We investigated all workers (9) employed by a cosmetic factory and exposed to argan powder to identify possible allergies related to exposure to argan powder. Patients were investigated in the occupational disease department and, according to their symptoms, underwent pulmonary function testing, methacholine challenge, specific inhalation challenge to argan powder, skin prick tests, and immunoblotting analysis. We report three cases of occupational asthma to argan powder and a probable case of rhinitis. Fifteen argan proteins were recognized by the patients' IgE. Identification of proteins, cross-reactions to nuts, and ELISA inhibition tests suggested that some argan allergens can cross-react in vitro with hazelnut allergens, including 11S globulin and vicilin. High-level exposure to argan powder should be considered to be a potential cause of IgE-mediated allergy, and workers handling argan powder should be carefully investigated. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

T Follicular Helper Cell Plasticity Shapes Pathogenic T Helper 2 Cell-Mediated Immunity to Inhaled House Dust Mite.

PubMed

Ballesteros-Tato, André; Randall, Troy D; Lund, Frances E; Spolski, Rosanne; Leonard, Warren J; León, Beatriz

2016-02-16

Exposure to environmental antigens, such as house dust mite (HDM), often leads to T helper 2 (Th2) cell-driven allergic responses. However, the mechanisms underlying the development of these responses are incompletely understood. We found that the initial exposure to HDM did not lead to Th2 cell development but instead promoted the formation of interleukin-4 (IL-4)-committed T follicular helper (Tfh) cells. Following challenge exposure to HDM, Tfh cells differentiated into IL-4 and IL-13 double-producing Th2 cells that accumulated in the lung and recruited eosinophils. B cells were required to expand IL-4-committed Tfh cells during the sensitization phase, but did not directly contribute to disease. Impairment of Tfh cell responses during the sensitization phase or Tfh cell depletion prevented Th2 cell-mediated responses following challenge. Thus, our data demonstrate that Tfh cells are precursors of HDM-specific Th2 cells and reveal an unexpected role of B cells and Tfh cells in the pathogenesis of allergic asthma. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of 7.5% CO2 challenge in generalized anxiety disorder.

PubMed

Seddon, Kate; Morris, Kelly; Bailey, Jayne; Potokar, John; Rich, Ann; Wilson, Sue; Bettica, Paolo; Nutt, David J

2011-01-01

We have previously developed a putative model of generalized anxiety disorder in healthy volunteers using a 20-minute 7.5% carbon dioxide (CO(2)) inhalation challenge. The aim of this study was to validate the 7.5% CO(2) paradigm by assessing its effects in patients with generalized anxiety disorder in a test-retest design. Twelve medication-free generalized anxiety disorder patients attended our lab for two study days. On each study day placebo (compressed air) and 7.5% CO(2) mixture were randomly administered over 20 min, at least 30 min apart, in a single blind, randomized, placebo-controlled cross-over design. Subjective ratings, cardiovascular measures and cortisol levels were collected throughout. CO(2) challenge significantly increased ratings for anxiety and other subjective symptoms associated with generalized anxiety disorder, compared with air. It also significantly increased systolic blood pressure on day 2, indicating increased autonomic arousal. There was no change between the two test days in mean anxiety rating scores, and there also appeared to be a correlation for individual scores on a number of the subjective measures. In conclusion, 20 min of 7.5% CO(2) gas inhalation increases anxiety responses in patients with generalized anxiety disorder, and this is reliable over time.

Diagnostic properties of the methacholine and mannitol bronchial challenge tests: a comparison study.

PubMed

Kim, Min-Hye; Song, Woo-Jung; Kim, Tae-Wan; Jin, Hyun-Jung; Sin, You-Seob; Ye, Young-Min; Kim, Sang-Heon; Park, Heung-Woo; Lee, Byung-Jae; Park, Hae-Sim; Yoon, Ho-Joo; Choi, Dong-Chull; Min, Kyung-Up; Cho, Sang-Heon

2014-08-01

Airway hyperresponsiveness is a common feature of asthma. Methacholine and mannitol are two representative agonists for bronchial challenge. They have theoretically different mechanisms of action, and may have different diagnostic properties. However, their difference has not been directly evaluated among Korean adults. In this study, we compare the diagnostic properties of methacholine and mannitol bronchial provocation tests. Asthmatic patients and non-asthmatic controls were recruited prospectively from four referral hospitals in Korea. Participants were challenged with each of methacholine and mannitol inhalation on different days. Their diagnostic utility was evaluated by calculating their sensitivity and specificity for asthma diagnosis. Response-dose ratio was also compared. A total of 50 asthmatic adults and 54 controls were enrolled (mean age 43.8 years). The sensitivity and specificity of mannitol challenge (defined by a PD15 of <635 mg) were 48.0% and 92.6%, respectively, whereas those of methacholine (defined by a PC20 of <16 mg/mL) were 42.0% and 98.1%, respectively. Twenty asthmatic participants (24%) showed positive response to a single agonist only. In the receiver operating curve analyses using response-dose ratio values, area under the curve was 0.77 (95% confidence interval (CI): 0.68-0.86) for mannitol, and 0.89 (95% CI: 0.83-0.95) for methacholine. The correlations between log- transformed mannitol and methacholine response-dose ratios were significant but moderate (r = 0.683, P < 0.001). The present study demonstrated overall similar diagnostic properties of two diagnostic tests, but also suggested their intercomplementary roles for asthma. The clinical trial registration number at ClinicalTrial.gov is NCT02104284. © 2014 Asian Pacific Society of Respirology.

Assessment of health effects in epidemiologic studies of air pollution.

PubMed Central

Samet, J M; Speizer, F E

1993-01-01

As we increasingly recognize the complexity of the pollutants in indoor and outdoor microenvironments, a broad array of inhaled mixtures has assumed scientific, public health, and regulatory importance. Few adverse effects of environmental pollutants are specific, that is, uniquely associated with a single agent; the adverse effects that might be considered in an investigation of the consequences of exposure to an inhaled complex mixture are generally nonspecific. In the context of this paper, we will refer to binary mixtures as complex, though we realize that a more precise definition of complexity would restrict the term to mixtures of three or more constituents. Their causes potentially include not only pollutant exposures through the medium of inhaled air but other environmental agents, such as infectious organisms and radiation, and inherent characteristics of the exposed persons, such as atopy. We review the outcome measures that have been used in epidemiologic studies of the health effects of single pollutants and complex mixtures. Some of these outcome measures have been carefully standardized, whereas others need similar standardization and modification to improve sensitivity and specificity for investigating the health effects of air pollution. PMID:8206024

Recent advances in delivery mechanisms for aerosol therapy during pediatric respiratory diseases.

PubMed

Wu, Yue'E; Zhang, Chonglin; Zhen, Qing

2018-04-01

The treatment of pediatric surgery diseases via utilization of aerosol delivery mechanisms is in progress for the betterment of pediatric care. Over the years, aerosol therapy has come to play an integral role in the treatment of pediatric respiratory diseases. Inhaled aerosol agents such as bronchodilators, corticosteroids, antibiotics, and mucolytics are commonly delivered to spontaneously breathing pediatric patients with a tracheostomy. Administering therapeutic inhaled aerosols to pediatric patients is challenging. The pediatric population ranges in age, which means patients with different airway sizes, breathing patterns, and cooperation levels. These patient-related factors impact the deposition of aerosol drugs in the lungs. The present review article will discuss the recent advancements in the delivery mechanisms for aerosol therapy in pediatric patients with respiratory diseases.

Surface modification of lactose inhalation blends by moisture.

PubMed

Watling, C P; Elliott, J A; Scruton, C; Cameron, R E

2010-05-31

We present an investigation of the effects of relative humidity (RH) on lactose powders during storage, with the aims of determining the humidity conditions under which lactose inhalation blends are stable, and characterising the surface changes that occur as a result of water condensation. Lactose inhalation powders manufactured by milling and sieving were stored in environments of RH from 32% to 100% (at room temperature) and changes in surface properties were observed using BET nitrogen adsorption, environmental scanning electron microscopy and laser diffraction particle size analysis. We found that the specific surface area of all lactose powders decreased during storage, with the rate of decrease and final drop being larger at higher RH (ranging from a 62% decrease at 100% RH to a 34% decrease at 32% RH, at room temperature). The specific surface area decrease corresponded to a reduction in the volume of fine particles (<5 microm) in the blend. Two effects were found to contribute to the decrease in specific surface area: the smoothing of coarse particles, attributed to the surface fine particles undergoing deliquescence due to their enhanced solubility by the Kelvin effect (i.e. due to their greater curvature and consequently greater surface energy), and solid bridging between fine particles in agglomerates, such that loose fine particles disappeared from the powder blend, having bonded with coarser particles. These changes in particle properties resulting from moisture exposure are expected to influence the fine particle fraction of drug released from the powder blends, and the observation that lactose inhalation blends were unstable even at 32% RH could potentially be a concern for the pharmaceutical industry. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Personal Exposure to Inhalable Dust and the Specific Latex Aero-Allergen, Hev b6.02, in Latex Glove Manufacturing in Thailand

PubMed Central

Sanguanchaiyakrit, Nuthchyawach; Povey, Andrew C.; de Vocht, Frank

2014-01-01

Objectives: Latex product manufacturing is an important industry in south-east Asia but has the potential for considerable occupational exposure of workers to latex allergens. Although exposure to latex allergens can result in adverse health reactions, few studies to characterize this exposure have been conducted to date. This study therefore aimed to characterize current airborne inhalable dust and the specific allergen, Hev b 6.02, exposures in this industry in Thailand. Methods: Workers were recruited from three factories in the southern part of Thailand. Full-shift inhalable dust personal air sampling was conducted using IOM sampling heads equipped with polytetrafluoroethylene filters at a 2.0 l min−1 flowrate. After weighing to determine inhalable dust levels, filters were extracted and analysed for Hev b 6.02 using an enzyme immunometric assay. Results: Two hundred and seventy-five workers agreed to participate, resulting in a total of 292 measurements. Geometric mean (GM) personal exposure to inhalable dust was 0.88mg m–3, but individual exposures up to 12.34mg m–3 were measured. The pattern of exposure was similar across factories, with highest exposures in the stripping (GM 2.08–4.05mg m–3 for the 3 factories) and tumbling departments (1.11–2.17mg m–3). Within-worker (day-to-day) variability contributed 92% to total variability. The Hev b 6.02 exposure pattern was similar with time-weighted average GM exposure levels in the oldest factory ranging from 8.7mg m–3 in the laboratory to 30.2mg m–3 in the stripping department. In contrast to inhalable dust exposure, total exposure variability was primary driven by variability between workers (67%). Conclusions: Workers in these latex product factories get routinely exposed to measurable Hev b 6.02 levels, which may give rise to increased incidence of allergic symptoms and occupational asthma. Also, in this measurement campaign a 10mg m–3, but not 15mg m–3, occupational exposure limit for inhalable dust was occasionally exceeded. Highest Hev b 6.02 exposures were found in the stripping and tumbling departments, which would be natural targets for interventions aimed at reducing exposure. PMID:24569810

Personal exposure to inhalable dust and the specific latex aero-allergen, Hev b6.02, in latex glove manufacturing in Thailand.

PubMed

Sanguanchaiyakrit, Nuthchyawach; Povey, Andrew C; de Vocht, Frank

2014-06-01

Latex product manufacturing is an important industry in south-east Asia but has the potential for considerable occupational exposure of workers to latex allergens. Although exposure to latex allergens can result in adverse health reactions, few studies to characterize this exposure have been conducted to date. This study therefore aimed to characterize current airborne inhalable dust and the specific allergen, Hev b 6.02, exposures in this industry in Thailand. Workers were recruited from three factories in the southern part of Thailand. Full-shift inhalable dust personal air sampling was conducted using IOM sampling heads equipped with polytetrafluoroethylene filters at a 2.0 l min(-1) flowrate. After weighing to determine inhalable dust levels, filters were extracted and analysed for Hev b 6.02 using an enzyme immunometric assay. Two hundred and seventy-five workers agreed to participate, resulting in a total of 292 measurements. Geometric mean (GM) personal exposure to inhalable dust was 0.88 mg m(-3), but individual exposures up to 12.34 mg m(-3) were measured. The pattern of exposure was similar across factories, with highest exposures in the stripping (GM 2.08-4.05 mg m(-3) for the 3 factories) and tumbling departments (1.11-2.17 mg m(-3)). Within-worker (day-to-day) variability contributed 92% to total variability. The Hev b 6.02 exposure pattern was similar with time-weighted average GM exposure levels in the oldest factory ranging from 8.7 mg m(-3) in the laboratory to 30.2mg m(-3) in the stripping department. In contrast to inhalable dust exposure, total exposure variability was primary driven by variability between workers (67%). Workers in these latex product factories get routinely exposed to measurable Hev b 6.02 levels, which may give rise to increased incidence of allergic symptoms and occupational asthma. Also, in this measurement campaign a 10mg m(-3), but not 15 mg m(-3), occupational exposure limit for inhalable dust was occasionally exceeded. Highest Hev b 6.02 exposures were found in the stripping and tumbling departments, which would be natural targets for interventions aimed at reducing exposure. © The Author 2014. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Patients' reasons for accepting a free community pharmacy asthma service.

PubMed

Kaae, Susanne; Sporrong, Sofia Kälvemark

2015-10-01

Challenges in recruiting patients at the pharmacy counter for cognitive services have been observed, hampering development in this area. To overcome this barrier, insight into the patient perspective is crucial to understanding their lack of appreciation of the services. However, very few studies have been conducted so far to explore why patients accept or decline offers of cognitive services at the pharmacy counter. To explore patients' reasons for accepting a particular cognitive service (the Inhaler Technique Assessment Service) a service intended to detect inhalation technique errors. The service is reimbursed by the Danish state and takes approximately 10 min. Setting Ten community pharmacies located in different regions of Denmark, including the center and suburbs of Copenhagen. Two types of interviews were conducted: long and short semi-structured interviews with 24 patients suffering mainly from asthma and COPD. Researchers from Copenhagen University conducted 11 long interviews and pharmacy internship students from Copenhagen University carried out 13 short interviews. The interviews were analyzed using descriptive analysis. Patients' perceived needs of an inhalation counseling service as well as their motivation for accepting the service, including their accounts of how the service was orally offered by staff. The majority of participants were used to using inhaler devices. The participants felt, for several reasons, little need of an inhaler service and seldom noticed the precise way the service was offered. Patients did not seem to accept the service expecting personal benefits. First timers appeared to accept the service to learn how to use the device correctly, whereas experienced users appeared to accept the ITAS to be helpful to staff or to learn more about health issues in general or were convinced by individual employees who showed a special interest in the participant receiving the service. Privacy problems were felt by several participants. The patients felt little need for the inhaler counseling service. Patients however accepted the service for various reasons of which the feeling how staff showing an interest in helping them seemed especially convincing.

Real-time measurement of dust in the workplace using video exposure monitoring: Farming to pharmaceuticals

NASA Astrophysics Data System (ADS)

Walsh, P. T.; Forth, A. R.; Clark, R. D. R.; Dowker, K. P.; Thorpe, A.

2009-02-01

Real-time, photometric, portable dust monitors have been employed for video exposure monitoring (VEM) to measure and highlight dust levels generated by work activities, illustrate dust control techniques, and demonstrate good practice. Two workplaces, presenting different challenges for measurement, were used to illustrate the capabilities of VEM: (a) poultry farming activities and (b) powder transfer operations in a pharmaceutical company. For the poultry farm work, the real-time monitors were calibrated with respect to the respirable and inhalable dust concentrations using cyclone and IOM reference samplers respectively. Different rankings of exposure for typical activities were found on the small farm studied here compared to previous exposure measurements at larger poultry farms: these were mainly attributed to the different scales of operation. Large variations in the ratios of respirable, inhalable and real-time monitor TWA concentrations of poultry farm dust for various activities were found. This has implications for the calibration of light-scattering dust monitors with respect to inhalable dust concentration. In the pharmaceutical application, the effectiveness of a curtain barrier for dust control when dispensing powder in a downflow booth was rapidly demonstrated.

Nanotechnology and pharmaceutical inhalation aerosols.

PubMed

Patel, A R; Vavia, P R

2007-02-01

Pharmaceutical inhalation aerosols have been playing a crucial role in the health and well being of millions of people throughout the world for many years. The technology's continual advancement, the ease of use and the more desirable pulmonary-rather-than-needle delivery for systemic drugs has increased the attraction for the pharmaceutical aerosol in recent years. But administration of drugs by the pulmonary route is technically challenging because oral deposition can be high, and variations in inhalation technique can affect the quantity of drug delivered to the lungs. Recent advances in nanotechnology, particularly drug delivery field have encouraged formulation scientists to expand their reach in solving tricky problems related to drug delivery. Moreover, application of nanotechnology to aerosol science has opened up a new category of pharmaceutical aerosols (collectively known as nanoenabled-aerosols) with added advantages and effectiveness. In this review, some of the latest approaches of nano-enabled aerosol drug delivery system (including nano-suspension, trojan particles, bioadhesive nanoparticles and smart particle aerosols) that can be employed successfully to overcome problems of conventional aerosol systems have been introduced.

An Autonomic Link Between Inhaled Diesel Exhaust and Impaired Cardiac Performance: Insight From Treadmill and Doubutamine Challenges in Heart Failure-Prone Rats

EPA Science Inventory

Background: Short-term exposure to vehicular emissions is associated with adverse cardiac events. Diesel exhaust (DE) is an ubiquitous air pollutant believed to provoke cardiac events partly through imbalance of the sympathetic and parasympathetic branches of the autonomic nervo...

Development of a Single High Fat Meal Challenge to Unmask Latent Cardiopulmonary Effects of Air Pollution Exposure in Rats

EPA Science Inventory

Stress tests are used clinically to determine the presence of underlying disease and predict future cardiovascular risk. In previous studies, we used treadmill exercise stress in rats to unmask the priming effects of air pollution inhalation. Other day-to-day activities stress th...

Emotional Avoidance and Panicogenic Responding to a Biological Challenge Procedure

ERIC Educational Resources Information Center

Karekla, Maria; Forsyth, John P.; Kelly, Megan M.

2004-01-01

Healthy undergraduates high (n = 27) and low (n = 27) in experiential avoidance underwent twelve 20 s inhalations of 20% carbon dioxide-enriched air, while physiological (e.g., skin conductance, heart rate, EMG, and end-tidal CO[subscript 2]) and subjective (e.g., subjective units of distress, evaluative ratings, number and severity of panic…

PLEURAL EFFECTS OF INDIUM PHOSPHIDE IN B6C3F1 MICE: NONFIBROUS PARTICULATE INDUCED PLEURAL FIBROSIS

PubMed Central

Kirby, Patrick J.; Shines, Cassandra J.; Taylor, Genie J.; Bousquet, Ronald W.; Price, Herman C.; Everitt, Jeffrey I.; Morgan, Daniel L.

2010-01-01

The mechanism(s) by which chronic inhalation of indium phosphide (InP) particles causes pleural fibrosis is not known. Few studies of InP pleural toxicity have been conducted because of the challenges in conducting particulate inhalation exposures, and because the pleural lesions developed slowly over the 2-year inhalation study. The authors investigated whether InP (1 mg/kg) administered by a single oropharyngeal aspiration would cause pleural fibrosis in male B6C3F1 mice. By 28 days after treatment, protein and lactate dehydrogenase (LDH) were significantly increased in bronchoalveolar lavage fluid (BALF), but were unchanged in pleural lavage fluid (PLF). A pronounced pleural effusion characterized by significant increases in cytokines and a 3.7-fold increase in cell number was detected 28 days after InP treatment. Aspiration of soluble InCl3 caused a similar delayed pleural effusion; however, other soluble metals, insoluble particles, and fibers did not. The effusion caused by InP was accompanied by areas of pleural thickening and inflammation at day 28, and by pleural fibrosis at day 98. Aspiration of InP produced pleural fibrosis that was histologically similar to lesions caused by chronic inhalation exposure, and in a shorter time period. This oropharyngeal aspiration model was used to provide an initial characterization of the progression of pleural lesions caused by InP. PMID:19995279

Impact of Utilizing Pharmacy Students as Workforce for Hawai‘i Asthma Friendly Pharmacy Project

PubMed Central

Nett, Blythe; Kishaba, Gregg; Gomez, Lara

2015-01-01

A partnership was formed between the University of Hawai‘i at Hilo Daniel K. Inouye College of Pharmacy (DKICP) and the Department of Health to carry out the Hawai‘i Asthma Friendly Pharmacy Project (HAFPP), which utilizes pharmacy students as a workforce to administer Asthma Control Tests™ (ACT), and provide Asthma Action Plans (AAP) and inhaler technique education. Evaluation of data from a pilot project in 2008 with first and second year students prompted more intensive training in therapeutics, inhaler medication training, and communication techniques. Data collection began when two classes of students were first and second year students and continued until the students became fourth year students in their advanced experiential ambulatory care clinic and retail community pharmacy rotations. Patients seen included pediatric (32%) and adult (68%) aged individuals. Hawai‘i County was the most common geographic site (50%) and most sites were retail pharmacies (72%). Administered ACT surveys (N=96) yielded a mean score of 19.64 (SD +/−3.89). In addition, 12% of patients had received previous ACT, and 47% had previous AAPs. Approximately 83% of patients received an additional intervention of AAP and inhaler education with 73% of these patients able to demonstrate back proper inhaler technique. Project challenges included timing of student training, revising curriculum and logistics of scheduling students to ensure consistent access to patients. PMID:25755914

Impact of utilizing pharmacy students as workforce for Hawai'i Asthma Friendly Pharmacy Project.

PubMed

Ma, Carolyn S; Nett, Blythe; Kishaba, Gregg; Gomez, Lara

2015-02-01

A partnership was formed between the University of Hawai'i at Hilo Daniel K. Inouye College of Pharmacy (DKICP) and the Department of Health to carry out the Hawai'i Asthma Friendly Pharmacy Project (HAFPP), which utilizes pharmacy students as a workforce to administer Asthma Control Tests™ (ACT), and provide Asthma Action Plans (AAP) and inhaler technique education. Evaluation of data from a pilot project in 2008 with first and second year students prompted more intensive training in therapeutics, inhaler medication training, and communication techniques. Data collection began when two classes of students were first and second year students and continued until the students became fourth year students in their advanced experiential ambulatory care clinic and retail community pharmacy rotations. Patients seen included pediatric (32%) and adult (68%) aged individuals. Hawai'i County was the most common geographic site (50%) and most sites were retail pharmacies (72%). Administered ACT surveys (N=96) yielded a mean score of 19.64 (SD +/-3.89). In addition, 12% of patients had received previous ACT, and 47% had previous AAPs. Approximately 83% of patients received an additional intervention of AAP and inhaler education with 73% of these patients able to demonstrate back proper inhaler technique. Project challenges included timing of student training, revising curriculum and logistics of scheduling students to ensure consistent access to patients.

A simple prediction tool for inhaled corticosteroid response in asthmatic children.

PubMed

Wu, Yi-Fan; Su, Ming-Wei; Chiang, Bor-Luen; Yang, Yao-Hsu; Tsai, Ching-Hui; Lee, Yungling L

2017-12-07

Inhaled corticosteroids are recommended as the first-line controller medication for childhood asthma owing to their multiple clinical benefits. However, heterogeneity in the response towards these drugs remains a significant clinical problem. Children aged 5 to 18 years with mild to moderate persistent asthma were recruited into the Taiwanese Consortium of Childhood Asthma Study. Their responses to inhaled corticosteroids were assessed based on their improvements in the asthma control test and peak expiratory flow. The predictors of responsiveness were demographic and clinical features that were available in primary care settings. We have developed a prediction model using logistic regression and have simplified it to formulate a practical tool. We assessed its predictive performance using the area under the receiver operating characteristic curve. Of the 73 asthmatic children with baseline and follow-up outcome measurements for inhaled corticosteroids treatment, 24 (33%) were defined as non-responders. The tool we have developed consisted of three predictors yielding a total score between 0 and 5, which are comprised of the following parameters: the age at physician-diagnosis of asthma, sex, and exhaled nitric oxide. Sensitivity and specificity of the tool for prediction of inhaled corticosteroids non-responsiveness, for a score of 3, were 0.75 and 0.69, respectively. The areas under the receiver operating characteristic curve for the prediction tool was 0.763. Our prediction tool represents a simple and low-cost method for predicting the response of inhaled corticosteroids treatment in asthmatic children.

Methamphetamine and amphetamine isomer concentrations in human urine following controlled Vicks VapoInhaler administration.

PubMed

Smith, Michael L; Nichols, Daniel C; Underwood, Paula; Fuller, Zachary; Moser, Matthew A; Flegel, Ron; Gorelick, David A; Newmeyer, Matthew N; Concheiro, Marta; Huestis, Marilyn A

2014-10-01

Legitimate use of legal intranasal decongestants containing l-methamphetamine may complicate interpretation of urine drug tests positive for amphetamines. Our study hypotheses were that commonly used immunoassays would produce no false-positive results and a recently developed enantiomer-specific gas chromatography-mass spectrometry (GC-MS) procedure would find no d-amphetamine or d-methamphetamine in urine following controlled Vicks VapoInhaler administration at manufacturer's recommended doses. To evaluate these hypotheses, 22 healthy adults were each administered one dose (two inhalations in each nostril) of a Vicks VapoInhaler every 2 h for 10 h on Day 1 (six doses), followed by a single dose on Day 2. Every urine specimen was collected as an individual void for 32 h after the first dose and assayed for d- and l-amphetamines specific isomers with a GC-MS method with >99% purity of R-(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl derivatives and 10 µg/L lower limits of quantification. No d-methamphetamine or d-amphetamine was detected in any urine specimen by GC-MS. The median l-methamphetamine maximum concentration was 62.8 µg/L (range: 11.0-1,440). Only two subjects had detectable l-amphetamine, with maximum concentrations coinciding with l-methamphetamine peak levels, and always ≤ 4% of the parent's maximum. Three commercial immunoassays for amphetamines EMIT(®) II Plus, KIMS(®) II and DRI(®) had sensitivities, specificities and efficiencies of 100, 97.8, 97.8; 100, 99.6, 99.6 and 100, 100, 100%, respectively. The immunoassays had high efficiencies, but our first hypothesis was not affirmed. The EMIT(®) II Plus assay produced 2.2% false-positive results, requiring an enantiomer-specific confirmation. Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Respiratory allergy to inhaled bat guano.

PubMed

el-Ansary, E H; Tee, R D; Gordon, D J; Taylor, A J

1987-02-07

In the Sudan many asthmatic patients attribute their symptoms to inhalation of bat droppings. Design of the roofs of many Sudanese buildings allows black bats to roost; guano drops through cracks in the ceiling into the rooms below where it can be inhaled and cause allergic respiratory disorders. Seven atopic patients seen at Sennar Hospital with bat-related case-histories were investigated. Six had bronchial asthma and allergic rhinitis and one had asthma alone. Extracts of yellow hairy bat, black bat, and bat droppings were made. All seven patients had a positive skin prick test and specific IgE antibodies (RAST) to bat droppings. Three patients also had a positive RAST to both yellow and black bats and one patient to yellow bat. Droppings are probably the major allergen source in bat-related respiratory allergy.

Carboxyhemoglobin formation secondary to nitric oxide therapy in the setting of interstitial lung disease and pulmonary hypertension.

PubMed

Ruisi, Phillip; Ruisi, Michael

2011-01-01

Carbon monoxide (CO) has been widely recognized as an exogenous poison, although endogenous mechanisms for its formation involve heme-oxygenase (HO) isoforms, more specifically HO-1, in the setting of oxidative stress such as acute respiratory distress syndrome, sepsis, trauma, and nitric oxide use have been studied. In patients with refractory hypoxemia, inhaled nitric oxide (iNO) therapy is used to selectively vasodilate the pulmonary vasculature and improve ventilation-perfusion match. Inhaled nitric oxide is rapidly inactivated on binding to hemoglobin in the formation of nitrosyl- and methemoglobin in the pulmonary vasculature. Hence, inhaled nitric oxide has minimal systemic dissemination. Several experimental design studies involving lab rats have demonstrated increased levels of carboxyhemoglobin and exhaled CO as a result of nitric oxide HO-1 induction.

A Systematic Analysis of the Sensitivity of Plasma Pharmacokinetics to Detect Differences in the Pulmonary Performance of Inhaled Fluticasone Propionate Products Using a Model-Based Simulation Approach.

PubMed

Weber, Benjamin; Hochhaus, Guenther

2015-07-01

The role of plasma pharmacokinetics (PK) for assessing bioequivalence at the target site, the lung, for orally inhaled drugs remains unclear. A validated semi-mechanistic model, considering the presence of mucociliary clearance in central lung regions, was expanded for quantifying the sensitivity of PK studies in detecting differences in the pulmonary performance (total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics) between test (T) and reference (R) inhaled fluticasone propionate (FP) products. PK bioequivalence trials for inhaled FP were simulated based on this PK model for a varying number of subjects and T products. The statistical power to conclude bioequivalence when T and R products are identical was demonstrated to be 90% for approximately 50 subjects. Furthermore, the simulations demonstrated that PK metrics (area under the concentration time curve (AUC) and C max) are capable of detecting differences between T and R formulations of inhaled FP products when the products differ by more than 20%, 30%, and 25% for total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics, respectively. These results were derived using a rather conservative risk assessment approach with an error rate of <10%. The simulations thus indicated that PK studies might be a viable alternative to clinical studies comparing pulmonary efficacy biomarkers for slowly dissolving inhaled drugs. PK trials for pulmonary efficacy equivalence testing should be complemented by in vitro studies to avoid false positive bioequivalence assessments that are theoretically possible for some specific scenarios. Moreover, a user-friendly web application for simulating such PK equivalence trials with inhaled FP is provided.

Spiromax, a New Dry Powder Inhaler: Dose Consistency under Simulated Real-World Conditions

PubMed Central

Canonica, Giorgio Walter; Arp, Jan; Keegstra, Johan René

2015-01-01

Abstract Background: Spiromax® is a novel dry powder inhaler for patients with asthma or chronic obstructive pulmonary disease (COPD). The studies presented here provide further data on attributes (in vitro dosing consistency with budesonide–formoterol (DuoResp) Spiromax; flow rates through empty versions of the Spiromax and Turbuhaler inhaler) of importance to patients with asthma or COPD. Methods: Dose-delivery studies were performed using low-, middle-, and high-strength DuoResp Spiromax. Dose consistency was assessed over inhaler life. Total emitted doses (TEDs) were measured at various flow rates, after exposure to high and low temperature or humidity, at different inhaler orientations, and after dropping the inhaler. The criterion for evaluating dose uniformity was whether mean TEDs were within the product specification limits. In separate studies, flow rates were measured after training, using the patient information leaflets, and again after enhanced training as part of a randomized, open-label, cross-over study. Results: Mean values for both budesonide and formoterol were within 85%–115% of the label claim for each strength of DuoResp Spiromax for initial dose uniformity and for the other investigated conditions (temperature, humidity, orientation, dropping, knocking), with the exception of approximately an 80% increase in first dose after dropping the inhaler (subsequent doses not affected). In the flow rate patient study, two patients' inhalations with Spiromax and six with Turbuhaler were <30 L/min. The majority of asthma patients [91% (Spiromax) versus 82% (Turbuhaler)] achieved the preferred flow rate of >60 L/min. Conclusions: DuoResp Spiromax consistently meets dose uniformity criteria, under controlled laboratory conditions and with variations intended to mimic real-world use. Following enhanced training, all patients in the flow study were able to achieve the minimal inspiratory flow rate of >30 L/min, which is required for effective treatment. PMID:26352860

Expansion and retention of pulmonary CD4+ T cells after prime boost vaccination correlates with improved longevity and strength of immunity against tularemia.

PubMed

Roberts, Lydia M; Wehrly, Tara D; Crane, Deborah D; Bosio, Catharine M

2017-05-02

Francisella tularensis subsp. tularensis strain SchuS4 (Ftt) is a highly virulent intracellular bacterium. Inhalation of 10 or fewer organisms results in an acute and potentially lethal disease called pneumonic tularemia. Ftt infections occur naturally in the U.S. and Ftt was developed as a bioweapon. Thus, there is a need for vaccines that protect against this deadly pathogen. Although a live vaccine strain of Francisella tularensis (LVS) exists, LVS fails to generate long-lived protective immunity against modest challenge doses of Ftt. We recently identified an important role for high avidity CD4 + T cells in short-term protection and hypothesized that expanding this pool of cells would improve overall vaccine efficacy with regard to longevity and challenge dose. In support of our hypothesis, application of a prime/boost vaccination strategy increased the pool of high avidity CD4 + T cells which correlated with improved survival following challenge with either increased doses of virulent Ftt or at late time points after vaccination. In summary, we demonstrate that both epitope selection and vaccination strategies that expand antigen-specific T cells correlate with superior immunity to Ftt as measured by survival. Copyright © 2017. Published by Elsevier Ltd.

N-nitrosamines as "special case" leachables in a metered dose inhaler drug product.

PubMed

Norwood, Daniel L; Mullis, James O; Feinberg, Thomas N; Davis, Letha K

2009-01-01

N-nitrosamines are chemical entities, some of which are considered to be possible human carcinogens, which can be found at trace levels in some types of foods, tobacco smoke, certain cosmetics, and certain types of rubber. N-nitrosamines are of regulatory concern as leachables in inhalation drug products, particularly metered dose inhalers, which incorporate rubber seals into their container closure systems. The United States Food and Drug Administration considers N-nitrosamines (along with polycyclic aromatic hydrocarbons and 2-mercaptobenzothiazole) to be "special case" leachables in inhalation drug products, meaning that there are no recognized safety or analytical thresholds and these compounds must therefore be identified and quantitated at the lowest practical level. This report presents the development of a quantitative analytical method for target volatile N-nitrosamines in a metered dose inhaler drug product, Atrovent HFA. The method incorporates a target analyte recovery procedure from the drug product matrix with analysis by gas chromatography/thermal energy analysis detection. The capability of the method was investigated with respect to specificity, linearity/range, accuracy (linearity of recovery), precision (repeatability, intermediate precision), limits of quantitation, standard/sample stability, and system suitability. Sample analyses showed that Atrovent HFA contains no target N-nitrosamines at the trace level of 1 ng/canister.

Predicting hypoxaemia during flights in children with cystic fibrosis

PubMed Central

Buchdahl, R; Babiker, A; Bush, A; Cramer, D

2001-01-01

BACKGROUND—We have previously suggested that it is possible to predict oxygen desaturation during flight in children with cystic fibrosis and chronic lung disease by non-invasive measurement of oxygen saturation following inhalation of 15% oxygen—the pre-flight hypoxic challenge. This study reports on the results of measurements over 5years.
METHODS—The study comprised a pre-flight hypoxic challenge measuring oxygen saturation by finger tip pulse oximetry (SpO2) during tidal breathing of 15% oxygen in nitrogen and spirometric testing 1 month before the flight followed by SpO2 measurements during intercontinental flights to and from holidays abroad with children in wake and sleep states.
RESULTS—Pre-flight tests were completed on 87 children with cystic fibrosis. Desaturation of <90% occurred in 10 children at some stage during the flight, three of whom received supplementary oxygen. Using a cut off SpO2 of 90%, the pre-flight hypoxic challenge correctly predicted desaturation in only two of these children. The sensitivity and specificity of the pre-flight hypoxic challenge were 20% and 99%, respectively, compared with 70% and 96% for spirometric tests (using a cut off for forced expiratory volume in 1 second (FEV1) of <50% predicted). Overall, pre-flight spirometric tests were a better predictor of desaturation during flight with the area under the Receiver Operating Characteristic (ROC) curve of 0.89 compared with 0.73 for the hypoxic challenge test.
CONCLUSIONS—In this group of subjects pre-flight spirometric testing was a better predictor of desaturation during flight than the pre-flight hypoxic challenge.

 PMID:11641514

Emotional reactivity to a single inhalation of 35% carbon dioxide and its association with later symptoms of posttraumatic stress disorder and anxiety in soldiers deployed to Iraq.

PubMed

Telch, Michael J; Rosenfield, David; Lee, Han-Joo; Pai, Anushka

2012-11-01

The identification of modifiable predeployment vulnerability factors that increase the risk of combat stress reactions among soldiers once deployed to a war zone offers significant potential for the prevention of posttraumatic stress disorder (PTSD) and other combat-related stress disorders. Adults with anxiety disorders display heightened emotional reactivity to a single inhalation of 35% carbon dioxide (CO(2)); however, data investigating prospective linkages between emotional reactivity to CO(2) and susceptibility to war-zone stress reactions are lacking. To investigate the association of soldiers' predeployment emotional reactivity to 35% CO(2) challenge with several indices of subsequent war-zone stress symptoms assessed monthly while deployed in Iraq. Prospective cohort study of 158 soldiers with no history of deployment to a war zone were recruited from the Texas Combat Stress Risk Study between April 2, 2007, and August 28, 2009. Multilevel regression models were used to investigate the association between emotional reactivity to 35% CO(2) challenge (assessed before deployment) and soldiers' reported symptoms of general anxiety/stress, PTSD, and depression while deployed to Iraq. Growth curves of PTSD, depression, and general anxiety/stress symptoms showed a significant curvilinear relationship during the 16-month deployment period. War-zone stressors reported in theater were associated with symptoms of general anxiety/stress, PTSD, and depression. Consistent with the prediction, soldiers' emotional reactivity to a single inhalation of 35% CO(2)-enriched air before deployment significantly potentiated the effects of war-zone stressors on the subsequent development of PTSD symptoms and general anxiety/stress symptoms but not on the development of depression, even after accounting for the effects of trait anxiety and the presence of past or current Axis I mental disorders. Soldiers' emotional reactivity to a 35% CO(2) challenge may serve as a vulnerability factor for increasing soldiers' risk for PTSD and general anxiety/stress symptoms in response to war-zone stressors.

Pathology and pathophysiology of inhalational anthrax in a guinea pig model.

PubMed

Savransky, Vladimir; Sanford, Daniel C; Syar, Emily; Austin, Jamie L; Tordoff, Kevin P; Anderson, Michael S; Stark, Gregory V; Barnewall, Roy E; Briscoe, Crystal M; Lemiale-Biérinx, Laurence; Park, Sukjoon; Ionin, Boris; Skiadopoulos, Mario H

2013-04-01

Nonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's "Animal Rule." However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of the Bacillus anthracis Ames strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50 of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 × 10(4) spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans.

Lung Deposition Analyses of Inhaled Toxic Aerosols in Conventional and Less Harmful Cigarette Smoke: A Review

PubMed Central

Kleinstreuer, Clement; Feng, Yu

2013-01-01

Inhaled toxic aerosols of conventional cigarette smoke may impact not only the health of smokers, but also those exposed to second-stream smoke, especially children. Thus, less harmful cigarettes (LHCs), also called potential reduced exposure products (PREPs), or modified risk tobacco products (MRTP) have been designed by tobacco manufacturers to focus on the reduction of the concentration of carcinogenic components and toxicants in tobacco. However, some studies have pointed out that the new cigarette products may be actually more harmful than the conventional ones due to variations in puffing or post-puffing behavior, different physical and chemical characteristics of inhaled toxic aerosols, and longer exposure conditions. In order to understand the toxicological impact of tobacco smoke, it is essential for scientists, engineers and manufacturers to develop experiments, clinical investigations, and predictive numerical models for tracking the intake and deposition of toxicants of both LHCs and conventional cigarettes. Furthermore, to link inhaled toxicants to lung and other diseases, it is necessary to determine the physical mechanisms and parameters that have significant impacts on droplet/vapor transport and deposition. Complex mechanisms include droplet coagulation, hygroscopic growth, condensation and evaporation, vapor formation and changes in composition. Of interest are also different puffing behavior, smoke inlet conditions, subject geometries, and mass transfer of deposited material into systemic regions. This review article is intended to serve as an overview of contributions mainly published between 2009 and 2013, focusing on the potential health risks of toxicants in cigarette smoke, progress made in different approaches of impact analyses for inhaled toxic aerosols, as well as challenges and future directions. PMID:24065038

Pathology and Pathophysiology of Inhalational Anthrax in a Guinea Pig Model

PubMed Central

Savransky, Vladimir; Sanford, Daniel C.; Syar, Emily; Austin, Jamie L.; Tordoff, Kevin P.; Anderson, Michael S.; Stark, Gregory V.; Barnewall, Roy E.; Briscoe, Crystal M.; Lemiale-Biérinx, Laurence; Park, Sukjoon; Ionin, Boris

2013-01-01

Nonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's “Animal Rule.” However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of the Bacillus anthracis Ames strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50 of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 × 104 spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans. PMID:23357384

Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation

PubMed Central

Schneider, Craig S.; Xu, Qingguo; Boylan, Nicholas J.; Chisholm, Jane; Tang, Benjamin C.; Schuster, Benjamin S.; Henning, Andreas; Ensign, Laura M.; Lee, Ethan; Adstamongkonkul, Pichet; Simons, Brian W.; Wang, Sho-Yu S.; Gong, Xiaoqun; Yu, Tao; Boyle, Michael P.; Suk, Jung Soo; Hanes, Justin

2017-01-01

Mucoadhesive particles (MAP) have been widely explored for pulmonary drug delivery because of their perceived benefits in improving particle residence in the lungs. However, retention of particles adhesively trapped in airway mucus may be limited by physiologic mucus clearance mechanisms. In contrast, particles that avoid mucoadhesion and have diameters smaller than mucus mesh spacings rapidly penetrate mucus layers [mucus-penetrating particles (MPP)], which we hypothesized would provide prolonged lung retention compared to MAP. We compared in vivo behaviors of variously sized, polystyrene-based MAP and MPP in the lungs following inhalation. MAP, regardless of particle size, were aggregated and poorly distributed throughout the airways, leading to rapid clearance from the lungs. Conversely, MPP as large as 300 nm exhibited uniform distribution and markedly enhanced retention compared to size-matched MAP. On the basis of these findings, we formulated biodegradable MPP (b-MPP) with an average diameter of <300 nm and examined their behavior following inhalation relative to similarly sized biodegradable MAP (b-MAP). Although b-MPP diffused rapidly through human airway mucus ex vivo, b-MAP did not. Rapid b-MPP movements in mucus ex vivo correlated to a more uniform distribution within the airways and enhanced lung retention time as compared to b-MAP. Furthermore, inhalation of b-MPP loaded with dexamethasone sodium phosphate (DP) significantly reduced inflammation in a mouse model of acute lung inflammation compared to both carrier-free DP and DP-loaded MAP. These studies provide a careful head-to-head comparison of MAP versus MPP following inhalation and challenge a long-standing dogma that favored the use of MAP for pulmonary drug delivery. PMID:28435870

Exploring Human Freeze Responses to a Threat Stressor

PubMed Central

Schmidt, Norman B.; Richey, J. Anthony; Zvolensky, Michael J.; Maner, Jon K.

2008-01-01

Despite the fundamental nature of tonic immobility in anxiety responses, surprisingly little empirical research has focused on the “freeze” response in humans. The present report evaluated frequency and predictors of a freeze response in the context of a biological challenge. A nonclinical sample (N = 404) underwent a 20-sec inhalation of 20% CO2/balance O2. Perceptions of immobility in the context of the challenge were reported in 13% of the sample, compared to 20% reporting a significant desire to flee. Subjective anxiety and panic during the challenge were associated with the freeze response, as were a number of anxiety symptom dimensions. PMID:17880916

Discovery of unique and ENM— specific pathophysiologic pathways: Comparison of the translocation of inhaled iridium nanoparticles from nasal epithelium versus alveolar epithelium towards the brain of rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kreyling, Wolfgang G., E-mail: kreyling@helmholtz-muenchen.de

The biokinetics of inhaled nanoparticles (NP) is more complex than that of larger particles since NP may NP deposited on the nasal mucosa of the upper respiratory tract (URT) may translocate to the olfactory bulb of the brain and also via the trigeminus (URT neuronal route); and (b) NP deposited in the lower respiratory tract (LRT) may cross the ABB into blood and enter the brain across the blood-brain-barrier (BBB) or take a neuronal route from enervated tracheo-bronchial epithelia via the vagus nerve. Translocation from both - the URT and the LRT - are quantified during the first 24 hmore » after a 1-hour aerosol inhalation of 20 nm-sized, {sup 192}Ir radiolabeled iridium NP by healthy adult rats using differential exposures: (I) nose-only exposure of the entire respiratory tract or (II) intratracheal (IT) inhalation of intubated and ventilated rats, thereby bypassing the URT and extrathoracic nasal passages. After nose-only exposure brain accumulation (BrAcc) is significantly nine-fold higher than after IT inhalation since the former results from both pathways (a + b) while the latter exposure comes only from pathway (b). Interestingly, there are significantly more circulating NP in blood 24 h after nose-only inhalation than after IT inhalation. Distinguishing translocation from URT versus LRT estimated from the differential inhalation exposures, the former is significantly higher (8-fold) than from the LRT. Although the BrAcc fraction is rather low compared to total NP deposition after this short-term exposure, this study proofs that inhaled insoluble NP can accumulate in the brain from both – URT and LRT which may trigger and/or modulate adverse health effects in the central nervous system (CNS) during chronic exposure. - Highlights: • Nanoparticle (NP) translocation from nose versus lungs to brain is differentiated. • Differential exposure of 20 nm radio-NP:nose-only versus intratracheal inhalation • The nose-brain path precedes via nerves, the lungs-brain path via circulation. • NP uptake in the rat brain is nine-fold higher from nose than from lungs. • Relative to deposited NP in both regions it is 45-fold higher than from the nose.« less

Inhalation Frequency Controls Reformatting of Mitral/Tufted Cell Odor Representations in the Olfactory Bulb.

PubMed

Díaz-Quesada, Marta; Youngstrom, Isaac A; Tsuno, Yusuke; Hansen, Kyle R; Economo, Michael N; Wachowiak, Matt

2018-02-28

In mammals, olfactory sensation depends on inhalation, which controls activation of sensory neurons and temporal patterning of central activity. Odor representations by mitral and tufted (MT) cells, the main output from the olfactory bulb (OB), reflect sensory input as well as excitation and inhibition from OB circuits, which may change as sniff frequency increases. To test the impact of sampling frequency on MT cell odor responses, we obtained whole-cell recordings from MT cells in anesthetized male and female mice while varying inhalation frequency via tracheotomy, allowing comparison of inhalation-linked responses across cells. We characterized frequency effects on MT cell responses during inhalation of air and odorants using inhalation pulses and also "playback" of sniffing recorded from awake mice. Inhalation-linked changes in membrane potential were well predicted across frequency from linear convolution of 1 Hz responses; and, as frequency increased, near-identical temporal responses could emerge from depolarizing, hyperpolarizing, or multiphasic MT responses. However, net excitation was not well predicted from 1 Hz responses and varied substantially across MT cells, with some cells increasing and others decreasing in spike rate. As a result, sustained odorant sampling at higher frequencies led to increasing decorrelation of the MT cell population response pattern over time. Bulk activation of sensory inputs by optogenetic stimulation affected MT cells more uniformly across frequency, suggesting that frequency-dependent decorrelation emerges from odor-specific patterns of activity in the OB network. These results suggest that sampling behavior alone can reformat early sensory representations, possibly to optimize sensory perception during repeated sampling. SIGNIFICANCE STATEMENT Olfactory sensation in mammals depends on inhalation, which increases in frequency during active sampling of olfactory stimuli. We asked how inhalation frequency can shape the neural coding of odor information by recording from projection neurons of the olfactory bulb while artificially varying odor sampling frequency in the anesthetized mouse. We found that sampling an odor at higher frequencies led to diverse changes in net responsiveness, as measured by action potential output, that were not predicted from low-frequency responses. These changes led to a reorganization of the pattern of neural activity evoked by a given odorant that occurred preferentially during sustained, high-frequency inhalation. These results point to a novel mechanism for modulating early sensory representations solely as a function of sampling behavior. Copyright © 2018 the authors 0270-6474/18/382189-18$15.00/0.

Nonspecific airway hyperreactivity in nonsmoking bituminous coal miners demonstrated by quantitative methacholine inhalation challenge

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hudgel, D.W.; Roe, R.

Because nonsmoking underground bituminous coal miners often have symptoms of chronic bronchitis and because a high proportion of patients with chronic bronchitis have nonspecific airway hyperreactivity, we hypothesized that coal miners would have a higher prevalence of nonspecific airway hyperreactivity than nonminer nonsmoking control subjects. By use of a quantitative methacholine provocative inhalation challenge test, we evaluated 22 underground bituminous coal miners and 41 nonminer age- and sex-matched control subjects from the same community. We found that a significantly higher proportion of miners had reactivity to inhalation of 100 mg/ml or less of methacholine, X2 = 6.19, p less thanmore » 0.02. The slope of phase III of the single-breath nitrogen washout test was higher in the reactive miners than in the nonreactive miners and reactive control subjects, even though the reactive miners had only been working underground 8 +/- 3 (SEM) years. Within the reactive miner subgroup, the higher the reactivity to methacholine, the more abnormal the slope of phase III of the single-breath nitrogen test, r = 0.79. Miners had more symptoms than controls; the presence of methacholine reactivity was not associated with increased symptoms. We conclude that the bituminous coal miners in our study had an increased prevalence of nonspecific airway hyperreactivity and that within the reactive miner subgroup there was evidence of early airways disease. We speculate that the nonspecific airway hyperreactivity may be related to, and also be an indicator of, lung injury in coal miners.« less

Use of long term dermal sensitization followed by intratracheal challenge method to identify low-dose chemical-induced respiratory allergic responses in mice.

PubMed

Fukuyama, Tomoki; Ueda, Hideo; Hayashi, Koichi; Tajima, Yukari; Shuto, Yasufumi; Saito, Toru R; Harada, Takanori; Kosaka, Tadashi

2008-10-01

The inhalation of many types of chemicals, including pesticides, perfumes, and other low-molecular weight chemicals, is a leading cause of allergic respiratory diseases. We attempted to develop a new test protocol to detect environmental chemical-related respiratory hypersensitivity at low and weakly immunogenic doses. We used long-term dermal sensitization followed by a low-dose intratracheal challenge to evaluate sensitization by the well-known respiratory sensitizers trimellitic anhydride (TMA) and toluene diisocyanate (TDI) and the contact sensitizer 2,4-dinitrochlorobenzene (DNCB). After topically sensitizing BALB/c mice (9 times in 3 weeks) and challenging them intratracheally with TMA, TDI, or DNCB, we assayed differential cell counts and chemokine levels in bronchoalveolar lavage fluid (BALF); lymphocyte counts, surface antigen expression of B cells, and local cytokine production in lung-associated lymph nodes (LNs); and antigen-specific IgE levels in serum and BALF. TMA induced marked increases in antigen-specific IgE levels in both serum and BALF, proliferation of eosinophils and chemokines (MCP-1, eotaxin, and MIP-1beta) in BALF, and proliferation of Th2 cytokines (interleukin (IL)-4, IL-10, and IL-13) in restimulated LN cells. TDI induced marked increases in levels of cytokines (IL-4, IL-10, IL-13, and IFN-gamma) produced by restimulated LN cells. In contrast, DNCB treatment yielded, at most, small, nonsignificant increases in all parameters. Our protocol thus detected respiratory allergic responses to low-molecular weight chemicals and may be useful for detecting environmental chemical-related respiratory allergy.

Diagnostic performance of the atopy patch test with inhalant allergens.

PubMed

Fuiano, N; Diddi, G; Delvecchio, M; Incorvaia, C

2015-01-01

This study evaluated the diagnostic performance of the atopy patch test (APT) compared with skin prick testing (SPT) and in vitro IgE measurement in a large group of patients with atopic dermatitis (AD) with or without respiratory symptoms (RS). The study included 521 patients (292 males, 229 females; age, 0.5-18 years; median age, 6 years) with AD and RS with different clinical presentations: current AD, 47 patients (Group A); current AD and RS, 72 patients (Group B), past AD and RS, 69 patients (Group C); and RS only, 280 patients (Group D). Fifty-three healthy individuals served as controls. All participants underwent the APT, SPT, and CAP/RAST with the most common inhalant allergens. The presence of a control group allowed calculation of specificity and positive and negative predictive values. A significant difference was found for a positive APT versus both SPT and CAP/RAST (P < .0001) but not for SPT versus CAP/RAST. The differences for APT were significant in all group comparisons except group B vs C and group C vs D. In the control group, the APT was positive in 2% of cases (specificity of 96.2%), SPT was positive in 6% of cases (specificity of 88.4%), and CAP/RAST was positive in 4% of cases (specificity of 92.5%). In young patients sensitized to inhalant allergens with AD in addition to RS, the APT has a superior diagnostic performance to SPT and in vitro IgE measurement.

[Exposure to ammonium persulphate by inhalation: effect on the NANC inhibitory neurotransmitters in the guinea pig trachea].

PubMed

Dellabianca, A; Tonini, S; Faniglione, M; De Amici, E; De Angelis, S; Balestra, B; Candura, S M

2007-01-01

To evaluate the effect of ammonium persulphate (AP) inhalation on NANC inhibitory (i-NANC) neurotransmitters of guinea pig airways, we exposed eight guinea pigs to AP (1 mg/m3), by aerosol inhalation for 30 minutes daily for three weeks. Control animals inhaled saline aerosol. After the last exposure, the isolated trachea was mounted in an organ bath and electrically stimulated in the presence of hyoscine, piperoxane and propranolol. The i-NANC responses were evaluated as decreases in intraluminal pressure and expressed as area under the curve (AUC, Pa x seconds). The isolated tracheae were treated with a-chymotrypsin, L-NAME, zinc protoporphyrin IX and ODQ, that inhibit the production or action of the single neurotransmitters, like peptides, NO and CO. In the exposed individuals, the NANC relaxations were below 50%, as compared to controls (P < 0.01). NO and CO were the neurotransmitters responsible for all the i-NANC responses, in similar proportions either in exposed individuals or in controls. In conclusion, ammonium persulphate exposure impairs the i-NANC control of airway tone without specifically affecting any neurotransmitter.

The value and safety of specific nasal provocation in the diagnosis of allergic rhinitis in mild persistent asthma under inhaled steroid therapy.

PubMed

Tuskan, Tansu Cengiz; Gemicioglu, Bilun; Ikitimur, Hande; Yilmaz, Nail; Tuskan, Kemal; Oz, Ferhan; Can, Gunay

2010-01-01

Although specific nasal provocation is an objective diagnostic test for allergic rhinitis, it can also increase the lower airway responsiveness in asthmatic patients. Our goal was to determine the value and safety of specific nasal provocation test for the diagnosis of allergic rhinitis in mild persistent asthmatic patients under low-dose inhaled steroid therapy. The study was performed on 32 mild persistent, stable, mite-sensitive allergic asthmatics (group 1), 9 mild persistent nonallergic asthmatics (group 2) and 9 healthy non-smokers (group 3). Nasal symptoms were noted, paranasal sinus computerized tomography (PNCT) and rhinoscopic evaluations were performed. Cases with pathologic-anatomic changes in PNCT and rhinoscopy were excluded. Symptom scoring, flow-volume, peak expiratory flow (PEF), serum and nasal lavage eosinophil cationic protein (ECP) and nasal lavage eosinophil counts were performed before mite specific nasal provocation test and at the 0th, 4th and 24th hours following the test. No adverse effects were observed in all diagnostic procedures. Total diagnostic value of nasal symptoms were found to be at 92%, while being 70% for rhinoscopy and 88% for specific nasal provocation test respectively in the diagnosis of allergic rhinitis in group 1. Statistically significant differences were found between basal nasal lavage eosinophil values (p < 0.001) and ECP levels (p < 0.05) when group 1 was compared with both group 2 and group 3. In the remaining measured values between three groups, no statistically significant differences were found. Specific nasal provocation test is a safe method for mild house dust mite allergic asthma cases under low-dose inhaled steroid therapy, but history of rhinitis might be sufficient for the diagnosis of allergic rhinitis.

Ovomucoid (Gal d 1) specific IgE detected by microarray system predict tolerability to boiled hen's egg and an increased risk to progress to multiple environmental allergen sensitisation.

PubMed

Alessandri, C; Zennaro, D; Scala, E; Ferrara, R; Bernardi, M Livia; Santoro, M; Palazzo, P; Mari, A

2012-03-01

Egg allergy is a very common finding in early childhood. Detecting hen's egg (HE) allergy outgrowing and reintroduction of food containing egg is a task for the allergist. We sought to evaluate the suitability of boiled egg food challenge compared with IgE to allergenic molecules from HE white using a microarray system. Sixty-eight children referring to our centre by the family paediatricians for a suspected egg allergy were enrolled. Patients underwent double-blind, placebo-controlled food challenge with boiled and raw eggs. Challenge outcomes were compared with skin tests performed using egg white and yolk commercial extracts, to prick-prick test with boiled and raw egg white and yolk, total IgE, egg white specific IgE detected using ImmunoCAP and IgE to egg allergens available on the immunosolid phase allergen chip (ISAC) 103 microarray. Nineteen subjects (28%) were reactive to both raw and boiled egg, 14 (20.5%) to raw egg only and 35 (51.4%) tolerated both boiled and raw egg. Efficiency analysis was carried out using both raw and boiled egg challenges as gold standard. Forty four of 47 Gal d 1 negative patients tolerated boiled egg (94%). Conversely, 20 of 21 Gal d 1 positive patients reacted to raw egg (95%). None of the other tests was able to discriminate patients' response to HE challenge. Furthermore, Gal d 1 positivity seems to lead to broader environmental allergen IgE sensitization. The Gal d 1 IgE reactivity appears to be a very good predictor of HE clinical allergy. Gal d 1 positive children have a high frequency of HE allergy, whereas Gal d 1 negative children have a high frequency of tolerance to boiled egg. Multiple specific IgE detection by means of ISAC improves the diagnostic approach in HE allergic children, disclosing other food and inhalant allergic sensitizations, anyhow requiring a comprehensive clinical evaluation. © 2011 Blackwell Publishing Ltd.

Assessment of airway hyperreactivity: comparison of forced spirometry and body plethysmography for methacholine challenge tests

PubMed Central

2009-01-01

Introduction Bronchial challenge tests by inhalation of aerosolized methacholine (MCH) are commonly used in the clinical diagnosis of airway hyperresponsiveness (AHR). While the detection of airway narrowing relies on the patient's cooperation performing forced spirometry, body plethysmographic measurements of airway resistance are less depending on the patient's cooperation and do not alter the respiratory tract by maximal maneuvers. Hence we compared both methods concerning their clinical value and correlation during MCH challenges in patients with asthma. Materials and Methods Cumulative MCH challenges test, consisting of up to 5 steps, evaluated with body plethysmography on each step were performed in 155 patients with bronchial asthma. Airway responses were recorded at each step of MCH application (Master-Screen Body, Cardinal Health, Höchberg). At the baseline test and after crossing the provocation dose (PD) threshold in body plethysmography (PD+100 sReff), forced expirations were performed and FEV1, FVC, and FEV1 %FVC were measured. Using regression analysis of the airway parameters and taking the MCH dose as the covariate, we could extrapolate to missing spirometric values and interpolate the estimated MCH dose when crossing the PD threshold (PD-20 FEV1) between two consecutive measurements. The administered PD+100 MCH doses for specific airway resistance, sRtot, and sReff were compared with resistance parameters Rtot and Reff, and to PD-20 of FEV1 and FEV1 %FVC. Results Regarding sReff we found a mild, moderate, or severe AHR in 114 patients (75%), but only 50 (32%) according to FEV1. A statistical analysis showed strongly linear correlated parameters of airway resistance, but no significant correlation between the results of body plethysmography and forced spirometry Conclusions Using MCH challenges, we found specific airway resistance to be the most sensitive parameter to detect AHR. Raw is largely independent of height and gender facilitating the interpretation of measurements carried out longitudinally. PMID:20156751

The evaluation of physical exam findings in patients assessed for suspected burn inhalation injury.

PubMed

Ching, Jessica A; Shah, Jehan L; Doran, Cody J; Chen, Henian; Payne, Wyatt G; Smith, David J

2015-01-01

The purpose of this investigation was to evaluate the utility of singed nasal hair (SN), carbonaceous sputum (CS), and facial burns (FB) as indicators of burn inhalation injury, when compared to the accepted standard of bronchoscopic diagnosis of inhalation injury. An institutional review board approved, retrospective review was conducted. All patients were suspected to have burn inhalation injury and subsequently underwent bronchoscopic evaluation. Data collected included: percent burn TBSA, burn injury mechanism, admission physical exam findings (SN, CS, FB), and bronchoscopy findings. Thirty-five males and twelve females met inclusion criteria (n = 47). Bronchoscopy was normal in 31 patients (66%). Data were analyzed as all patients and in subgroups according to burn TBSA and an enclosed space mechanism of injury. Physical exam findings (SN, CS, FB) were evaluated individually and in combination. Overall, the sensitivities, specificities, positive predictive values, and negative predictive values calculated were poor and inconsistent, and they did not improve within subgroup analysis or when physical findings were combined. Further statistical analysis suggested the physical findings, whether in isolation or in combination, have poor discrimination between patients that have and do not have inhalation injury (AUC < 0.7, P > .05) and poor agreement with the diagnosis made by bronchoscopy (κ < 0.4, P > .05). This remained true in the subgroup analysis as well. Our data demonstrated the findings of SN, CS, and FB are unreliable evidence for inhalation injury, even in the context of an enclosed space mechanism of injury. Thus, these physical findings are not absolute indicators for intubation and should be interpreted as one component of the history and physical.

Predicting lung dosimetry of inhaled particleborne benzo[a]pyrene using physiologically based pharmacokinetic modeling

PubMed Central

Campbell, Jerry; Franzen, Allison; Van Landingham, Cynthia; Lumpkin, Michael; Crowell, Susan; Meredith, Clive; Loccisano, Anne; Gentry, Robinan; Clewell, Harvey

2016-01-01

Abstract Benzo[a]pyrene (BaP) is a by-product of incomplete combustion of fossil fuels and plant/wood products, including tobacco. A physiologically based pharmacokinetic (PBPK) model for BaP for the rat was extended to simulate inhalation exposures to BaP in rats and humans including particle deposition and dissolution of absorbed BaP and renal elimination of 3-hydroxy benzo[a]pyrene (3-OH BaP) in humans. The clearance of particle-associated BaP from lung based on existing data in rats and dogs suggest that the process is bi-phasic. An initial rapid clearance was represented by BaP released from particles followed by a slower first-order clearance that follows particle kinetics. Parameter values for BaP-particle dissociation were estimated using inhalation data from isolated/ventilated/perfused rat lungs and optimized in the extended inhalation model using available rat data. Simulations of acute inhalation exposures in rats identified specific data needs including systemic elimination of BaP metabolites, diffusion-limited transfer rates of BaP from lung tissue to blood and the quantitative role of macrophage-mediated and ciliated clearance mechanisms. The updated BaP model provides very good prediction of the urinary 3-OH BaP concentrations and the relative difference between measured 3-OH BaP in nonsmokers versus smokers. This PBPK model for inhaled BaP is a preliminary tool for quantifying lung BaP dosimetry in rat and humans and was used to prioritize data needs that would provide significant model refinement and robust internal dosimetry capabilities. PMID:27569524

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trott, Donna M.; LePage, Jane; Hebert, Vincent

A regional air assessment was performed to characterize volatile natural isothiocyanate (NITC) compounds in air during soil incorporation of mustard cover crops in Washington State. Field air sampling and analytical methods were developed specific to three NITCs known to be present in air at appreciable concentrations during/after field incorporation. The maximum observed concentrations in air for the allyl, benzyl, and phenethyl isothiocyanates were respectively 188, 6.1, and 0.7 lg m-3 during mustard incorporation. Based on limited inhalation toxicity information, airborne NITC concentrations did not appear to pose an acute human inhalation exposure concern to field operators and bystanders.

Inhalation Toxicity of Cogenerated Graphite Flake and Fog Oil Smoke in the Brown-Headed Cowbird and the Red-Winged Blackbird, Size-Specific Inhalation Surrogates for the Red-Cockaged Woodpecker

DTIC Science & Technology

2005-01-01

graphite flakes for infrared obscuration are being deployed for training scenarios. The effect of this combination on avian species was unknown. Our...Hematological response was normal and no toxic effects in eryth- rocytes or leukocytes were found. White blood cell counts, spleen weights, and incidence of...5 List of Figures and Tables Figures 1. Exposure system used for testing the effects of fog oil and graphite flake aerosols on avian health

IRIS Toxicological Review of Ammonia Noncancer Inhalation ...

EPA Pesticide Factsheets

In September 2016, EPA finalized the IRIS assessment of Ammonia (Noncancer Inhalation). The Toxicological Review was reviewed internally by EPA and by other federal agencies and White House Offices before public release in June 2016. Consistent with the May 2009 IRIS assessment development process, all written comments on IRIS assessments submitted by other federal agencies and White House Offices are made publicly available. Accordingly, interagency comments and the interagency science discussion materials provided to other agencies, including interagency review drafts of the IRIS Toxicological Review of Ammonia (Noncancer Inhalation) are posted on this site. Note: No major science comments were received on the Interagency Science Discussion Draft. EPA is undertaking an Integrated Risk Information System (IRIS) health assessment for ammonia. IRIS is an EPA database containing Agency scientific positions on potential adverse human health effects that may result from chronic (or lifetime) exposure to chemicals in the environment. IRIS contains chemical-specific summaries of qualitative and quantitative health information in support of two steps of the risk assessment paradigm, i.e., hazard identification and dose-response evaluation. IRIS assessments are used in combination with specific situational exposure assessment information to evaluate potential public health risk associated with environmental contaminants.

Checklists for powder inhaler technique: a review and recommendations.

PubMed

Basheti, Iman A; Bosnic-Anticevich, Sinthia Z; Armour, Carol L; Reddel, Helen K

2014-07-01

Turbuhaler and Diskus are commonly used powder inhaler devices for patients with respiratory disease. Their effectiveness is limited in part by a patient's ability to use them correctly. This has led to numerous studies being conducted over the last decade to assess the correct use of these devices by patients and health care professionals. These studies have generally used device-specific checklists to assess technique, this being the most feasible and accessible method for assessment. However, divergence between the checklists and scoring systems for the same device in different studies makes direct comparison of results difficult and at times inappropriate. Little evidence is available to assess the relative importance of different criteria; however, brief patient training based on specific inhaler technique checklists leads to significant improvement in asthma outcomes. This paper reviews common checklists and scoring systems used for Turbuhaler and Diskus, discusses the problem of heterogeneity between different checklists, and finally recommends suitable checklists and scoring systems for these devices based on the literature and previous findings. Only when similar checklists are used across different research studies will accurate comparisons and meta-analysis be possible. Copyright © 2014 by Daedalus Enterprises.

Occupational IgE-mediated asthma, rhinoconjunctivitis, and contact urticaria caused by Easter lily (Lilium longiflorum) and tulip.

PubMed

Piirilä, P; Kanerva, L; Alanko, K; Estlander, T; Keskinen, H; Pajari-Backas, M; Tuppurainen, M

1999-03-01

We report on IgE-mediated asthma, rhinoconjunctivitis, and contact urticaria to two Liliaceae plants, tulip and Easter lily (Lilium longiflorum), diagnosed in a floral shop worker. Occupational asthma was diagnosed according to patient history, PEF monitoring, and a work-simulating provocation test. Flower-specific IgE was studied, and RAST inhibition tests were performed. Skin prick testing showed positive reactions to tulip, Easter lily, and chrysanthemum. Total IgE was 180 kU/I, and specific IgE to tulip was 2.6 and to Easter lily 6.5 kU/I. In the RAST-inhibition test, no cross-reactivity was found. Occupational asthma was diagnosed by peak flow monitoring at work and at home, as well as specific inhalation challenge with Easter lily, with an immediate 18% reduction in PEF. In addition, contact urticaria and conjunctivitis were diagnosed. After a 9-year follow-up without exposure to lilies, the skin prick tests to L. longiflorum and tulip were still positive, but the specific IgE had disappeared. A case of IgE-mediated occupational asthma, rhinoconjunctivitis, and contact urticaria caused by L. longiflorum and tulip is presented. RAST inhibition tests indicated concomitant sensitization to the two Liliaceae plants.

32 CFR 218.3 - Dose reconstruction methodology.

Code of Federal Regulations, 2013 CFR

2013-07-01

... effects of shot-specific parameters such as weapon type and yield, neutron and gamma output, source and... specific personnel activities. Due to the range of activities, times, geometries, shielding, and weapon... that could have led to atypical doses. Radiation dose from neutrons and dose commitments due to inhaled...

32 CFR 218.3 - Dose reconstruction methodology.

Code of Federal Regulations, 2014 CFR

2014-07-01

... effects of shot-specific parameters such as weapon type and yield, neutron and gamma output, source and... specific personnel activities. Due to the range of activities, times, geometries, shielding, and weapon... that could have led to atypical doses. Radiation dose from neutrons and dose commitments due to inhaled...

32 CFR 218.3 - Dose reconstruction methodology.

Code of Federal Regulations, 2012 CFR

2012-07-01

... effects of shot-specific parameters such as weapon type and yield, neutron and gamma output, source and... specific personnel activities. Due to the range of activities, times, geometries, shielding, and weapon... that could have led to atypical doses. Radiation dose from neutrons and dose commitments due to inhaled...

Comparison between Newly Developed and Commercial Inhalant Skin Prick Test Reagents Using In Vivo and In Vitro Methods

PubMed Central

2018-01-01

Background We developed skin prick test (SPT) reagents for common inhalant allergens that reflected the real exposure in Korea. The study aim was to evaluate diagnostic usefulness and allergen potency of our inhalant SPT reagents in comparison with commercial products. Methods We produced eight common inhalant allergen SPT reagents using total extract (Prolagen): Dermatophagoides farinae, Dermatophagoides pteronyssinus, oak, ragweed, mugwort, Humulus japonicus pollens, as well as cat and dog allergens. We compared the newly developed reagents with three commercially available SPT reagents (Allergopharma, Hollister-Stier, Lofarma). We measured total protein concentrations, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), major allergen concentration, and biological allergen potencies measured by immunoglobulin E (IgE) immunoblotting and ImmunoCAP inhibition test. Results Diagnostic values of these SPT reagents were expressed as positivity rate and concordance rate of the results from ImmunoCAP allergen-specific IgE test in 94 allergic patients. In vitro analysis showed marked differences in protein concentrations, SDS-PAGE features, major allergen concentrations, and biological allergen potencies of four different SPT reagents. In vivo analysis showed that positive rates and concordance rates of Prolagen® SPT reagents were similar compared to the three commercial SPT reagents. Conclusion The newly developed Prolagen® inhalant SPT reagents are not inferior to the commercially available SPT reagents in allergy diagnosis. PMID:29573248

Inhalable microparticles containing large payload of anti-tuberculosis drugs.

PubMed

Muttil, Pavan; Kaur, Jatinder; Kumar, Kaushlendra; Yadav, Awadh Bihari; Sharma, Rolee; Misra, Amit

2007-10-01

Microparticles containing large payloads of two anti-tuberculosis (TB) drugs were prepared and evaluated for suitability as a dry powder inhalation targeting alveolar macrophages. A solution containing one part each of isoniazid and rifabutin, plus two parts poly(lactic acid) (L-PLA) was spray-dried. Drug content and in vitro release were assayed by HPLC, and DSC was used to elucidate release behaviour. Particle size was measured by laser scattering and aerosol characteristics by cascade impaction using a Lovelace impactor. Microparticles were administered to mice using an in-house inhalation apparatus or by intra-tracheal instillation. Drugs in solution were administered orally and by intra-cardiac injection. Flow cytometry and HPLC were used to investigate the specificity and magnitude of targeting macrophages. Microparticles having drug content approximately 50% (w/w), particle size approximately 5 microm and satisfactory aerosol characteristics (median mass aerodynamic diameter, MMAD=3.57 microm; geometric standard deviation, GSD=1.41 microm; fine particle fraction, FPF(<4.6 microm)=78.91+/-8.4%) were obtained in yields of >60%. About 70% of the payload was released in vitro in 10 days. Microparticles targeted macrophages and not epithelial cells on inhalation. Drug concentrations in macrophages were approximately 20 times higher when microparticles were inhaled rather than drug solutions administered. Microparticles were thus deemed suitable for enhanced targeted drug delivery to lung macrophages.

Ceftazidime improves hemodynamics and oxygenation in ovine smoke inhalation injury and septic shock.

PubMed

Maybauer, Marc O; Maybauer, Dirk M; Fraser, John F; Traber, Lillian D; Westphal, Martin; Cox, Robert A; Huda, Ruksana; Nakano, Yoshimitsu Y; Enkhbaatar, Perenlei; Hawkins, Hal K; Herndon, David N; Traber, Daniel L

2007-07-01

To investigate ceftazidime in acute lung injury (ALI) and sepsis. Prospective, randomized, controlled animal study in an investigational ICU at a university hospital. Eighteen female Merino sheep were prepared for chronic study and subjected to smoke inhalation and septic challenge according to an established protocol. Whereas global hemodynamics and oxygenation remained stable in sham animals (no injury, no treatment), the injury contributed to a hypotensive-hyperdynamic circulation in the control group (smoke inhalation and sepsis, no treatment), as indicated by a significant increase in cardiac index) and heart rate and a drop in mean arterial pressure. Treatment with ceftazidime (smoke inhalation and sepsis, treatment group) stabilized cardiac index and heart rate and attenuated the decrease in mean arterial pressure. The deterioration in PaO2/FiO2 ratio and pulmonary shunt fraction (Qs/Qt) was significantly delayed and blunted by ceftazidime. At 24 h after injury a significant increase in airway obstruction scores of bronchi and bronchioles in both injured groups was observed. Ceftazidime significantly reduced airway obstruction vs. control animals. Whereas plasma nitrate/nitrite levels increased similarly in the two injured groups, lung 3-nitrotyrosine content remained at the baseline level in the ceftazidime group. In ovine lung injury ceftazidime improves global hemodynamics and oxygenation not only by bacterial clearance but also via reduction in toxic nitrogen species such as 3-nitrotyrosine. Therefore ceftazidime appears as a clinically relevant adjunct in the common setting of sepsis-associated lung injury.

Modulation of the allergen-induced human IgE response in Hu-SCID mice: inhibitory effect of human recombinant IFN-gamma and allergen-derived lipopeptide.

PubMed

Duez, C; Gras-Masse, H; Hammad, H; Akoum, H; Didierlaurent, A; André, C; Tonnel, A B; Pestel, J

2001-01-01

We have previously established a model to study the in vivo human IgE response using humanized SCID mice. Allergic SCID mice were obtained following intraperitoneal injection with mononuclear cells from Dermatophagoides pteronyssinus (Dpt)-sensitive patients, and sensitization by Dpt allergen intraperitoneal injection (immunization) or Dpt aerosol (inhalation). Human serum IgE was measured in allergic SCID mice after administration of human recombinant IFN-gamma or the lipopeptide LP 52-71 (derived from peptide p52-71 from Der p 1, Dpt major allergen, coupled to a lipophilic moiety), during the immunization or the inhalation phase. IFN-gamma inhibited human IgE production when given at the time of immunization, but not during inhalation. This effect was long-lasting as Dpt aerosol, given one month after immunization and IFN-gamma administration, failed to increase IgE levels. Unlike Dpt or p52-71, LP 52-71 failed to induce human IgE production at day 14 and 21 after its injection, but did inhibit the development of the IgE response after a secondary Dpt-challenge. Moreover, LP 52-71 administration 14 days after Dpt inhalation decreased IgE levels, in contrast to peptide 52-71, which increased IgE levels. Thus, taken together these results indicate that the development of the human IgE response in allergic SCID mice can be modulated by modified allergen and a Th1 cytokine.

Effects of acute inhalation of aerosols generated during resistance spot welding with mild-steel on pulmonary, vascular and immune responses in rats.

PubMed

Zeidler-Erdely, Patti C; Meighan, Terence G; Erdely, Aaron; Fedan, Jeffrey S; Thompson, Janet A; Bilgesu, Suzan; Waugh, Stacey; Anderson, Stacey; Marshall, Nikki B; Afshari, Aliakbar; McKinney, Walter; Frazer, David G; Antonini, James M

2014-10-01

Spot welding is used in the automotive and aircraft industries, where high-speed, repetitive welding is needed to join thin sections of metal. Epoxy adhesives are applied as sealers to the metal seams. Pulmonary function abnormalities and airway irritation have been reported in spot welders, but no animal toxicology studies exist. Therefore, the goal of this study was to investigate vascular, immune and lung toxicity measures after exposure to these metal fumes in an animal model. Male Sprague-Dawley rats were exposed by inhalation to 25 mg/m³ to either mild-steel spot welding aerosols with sparking (high metal, HM) or without sparking (low metal, LM) for 4 h/d for 3, 8 and 13 d. Shams were exposed to filtered air. Bronchoalveolar lavage (BAL), lung gene expression and ex vivo BAL cell challenge were performed to assess lung toxicity. Lung resistance (R(L)) was evaluated before and after challenge with inhaled methacholine (MCh). Functional assessment of the vascular endothelium in isolated rat tail arteries and leukocyte differentiation in the spleen and lymph nodes via flow cytometry was also done. Immediately after exposure, baseline R(L) was significantly elevated in the LM spot welding aerosols, but returned to control level by 24 h postexposure. Airway reactivity to MCh was unaffected. Lung inflammation and cytotoxicity were mild and transient. Lung epithelial permeability was significantly increased after 3 and 8 d, but not after 13 d of exposure to the HM aerosol. HM aerosols also caused vascular endothelial dysfunction and increased CD4+, CD8+ and B cells in the spleen. Only LM aerosols caused increased IL-6 and MCP-1 levels compared with sham after ex vivo LPS stimulation in BAL macrophages. Acute inhalation of mild-steel spot welding fumes at occupationally relevant concentrations may act as an irritant as evidenced by the increased R(L) and result in endothelial dysfunction, but otherwise had minor effects on the lung.

Effect of treatment with geraniol on ovalbumin-induced allergic asthma in mice.

PubMed

Xue, Zheng; Zhang, Xin-Guang; Wu, Jie; Xu, Wan-Chao; Li, Li-Qing; Liu, Fei; Yu, Jian-Er

2016-06-01

Asthma, a complex highly prevalent airway disease, is a major public health problem for which current treatment options are inadequate. To evaluate the antiasthma activity of geraniol and investigate its underlying molecular mechanisms. In a standard experimental asthma model, Balb/c mice were sensitized with ovalbumin, treated with geraniol (100 or 200 mg/kg) or a vehicle control, during ovalbumin challenge. Treatment of ovalbumin-sensitized/challenged mice with geraniol significantly decreased airway hyperresponsiveness to inhaled methacholine. Geraniol treatment reduced eotaxin levels in bronchoalveolar lavage fluid and attenuated infiltration of eosinophils induced by ovalbumin. Geraniol treatment reduced TH2 cytokines (including interleukins 4, 5, and 13), increased TH1 cytokine interferon γ in bronchoalveolar lavage fluid, and reduced ovalbumin-specific IgE in serum. In addition, treatment of ovalbumin-sensitized/challenged mice with geraniol enhanced T-bet (TH1 response) messenger RNA expression and reduced GATA-3 (TH2 response) messenger RNA expression in lungs. Furthermore, treatment of ovalbumin -sensitized/challenged mice with geraniol further enhanced Nrf2 protein expression and activated Nrf2-directed antioxidant pathways, such as glutamate-cysteine ligase, superoxide dismutase, and glutathione S-transferase, and enhanced formation of reduced glutathione and reduced formation of malondialdehyde in lungs. Geraniol attenuated important features of allergic asthma in mice, possibly through the modulation of TH1/TH2 balance and activation the of Nrf2/antioxidant response element pathway. Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

The preventive effect and duration of action of two doses of inhaled furosemide on exercise-induced asthma in children.

PubMed

Novembre, E; Frongia, G; Lombardi, E; Resti, M; Zammarchi, E; Vierucci, A

1995-12-01

Exercise-induced asthma can be prevented by treatment with inhaled furosemide. In this study we evaluated the effect and duration of action of two doses (15 and 30 mg) of inhaled furosemide in prevention of exercise-induced asthma in children. Ten children with exercise-induced asthma (8 boys and 2 girls, aged 6 to 13 years) were included in the study. Each patient was tested with three treatment regimens (placebo, 15 mg of furosemide, and 30 mg of furosemide) in random order on 3 separate days. Patients performed exercise challenges on a treadmill at 20 minutes and 1, 2, 3, and 6 hours after each treatment. Pulmonary function, urinary output, and fluid intake were monitored. Both doses of furosemide had a significantly greater protective effect than placebo, but there was no significant difference between the two doses of furosemide. The higher dose of furosemide was associated with increased urinary output and had a longer duration of action. A 30 mg dose of furosemide is more effective for treatment of exercise-induced asthma in terms of duration but has a significant diuretic effect.

Carcinogenicity of multi-walled carbon nanotubes: challenging issue on hazard assessment.

PubMed

Fukushima, Shoji; Kasai, Tatsuya; Umeda, Yumi; Ohnishi, Makoto; Sasaki, Toshiaki; Matsumoto, Michiharu

2018-01-25

This report reviews the carcinogenicity of multi-walled carbon nanotubes (MWCNTs) in experimental animals, concentrating on MWNT-7, a straight fibrous MWCNT. MWCNTs were administered to mice and rats by intraperitoneal injection, intrascrotal injection, subcutaneous injection, intratracheal instillation and inhalation. Intraperitoneal injection of MWNT-7 induced peritoneal mesothelioma in mice and rats. Intrascrotal injection induced peritoneal mesothelioma in rats. Intratracheal instillation of MWCNT-N (another straight fibrous MWCNT) induced both lung carcinoma and pleural mesothelioma in rats. In the whole body inhalation studies, in mice MWNT-7 promoted methylcholanthrene-initiated lung carcinogenesis. In rats, inhalation of MWNT-7 induced lung carcinoma and lung burdens of MWNT-7 increased with increasing concentration of airborne MWNT-7 and increasing duration of exposure. Straight, fibrous MWCNTs exerted carcinogenicity in experimental animals. Phagocytosis of MWCNT fibers by macrophages was very likely to be a principle factor in MWCNT lung carcinogenesis. Using no-observed-adverse-effect level-based approach, we calculated that the occupational exposure limit (OEL) of MWNT-7 for cancer protection is 0.15 μg/m 3 for a human worker. Further studies on the effects of the shape and size of MWCNT fibers and mode of action on the carcinogenicity are required.

Managing Pseudomonas aeruginosa respiratory infections in cystic fibrosis.

PubMed

Langan, Katherine M; Kotsimbos, Tom; Peleg, Anton Y

2015-12-01

The current guidelines and recent clinical research in the management of Pseudomonas aeruginosa respiratory infections in cystic fibrosis (CF) are reviewed. Areas where further research is required will also be highlighted. P. aeruginosa is a key respiratory pathogen in CF. Inhaled tobramycin or colistin is recommended for early eradication to prevent establishment of chronic infection. Other antibiotic options are currently being investigated. The long-term success of eradication strategies is also now being assessed. The use of inhaled antibiotics in the management of chronic P. aeruginosa infection is an area of active investigation. Acute pulmonary exacerbations are still a major cause of morbidity and mortality. Guidelines continue to recommend combination intravenous therapy but further research is required to clarify the advantage of this approach. Multidrug resistance is common and potentially more effective antipseudomonal antibiotics may soon become available. The management of P. aeruginosa respiratory infection in CF remains a challenging area, especially in the setting of multidrug resistance. The role of inhaled antibiotics continues to be expanded. Further research is required in the key areas of eradication and management of chronic infection and acute pulmonary exacerbations to identify those treatments that optimize long-term, clinical benefits.

Computational Fluid Dynamics Modeling of Bacillus anthracis Spore Deposition in Rabbit and Human Respiratory Airways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kabilan, Senthil; Suffield, Sarah R.; Recknagle, Kurtis P.

Three-dimensional computational fluid dynamics and Lagrangian particle deposition models were developed to compare the deposition of aerosolized Bacillus anthracis spores in the respiratory airways of a human with that of the rabbit, a species commonly used in the study of anthrax disease. The respiratory airway geometries for each species were derived from computed tomography (CT) or µCT images. Both models encompassed airways that extended from the external nose to the lung with a total of 272 outlets in the human model and 2878 outlets in the rabbit model. All simulations of spore deposition were conducted under transient, inhalation-exhalation breathing conditionsmore » using average species-specific minute volumes. The highest exposure concentration was modeled in the rabbit based upon prior acute inhalation studies. For comparison, human simulation was also conducted at the same concentration. Results demonstrated that regional spore deposition patterns were sensitive to airway geometry and ventilation profiles. Due to the complex airway geometries in the rabbit nose, higher spore deposition efficiency was predicted in the upper conducting airways compared to the human at the same air concentration of anthrax spores. As a result, higher particle deposition was predicted in the conducting airways and deep lung of the human compared to the rabbit lung due to differences in airway branching pattern. This information can be used to refine published and ongoing biokinetic models of inhalation anthrax spore exposures, which currently estimate deposited spore concentrations based solely upon exposure concentrations and inhaled doses that do not factor in species-specific anatomy and physiology.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harkema, J.R.

The nasal cavity is susceptible to chemically induced injury as a result of exposure to inhaled irritants. Some responses of the nasal mucosa to inhaled toxicants are species specific. These species-related differences in response may be due to variations in structural, physiologic, and biochemical factors, such as gross nasal cavity structure, distribution of luminal epithelial cell populations along the nasal airway, intranasal airflow patterns, nasal mucociliary apparatus, and nasal xenobiotic metabolism among animal species. This paper reviews the comparative anatomy and irritant-induced pathology of the nasal cavity in laboratory animals. The toxicologist, pathologist, and environmental risk assessor must have amore » good working knowledge of the similarities and differences in normal nasal structure and response to injury among species before they can select animal models for nasal toxicity studies, recognize toxicant-induced lesions in the nasal airway, and extrapolate experimental results to estimate the possible effects of an inhaled toxicant on the human nasal airway.« less

Carbon dioxide inhalation treatments of neurotic anxiety. An overview.

PubMed

Wolpe, J

1987-03-01

A lucky chance more than 30 years ago revealed the remarkable efficacy of single inhalations of high concentrations of carbon dioxide in eliminating or markedly reducing free-floating anxiety. The reduction of anxiety lasts for days, weeks, or longer--well beyond the persistence of carbon dioxide in the body. The effects are explicable on the hypothesis that free-floating anxiety is anxiety conditioned to continuously present sources of stimulation, such as background noise or the awareness of space or time, and that the anxiety response habit is weakened when the anxiety is inhibited by the competition of responses that carbon dioxide induces. More recently, it has become apparent that inhalations of carbon dioxide, applied in a different manner, are effective in overcoming maladaptive anxiety responses to specific stimuli, e.g., social stimuli. The substance is also proving to be a valuable resource in the treatment of the common variety of panic attacks.

Continuous alternating inhaled antibiotic therapy in CF: A single center retrospective analysis.

PubMed

Van de Kerkhove, C; Goeminne, P C; Kicinski, M; Nawrot, T S; Lorent, N; Van Bleyenbergh, P; De Boeck, K; Dupont, L J

2016-11-01

The efficacy of inhaled antibiotics to treat chronic Pseudomonas aeruginosa pulmonary infection in patients with cystic fibrosis (CF) has been well established. Few data are available on the value of continuous alternating inhaled antibiotic therapy (CAIT), a strategy increasingly used in the management of CF. To investigate the effect of CAIT on clinical outcome in adult CF patients treated at the University Hospital Leuven. Patients with a documented CF diagnosis who received inhaled antibiotics between March 2010 and January 2015 were retrospectively evaluated. In patients receiving CAIT patient characteristics, recorded spirometry data and number of IV antibiotic days were collected retrospectively at fixed time intervals, from 6months before to one year after the start of the 2nd inhaled antibiotic. For patients on inhaled antibiotic monotherapy (IAMT), the same data were obtained at similar intervals during the study period. A total of 49 of 89 patients using chronic inhaled antibiotic therapy received CAIT. Patients receiving CAIT had a lower baseline FEV 1 and were more likely to be homozygous for F508del compared to patients receiving IAMT. FEV 1 deteriorated on average by a factor of 0.904 per year (95% CI: 0.851-0.960) prior to the start of CAIT. The initiation of CAIT was associated with an average improvement in FEV 1 by a factor of 1.148 per year (95% CI: 1.068-1.236, p=0.0002). The analysis of specific types of antibiotics revealed evidence of positive effects of adding COLI to TOBI and COLI to AZLI. We found no effect of the initiation of CAIT on the number of IV antibiotic days (p=0.80). CF patients with more advanced lung disease are more likely to receive CAIT. In this patient group, CAIT was associated with a significant improvement in FEV 1 . Further data are warranted to identify the value of CAIT. Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Coupled in silico platform: Computational fluid dynamics (CFD) and physiologically-based pharmacokinetic (PBPK) modelling.

PubMed

Vulović, Aleksandra; Šušteršič, Tijana; Cvijić, Sandra; Ibrić, Svetlana; Filipović, Nenad

2018-02-15

One of the critical components of the respiratory drug delivery is the manner in which the inhaled aerosol is deposited in respiratory tract compartments. Depending on formulation properties, device characteristics and breathing pattern, only a certain fraction of the dose will reach the target site in the lungs, while the rest of the drug will deposit in the inhalation device or in the mouth-throat region. The aim of this study was to link the Computational fluid dynamics (CFD) with physiologically-based pharmacokinetic (PBPK) modelling in order to predict aerolisolization of different dry powder formulations, and estimate concomitant in vivo deposition and absorption of amiloride hydrochloride. Drug physicochemical properties were experimentally determined and used as inputs for the CFD simulations of particle flow in the generated 3D geometric model of Aerolizer® dry powder inhaler (DPI). CFD simulations were used to simulate air flow through Aerolizer® inhaler and Discrete Phase Method (DPM) was used to simulate aerosol particles deposition within the fluid domain. The simulated values for the percent emitted dose were comparable to the values obtained using Andersen cascade impactor (ACI). However, CFD predictions indicated that aerosolized DPI have smaller particle size and narrower size distribution than assumed based on ACI measurements. Comparison with the literature in vivo data revealed that the constructed drug-specific PBPK model was able to capture amiloride absorption pattern following oral and inhalation administration. The PBPK simulation results, based on the CFD generated particle distribution data as input, illustrated the influence of formulation properties on the expected drug plasma concentration profiles. The model also predicted the influence of potential changes in physiological parameters on the extent of inhaled amiloride absorption. Overall, this study demonstrated the potential of the combined CFD-PBPK approach to model inhaled drug bioperformance, and suggested that CFD generated results might serve as input for the prediction of drug deposition pattern in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

Protection of non-human primates against glanders with a gold nanoparticle glycoconjugate vaccine

PubMed Central

Torres, Alfredo G.; Gregory, Anthony E.; Hatcher, Christopher L.; Vinet-Oliphant, Heather; Morici, Lisa A.; Titball, Richard W.; Roy, Chad J.

2014-01-01

The Gram-negative Burkholderia mallei is a zoonotic pathogen and the causative agent of glanders disease. Because the bacteria maintain the potential to be used as a biothreat agent, vaccine strategies are required for human glanders prophylaxis. A rhesus macaque (Macaca mulatta) model of pneumonic (inhalational) glanders was established and the protective properties of a nanoparticle glycoconjugate vaccine composed of B. thailandensis LPS conjugated to FliC was evaluated. An aerosol challenge dose of ~1×104 CFU B. mallei produced mortality in 50% of naïve animals (n = 2/4), 2–3 days post-exposure. Although survival benefit was not observed by vaccination with a glycoconjugate glanders vaccine (p=0.42), serum LPS-specific IgG titres were significantly higher on day 80 in 3 vaccinated animals who survived compared with 3 vaccinated animals who died. Furthermore, B. mallei was isolated from multiple organs of both non-vaccinated survivors, but not from any organs of 3 vaccinated survivors at 30 days post-challenge. Taken together, this is the first time a candidate vaccine has been evaluated in a non-human primate aerosol model of glanders and represents the initial step for consideration in pre-clinical studies. PMID:25533326

Analysis of the mechanisms that underlie absorption of botulinum toxin by the inhalation route.

PubMed

Al-Saleem, Fetweh H; Ancharski, Denise M; Joshi, Suresh G; Elias, M; Singh, Ajay; Nasser, Zidoon; Simpson, Lance L

2012-12-01

Botulinum toxin is a highly potent oral and inhalation poison, which means that the toxin must have an efficient mechanism for penetration of epithelial barriers. To date, three models for toxin passage across epithelial barriers have been proposed: (i) the toxin itself undergoes binding and transcytosis; (ii) an auxiliary protein, HA35, transports toxin from the apical to the basal side of epithelial cells; and (iii) an auxiliary protein, HA35, acts on the basal side of epithelial cells to disrupt tight junctions, and this permits paracellular flux of toxin. These models were evaluated by studying toxin absorption following inhalation exposure in mice. Three types of experiments were conducted. In the first, the potency of pure neurotoxin was compared with that of progenitor toxin complex, which contains HA35. The results showed that the rate and extent of toxin absorption, as well as the potency of absorbed toxin, did not depend upon, nor were they enhanced by, the presence of HA35. In the second type of experiment, the potencies of pure neurotoxin and progenitor toxin complex were compared in the absence or presence of antibodies on the apical side of epithelial cells. Antibodies directed against the neurotoxin protected against challenge, but antibodies against HA35 did not. In the final type of experiment, the potency of pure neurotoxin and toxin complex was compared in animals pretreated to deliver antibodies to the basal side of epithelial cells. Once again, antibodies directed against the neurotoxin provided resistance to challenge, but antibodies directed against HA35 did not. Taken collectively, the data indicate that the toxin by itself is capable of crossing epithelial barriers. The data do not support any hypothesis in which HA35 is essential for toxin penetration of epithelial barriers.

Effects of drug treatment on inflammation and hyperreactivity of airways and on immune variables in cats with experimentally induced asthma.

PubMed

Reinero, Carol R; Decile, Kendra C; Byerly, Jenni R; Berghaus, Roy D; Walby, William E; Berghaus, Londa J; Hyde, Dallas M; Schelegle, Edward S; Gershwin, Laurel J

2005-07-01

To compare the effects of an orally administered corticosteroid (prednisone), an inhaled corticosteroid (flunisolide), a leukotriene-receptor antagonist (zafirlukast), an antiserotonergic drug (cyproheptadine), and a control substance on the asthmatic phenotype in cats with experimentally induced asthma. 6 cats with asthma experimentally induced by the use of Bermuda grass allergen (BGA). A randomized, crossover design was used to assess changes in the percentage of eosinophils in bronchoalveolar lavage fluid (BALF); airway hyperresponsiveness; blood lymphocyte phenotype determined by use of flow cytometry; and serum and BALF content of BGA-specific IgE, IgG, and IgA determined by use of ELISAs. Mean +/- SE eosinophil percentages in BALF when cats were administered prednisone (5.0 +/- 2.3%) and flunisolide (2.5 +/- 1.7%) were significantly lower than for the control treatment (33.7 +/- 11.1%). We did not detect significant differences in airway hyperresponsiveness or lymphocyte surface markers among treatments. Content of BGA-specific IgE in serum was significantly lower when cats were treated with prednisone (25.5 +/- 5.4%), compared with values for the control treatment (63.6 +/- 12.9%); no other significant differences were observed in content of BGA-specific immunoglobulins among treatments. Orally administered and inhaled corticosteroids decreased eosinophilic inflammation in airways of cats with experimentally induced asthma. Only oral administration of prednisone decreased the content of BGA-specific IgE in serum; no other significant local or systemic immunologic effects were detected among treatments. Inhaled corticosteroids can be considered as an alternate method for decreasing airway inflammation in cats with asthma.

Estimating Supplies Program: Evaluation Report

DTIC Science & Technology

2002-12-24

Inhalation, Non-vaccinated1, Incubating, Asymptomatic 352 Anthrax, Inhalation, Non-vaccinated, Prodromal 353 Anthrax, Inhalation, Non-vaccinated, Acute...B-11 PC Code PC Description 354 Anthrax, Inhalation, Vaccinated, Asymptomatic 355 Anthrax, Inhalation, Vaccinated, Prodromal 356...Anthrax, Inhalation, Vaccinated, Acute 357 Plague, Inhalation, Incubating, Asymptomatic 358 Plague, Inhalation, Acute 359 Plague Meningitis 360

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

PubMed Central

Kuempel, Eileen D.; Sweeney, Lisa M.; Morris, John B.; Jarabek, Annie M.

2015-01-01

The purpose of this article is to provide an overview and practical guide to occupational health professionals concerning the derivation and use of dose estimates in risk assessment for development of occupational exposure limits (OELs) for inhaled substances. Dosimetry is the study and practice of measuring or estimating the internal dose of a substance in individuals or a population. Dosimetry thus provides an essential link to understanding the relationship between an external exposure and a biological response. Use of dosimetry principles and tools can improve the accuracy of risk assessment, and reduce the uncertainty, by providing reliable estimates of the internal dose at the target tissue. This is accomplished through specific measurement data or predictive models, when available, or the use of basic dosimetry principles for broad classes of materials. Accurate dose estimation is essential not only for dose-response assessment, but also for interspecies extrapolation and for risk characterization at given exposures. Inhalation dosimetry is the focus of this paper since it is a major route of exposure in the workplace. Practical examples of dose estimation and OEL derivation are provided for inhaled gases and particulates. PMID:26551218

Aspergillus fumigatus viability drives allergic responses to inhaled conidia.

PubMed

Nayak, Ajay P; Croston, Tara L; Lemons, Angela R; Goldsmith, W T; Marshall, Nikki B; Kashon, Michael L; Germolec, Dori R; Beezhold, Donald H; Green, Brett J

2018-04-13

Aspergillus fumigatus induced allergic airway disease has been shown to involve conidial germination in vivo but the immunological mechanisms remain uncharacterized. A subchronic murine exposure model was used to examine the immunological mediators that are regulated in response to either culturable or non-culturable A. fumigatus conidia. Female B6C3F1/N mice were repeatedly dosed via inhalation with 1 x 105 viable or heat inactivated conidia (HIC), twice a week for 13 weeks (26 exposures). Control mice inhaled HEPA-filtered air. The influence of A. fumigatus conidial germination on the pulmonary immunopathological outcomes was evaluated by flow cytometry analysis of cellular infiltration in the airways, assessment of lung mRNA expression, and quantitative proteomics and histopathology of whole lung tissue. Repeated inhalation of viable conidia, but not HIC, resulted in allergic inflammation marked by vascular remodeling, extensive eosinophilia, and accumulation of alternatively activated macrophages (AAMs) in the murine airways. More specifically, mice that inhaled viable conidia resulted in a mixed TH1 and TH2 (IL-13) cytokine response. Recruitment of eosinophils corresponded with increased Ccl11 transcripts. Furthermore, genes associated with M2 or alternatively activated macrophage polarization (e.g. Arg1, Chil3 and Retnla) were significantly upregulated in viable A. fumigatus exposed mice. In mice inhaling HIC, CD4+ T cells expressing IFN-γ (TH1) dominated the lymphocytic infiltration. Quantitative proteomics of the lung revealed metabolic reprogramming accompanied by mitochondrial dysfunction and endoplasmic reticulum stress stimulated by oxidative stress from repetitive microbial insult. Our studies demonstrate that A. fumigatus conidial viability in vivo is critical to the immunopathological presentation of chronic fungal allergic disease. Copyright © 2018. Published by Elsevier Inc.

Methanol toxicity secondary to inhalant abuse in adult men.

PubMed

Wallace, Erik A; Green, Adam S

2009-03-01

The purpose of this report is to evaluate the presentation, treatment, and outcomes of adults with methanol toxicity from inhalation of carburetor cleaning fluid fumes. Retrospective chart review of adults with positive serum volatile screen for methanol and history of carburetor cleaning fluid fume inhalation. Sixteen patients were admitted 68 times. Eleven Native American patients accounted for 90% of admissions. Sixty-five cases presented with nausea/vomiting; 27 with intoxication or altered mental status; 21 with specific visual complaints. About 93% had a pH <7.35, 96% had serum bicarbonate <20 mEq/L, 81% had osmolal gap >or=10 mOsm/L, and 69% had anion gap >16. Ten had an initial serum methanol level <20 mg/dL, 29 cases 20-49 mg/dL, 19 cases >or=50 mg/dL. Six patients had a measurable serum ethanol level. Of the 29 patients with a methanol level of 20-49 mg/dL, 20 received intravenous antidote (ethanol or fomepizole); three received an antidote and hemodialysis. All who presented with a serum methanol level >or=50 mg/dL received intravenous ethanol or fomepizole. All visual symptoms resolved before discharge and all patients survived without sequelae. Discussion. This is the largest reported number of cases of methanol toxicity from the inhalation of carburetor cleaning fluid fumes and demonstrates a problem with recurrent abuse among some older Native American men. Intentional inhalation of methanol fumes may produce toxicity. Clinicians need to question patients, especially older Native American men, regarding the possible inhalation of carburetor cleaning fluid fumes in those who present with an unexplained metabolic anion gap acidosis.

Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data.

PubMed

Andreae, Michael H; Carter, George M; Shaparin, Naum; Suslov, Kathryn; Ellis, Ronald J; Ware, Mark A; Abrams, Donald I; Prasad, Hannah; Wilsey, Barth; Indyk, Debbie; Johnson, Matthew; Sacks, Henry S

2015-12-01

Chronic neuropathic pain, the most frequent condition affecting the peripheral nervous system, remains underdiagnosed and difficult to treat. Inhaled cannabis may alleviate chronic neuropathic pain. Our objective was to synthesize the evidence on the use of inhaled cannabis for chronic neuropathic pain. We performed a systematic review and a meta-analysis of individual patient data. We registered our protocol with PROSPERO CRD42011001182. We searched in Cochrane Central, PubMed, EMBASE, and AMED. We considered all randomized controlled trials investigating chronic painful neuropathy and comparing inhaled cannabis with placebo. We pooled treatment effects following a hierarchical random-effects Bayesian responder model for the population-averaged subject-specific effect. Our evidence synthesis of individual patient data from 178 participants with 405 observed responses in 5 randomized controlled trials following patients for days to weeks provides evidence that inhaled cannabis results in short-term reductions in chronic neuropathic pain for 1 in every 5 to 6 patients treated (number needed to treat = 5.6 with a Bayesian 95% credible interval ranging between 3.4 and 14). Our inferences were insensitive to model assumptions, priors, and parameter choices. We caution that the small number of studies and participants, the short follow-up, shortcomings in allocation concealment, and considerable attrition limit the conclusions that can be drawn from the review. The Bayes factor is 332, corresponding to a posterior probability of effect of 99.7%. This novel Bayesian meta-analysis of individual patient data from 5 randomized trials suggests that inhaled cannabis may provide short-term relief for 1 in 5 to 6 patients with neuropathic pain. Pragmatic trials are needed to evaluate the long-term benefits and risks of this treatment. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Impact of Internal and External Factors on EBC-pH and FeNO Changes in Humans Following Challenge with Ethyl Acrylate.

PubMed

Hoffmeyer, F; Sucker, K; Berresheim, H; Monsé, C; Jettkant, B; Beine, A; Raulf, M; Bünger, J; Brüning, T

2017-01-01

Acute effects of ethyl acrylate exposure at 5 ppm for 4 h include changes of pH in exhaled breath condensate (EBC-pH) and exhaled nitric oxide (FeNO). So far, few data have been reported for atopic persons or the impact of the exposure conditions on biomarkers, e.g., constant versus variable application of irritants. Nine atopic and eighteen healthy volunteers without bronchial hyperresponsiveness were exposed for 4 h to ethyl acrylate concentrations of 0.05 ppm (sham), 5 ppm (constant concentration), and 0-10 ppm (variable, mean concentration of 5 ppm) in an exposure laboratory. A positive atopic status was defined according to specific IgE concentrations to common inhalant allergens (sx1 ≥ 0.35 kU/L). Biomarker levels were assessed before and after challenge and adjusted for levels after sham exposure (net response). Ethyl acrylate at constant, but not at variable concentrations induced a significant change in the net responses of EBC-pH and FeNO. Concerning FeNO, this could be observed only for atopic persons. The changes of biomarker levels were related to their baseline values. Biomarker responses to challenge with ethyl acrylate may be influenced by the patterns of application as well as baseline airway inflammation and atopic status of the volunteers.

Cough-variant asthma: a diagnostic dilemma in the occupational setting.

PubMed

Lipińska-Ojrzanowska, A; Wiszniewska, M; Walusiak-Skorupa, J

2015-03-01

Cough-variant asthma (Corrao's syndrome) is defined as the presence of chronic non-productive cough in patients with bronchial hyperresponsiveness (BHR) and response to bronchodilator therapy. This variant of asthma may present a diagnostic problem in occupational medicine. To describe additional evaluation of cough-variant asthma in a cyanoacrylate-exposed worker in whom standard diagnostic testing was negative. A female beautician was evaluated for suspected occupational allergic rhinitis and asthma. A specific inhalation challenge test (SICT) was performed with cyanoacrylate glues used for applying artificial eyelashes and nails. Spirometry and peak expiratory flow (PEF) measurements were recorded hourly for 24h; methacholine challenge testing was performed and nasal lavage (NL) samples were analysed for eosinophilia. After SICT, the patient developed sneezing, nasal airflow obstruction and cough. Declines in forced expiratory volume in 1 s and PEF were not observed. Eosinophil proportions in NL fluid increased markedly at 4 and 24h after SICT. A significant increase in BHR also occurred 24h after SICT. Clinical symptoms, post-challenge BHR and increased NL eosinophil counts confirmed a positive response to SICT and validated the diagnosis of cough-variant occupational asthma. SICT may be useful in cases where history and clinical data suggest cough-variant asthma and spirometric indices are negative. © The Author 2014. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Animal models of asthma: utility and limitations.

PubMed

Aun, Marcelo Vivolo; Bonamichi-Santos, Rafael; Arantes-Costa, Fernanda Magalhães; Kalil, Jorge; Giavina-Bianchi, Pedro

2017-01-01

Clinical studies in asthma are not able to clear up all aspects of disease pathophysiology. Animal models have been developed to better understand these mechanisms and to evaluate both safety and efficacy of therapies before starting clinical trials. Several species of animals have been used in experimental models of asthma, such as Drosophila , rats, guinea pigs, cats, dogs, pigs, primates and equines. However, the most common species studied in the last two decades is mice, particularly BALB/c. Animal models of asthma try to mimic the pathophysiology of human disease. They classically include two phases: sensitization and challenge. Sensitization is traditionally performed by intraperitoneal and subcutaneous routes, but intranasal instillation of allergens has been increasingly used because human asthma is induced by inhalation of allergens. Challenges with allergens are performed through aerosol, intranasal or intratracheal instillation. However, few studies have compared different routes of sensitization and challenge. The causative allergen is another important issue in developing a good animal model. Despite being more traditional and leading to intense inflammation, ovalbumin has been replaced by aeroallergens, such as house dust mites, to use the allergens that cause human disease. Finally, researchers should define outcomes to be evaluated, such as serum-specific antibodies, airway hyperresponsiveness, inflammation and remodeling. The present review analyzes the animal models of asthma, assessing differences between species, allergens and routes of allergen administration.

Inhaled uranium ore dust and lung cancer risk in rats.

PubMed

Mitchel, R E; Jackson, J S; Heinmiller, B

1999-02-01

Using a nose-only inhalation system, male Sprague-Dawley rats were exposed 4.2 h d(-1), 5 days per week for 65 weeks to one of two concentrations of natural uranium ore dust aerosol (44% U, 50 mg m(-3) and 19 mg m(-3)) without significant radon content. After inhalation exposure ceased, the rats were allowed to live for their natural lifetime. Lung uranium burdens, measured at the time of death of each animal, declined exponentially after dust inhalation ceased, and the rate of decline was independent of the initial lung burden. Lymph node specific burdens ranged from 1 to 60 fold greater than the specific lung burden in the same animal. No lymph node tumors were observed. The frequency of primary malignant lung tumors was 0.016, 0.175 and 0.328 and primary non-malignant lung tumors 0.016, 0.135 and 0.131 in the control, low and high aerosol exposed groups, respectively. There was no difference in tumor latency between the groups. Absorbed dose to the lung was calculated for each animal in the study. The average doses for all the animals exposed to the low and high dust aerosol concentrations were 0.87 Gy and 1.64 Gy respectively, resulting in an average risk of malignant lung tumors of about 0.20 tumors per animal per Gy in both groups. The frequency of primary lung tumors was also calculated as a function of dose increment for both exposed groups individually and combined. The data indicate that, in spite of the above result, lung tumor frequency was not directly proportional to dose. However, when malignant lung tumor frequency was calculated as a function of dose rate (as measured by the lung burden at the end of dust inhalation) a direct linear relationship was seen (p < 0.01) suggesting dose rate may be a more important determinant of lung cancer risk than dose. Conversely, non-malignant lung tumors were significantly correlated with low lung burdens (p = 0.01). We conclude that chronic inhalation of natural uranium ore dust alone in rats creates a risk of primary malignant and non-malignant lung tumor formation and that malignant tumor risk was not directly proportional to dose, but was directly proportional to dose rate.

Age-specific inhalation radiation dose commitment factors for selected radionuclides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strenge, D.L.; Peloquin, R.A.; Baker, D.A.

Inhalation dose commitment factors are presented for selected radionuclides for exposure of individuals in four age groups: infant, child, teen and adult. Radionuclides considered are /sup 35/S, /sup 36/Cl, /sup 45/Ca, /sup 67/Ga, /sup 75/Se, /sup 85/Sr, /sup 109/Cd, /sup 113/Sn, /sup 125/I, /sup 133/Ba, /sup 170/Tm, /sup 169/Yb, /sup 182/Ta, /sup 192/Ir, /sup 198/Au, /sup 201/Tl, /sup 204/Tl, and /sup 236/Pu. The calculational method is based on the human metabolic model of ICRP as defined in Publication 2 (ICRP 1959) and as used in previous age-specific dose factor calculations by Hoenes and Soldat (1977). Dose commitment factors are presentedmore » for the following organs of reference: total body, bone, liver, kidney, thyroid, lung and lower large intestine.« less

Cancer mortality and occupational exposure to aromatic amines and inhalable aerosols in rubber tire manufacturing in Poland.

PubMed

de Vocht, Frank; Sobala, Wojciech; Wilczynska, Urszula; Kromhout, Hans; Szeszenia-Dabrowska, Neonila; Peplonska, Beata

2009-08-01

Most data on carcinogenic risk in the rubber industry are based on data from Western countries. This study assessed cancer risks in a retrospective cohort in a Polish tire manufacturing plant, relying on quantified exposure to inhalable aerosols and aromatic amines instead of job titles or external comparisons. Cumulative exposure for all exposures was assigned to cohort members based on estimates from a company-specific JEM. Cancer risks associated with cumulative exposure adjusted for co-exposures, gender and year of birth were calculated. Exposure levels were higher for women than for men. Aromatic amine exposure was significantly associated with increased urinary bladder cancer risk (RR=7.32-8.27), depending on exposure level, and prostate cancer at low levels only (RR=5.86). In women, increased risks were found for all cancers (RR=2.50) and of the digestive organs and peritoneum (RR=4.54) at low level only, while an exposure-response association with breast cancer risk was found. Inhalable aerosol exposure was associated with cancers of the liver and intrahepatic bile ducts in a dose-dependent manner, while dose-dependent reduced risks were found for respiratory cancers (most notably the larynx) and cancer of the colon. Increased risks for specific cancer sites in this rubber plant were similar to Western Europe and the US. However, several cancer risks were gender-specific which could relate to higher exposure levels in women or to differences in exposures to chemicals not assessed in this study.

Vanadium inhalation induces retinal Müller glial cell (MGC) alterations in a murine model.

PubMed

Cervantes-Yépez, Silvana; López-Zepeda, Lorena Sofía; Fortoul, Teresa I

2018-06-01

Vanadium (V) is a transition metal adhered to suspended particles. Previous studies demonstrated that V inhalation causes oxidative stress in the ependymal epithelium, the choroid plexus on brain lateral ventricles and in the retina. Inhaled-V reaches the eye´s retina through the systemic circulation; however, its effect on the retina has not been widely studied. The Müller glial cell provides support and structure to the retina, facilitates synapses and regulates the microenvironment and neuronal metabolism. Hence, it is of great interest to study the effect of V exposure on the expression and localization of specific biomarkers on this cell. Male CD-1 mice were exposed to V inhalation 1 h/twice/week for 4 and 8-Wk. Expression changes in the retina of Glial fibrillary acidic protein, highly expressed in Müller glial cell when retina is damaged, and Glutamine synthetase, important in preventing excitotoxicity in the retina, were analysed by immunohistochemistry. Glial fibrillary acidic protein expression increased at 4-Wk of V inhalation compared to the control and decreased at 8-Wk of exposure. A time-dependent gradual reduction in glutamine synthetase expression was observed. Changes in glial fibrillary acidic protein expression induced by V suggest retinal damage, whereas glutamine synthetase gradual reduction might indicate that photoreceptors, which produce most of the glutamine synthetase substrate in the retina, are degenerating, probably as a consequence of the oxidative stress induced by V.

The enigma of inhaled salbutamol and sport: unresolved after 45 years.

PubMed

Fitch, Ken D

2017-07-01

During the past 45 years, there have been more changes on the World Anti-Doping Agency's (WADA) Prohibited List (the List) to the status of inhaled salbutamol than any other substance. With 658 athletes, 6.1% of all participating athletes approved to inhale salbutamol at the 2008 Beijing Games, it is one of the medications used most frequently by Olympic athletes. Nevertheless, since the 2008 Games, WADA has made numerous changes to inhaled salbutamol on the List including prohibiting its use, then a year later permitting it without prior notification and recommending a pharmacokinetic study if an athlete exceeds the urinary threshold of 1000 ng/mL. Recently, an elite athlete undertook two pharmacokinetic studies and the results have raised several questions. These include whether WADA should continue to permit nebulized salbutamol as an acceptable method of inhalation and there is some justification for nebulized salbutamol to be prohibited in sport. Another question is whether the modified advisory on salbutamol in the 2017 List appropriately informs athletes of the risks of exceeding the urinary threshold and the recent changes may not inform athletes optimally. Finally, concern is expressed at the persistent failure of WADA to apply a correction down to a specific gravity of 1.020 when an exogenous substance is identified in the urine of a dehydrated athlete. It is recommended that this should be implemented. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of lung disease on the three-dimensional structure and air flow pattern in the human airway tree

NASA Astrophysics Data System (ADS)

van de Moortele, Tristan; Nemes, Andras; Wendt, Christine; Coletti, Filippo

2016-11-01

The morphological features of the airway tree directly affect the air flow features during breathing, which determines the gas exchange and inhaled particle transport. Lung disease, Chronic Obstructive Pulmonary Disease (COPD) in this study, affects the structural features of the lungs, which in turn negatively affects the air flow through the airways. Here bronchial tree air volume geometries are segmented from Computed Tomography (CT) scans of healthy and diseased subjects. Geometrical analysis of the airway centerlines and corresponding cross-sectional areas provide insight into the specific effects of COPD on the airway structure. These geometries are also used to 3D print anatomically accurate, patient specific flow models. Three-component, three-dimensional velocity fields within these models are acquired using Magnetic Resonance Imaging (MRI). The three-dimensional flow fields provide insight into the change in flow patterns and features. Additionally, particle trajectories are determined using the velocity fields, to identify the fate of therapeutic and harmful inhaled aerosols. Correlation between disease-specific and patient-specific anatomical features with dysfunctional airflow patterns can be achieved by combining geometrical and flow analysis.

Cutaneous anthrax: an overview.

PubMed

Celia, Frank

2002-04-01

The recent acts of bioterrorism have raised new questions about this uncommon disease. Clinicians are puzzled as to why some of the victims exposed to Bacillus anthracis spores developed the cutaneous form of the disease and others the inhalational form. Despite these questions, cutaneous anthrax remains relatively simple to treat effectively. The real clinical challenge lies in the diagnosis, especially being able to distinguish it from a spider bite.

High-resolution 3D MR microangiography of the rat ocular circulation.

PubMed

Shih, Yen-Yu I; Muir, Eric R; Li, Guang; De La Garza, Bryan H; Duong, Timothy Q

2012-07-01

To develop high-spatial-resolution magnetic resonance (MR) microangiography techniques to image the rat ocular circulation. Animal experiments were performed with institutional Animal Care Committee approval. MR microangiography (resolution, 84×84×84 μm or 42×42×84 μm) of the rat eye (eight rats) was performed by using a custom-made small circular surface coil with an 11.7-T MR unit before and after monocrystalline iron oxide nanoparticle (MION) injection. MR microangiography measurements were made during air, oxygen, and carbogen inhalation. From three-dimensional MR microangiography, the retina was virtually flattened to enable en face views of various retinal depths, including the retinal and choroidal vascular layers. Signal intensity changes within the retinal or choroidal arteries and veins associated with gas challenges were analyzed. Statistical analysis was performed by using paired t tests, with P<.05 considered to indicate a significant difference. Bonferroni correction was used to adjust for multiple comparisons. The central retinal artery, long posterior ciliary arteries, and choroidal vasculature could be distinguished on MR microangiograms of the eye. With MR microangiography, retinal arteries and veins could be distinguished on the basis of blood oxygen level-dependent contrast. Carbogen inhalation-enhanced MR microangiography signal intensity in both the retina (P=.001) and choroid (P=.027) compared with oxygen inhalation. Carbogen inhalation showed significantly higher signal intensity changes in the retinal arteries (P=.001, compared with oxygen inhalation), but not in the veins (P=.549). With MION administration, MR microangiography depicted retinal arterial vasoconstriction when the animals were breathing oxygen (P=.02, compared with animals breathing air). MR microangiography of the eye allows depth-resolved imaging of small angiographic details of the ocular circulation. This approach may prove useful in studying microvascular pathologic findings and neurovascular dysfunction in the eye and retina. © RSNA, 2012.

An Apparatus to Deliver Mannitol Powder for Bronchial Provocation in Children Under Six Years Old.

PubMed

Tang, Patricia; Leung, Sharon S Y; Hor, Eleanor; Ruzycki, Conor A; Carrigy, Nicholas B; Finlay, Warren H; Brannan, John D; Devadason, Sunalene; Anderson, Sandra D; Sly, Peter D; Samnick, Kevin; Chan, Hak-Kim

2015-12-01

Currently bronchial provocation testing (BPT) using mannitol powder cannot be performed in children under 6 years. A primary reason is it is challenging for children at this age to generate a consistent inspiratory effort to inhale mannitol efficiently from a dry powder inhaler. A prototype system, which does not require any inhalation training from the pediatric subject, is reported here. It uses an external source of compressed air to disperse mannitol powder into a commercial holding chamber. Then the subject uses tidal breathing to inhale the aerosol. The setup consists of a commercially available powder disperser and Volumatic™ holding chamber. Taguchi experimental design was used to identify the effect of dispersion parameters (flow rate of compressed air, time compressed air is applied, mass of powder, and the time between dispersion and inhalation) on the fine particle dose (FPD). The prototype was tested in vitro using a USP throat connected to a next generation impactor. The aerosols from the holding chamber were drawn at 10 L/min. A scaling factor for estimating the provoking dose to induce a 15% reduction in forced expiratory volume in 1 second (FEV1) (PD15) was calculated using anatomical dimensions of the human respiratory tract at various ages combined with known dosing values from the adult BPT. Consistent and doubling FPDs were successfully generated based on the Taguchi experimental design. The FPD was reliable over a range of 0.8 (±0.09) mg to 14 (±0.94) mg. The calculated PD15 for children aged 1-6 years ranged from 7.1-30 mg. The FPDs generated from the proposed set up are lower than the calculated PD15 and therefore are not expected to cause sudden bronchoconstriction. A prototype aerosol delivery system has been developed that is consistently able to deliver doubling doses suitable for bronchial provocation testing in young children.

Attempts to counteract phosgene-induced acute lung injury by instant high-dose aerosol exposure to hexamethylenetetramine, cysteine or glutathione.

PubMed

Pauluhn, Jürgen; Hai, Chun Xue

2011-01-01

Phosgene is an important high-production-volume intermediate with widespread industrial use. Consistent with other lung irritants causing ALI (acute lung injury), mode-of-action-based countermeasures remain rudimentary. This study was conducted to analyze whether extremely short high-level exposure to phosgene gas could be mitigated using three different inhaled nucleophiles administered by inhalation instantly after exposure to phosgene. Groups of young adult male Wistar rats were acutely exposed to carbonyl chloride (phosgene) using a directed-flow nose-only mode of exposure of 600 mg/m³ for 1.5 min (225 ppm × min). Immediately after exposure to phosgene gas the rats were similarly exposed to three strong nucleophiles with and without antioxidant properties for 5 or 15 min. The following nucleophiles were used: hexamethylenetetramine (HMT), l-cysteine (Cys), and l-glutathione (GSH). The concentration of the aerosol (mass median aerodynamic diameter 1.7-2 µm) was targeted to be in the range of 1 mg/L. Cys and GSH have antioxidant properties in addition. The calculated alveolar molar dosage of phosgene was 9 µmol/kg. At 15-min exposure duration, the respective inhaled dose of HMT, Csy, and GSH were 111, 103, and 46 µmol/kg, respectively. The alveolar dose of drugs was ~10-times lower. The efficacy of treatment was judged by protein concentrations in bronchoalveolar lavage fluid (BALF) collected 1 day post-exposure. In spite of using optimized aerosolization techniques, none of the nucleophiles chosen had any mitigating effect on BALF-protein extravasation. This finding appear to suggest that inhaled phosgene gas acylates instantly nucleophilic moieties at the site of initial deposition and that the resultant reaction products can not be reactivated even following instant inhalation treatment with competing nucleophilic agents. In spite of using maximal technically attainable concentrations, it appears to be experimentally challenging to deliver such nucleophiles to the lower respiratory tract at high dosages.

Pulmonary immunization of chickens using non-adjuvanted spray-freeze dried whole inactivated virus vaccine completely protects against highly pathogenic H5N1 avian influenza virus.

PubMed

Peeters, Ben; Tonnis, Wouter F; Murugappan, Senthil; Rottier, Peter; Koch, Guus; Frijlink, Henderik W; Huckriede, Anke; Hinrichs, Wouter L J

2014-11-12

Highly pathogenic avian influenza (HPAI) H5N1 virus is a major threat to public health as well as to the global poultry industry. Most fatal human infections are caused by contact with infected poultry. Therefore, preventing the virus from entering the poultry population is a priority. This is, however, problematic in emergency situations, e.g. during outbreaks in poultry, as there are currently no mass application methods to effectively vaccinate large numbers of birds within a short period of time. To evaluate the suitability of needle-free pulmonary immunization for mass vaccination of poultry against HPAI H5N1, we performed a proof-of-concept study in which we investigated whether non-adjuvanted spray-freeze-dried (SFD) whole inactivated virus (WIV) can be used as a dry powder aerosol vaccine to immunize chickens. Our results show that chickens that received SFD-WIV vaccine as aerosolized powder directly at the syrinx (the site of the tracheal bifurcation), mounted a protective antibody response after two vaccinations and survived a lethal challenge with HPAI H5N1. Furthermore, both the number of animals that shed challenge virus, as well as the level of virus shedding, were significantly reduced. Based on antibody levels and reduction of virus shedding, pulmonary vaccination with non-adjuvanted vaccine was at least as efficient as intratracheal vaccination using live virus. Animals that received aerosolized SFD-WIV vaccine by temporary passive inhalation showed partial protection (22% survival) and a delay in time-to-death, thereby demonstrating the feasibility of the method, but indicating that the efficiency of vaccination by passive inhalation needs further improvement. Altogether our results provide a proof-of-concept that pulmonary vaccination using an SFD-WIV powder vaccine is able to protect chickens from lethal HPAI challenge. If the efficacy of pulmonary vaccination by passive inhalation can be improved, this method might be suitable for mass application. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of inhaled fine dust on lung tissue changes and antibody response induced by spores of opportunistic fungi in goats.

PubMed

Purdy, Charles W; Layton, Robert C; Straus, David C; Ayers, J R

2008-04-01

To investigate the effects of sterile fine dust aerosol inhalation on antibody responses and lung tissue changes induced by Mucor ramosissimus or Trichoderma viride spores following intratracheal inoculation in goats. 36 weanling Boer-Spanish goats. 6 goats were allocated to each of 2 M ramosissimus-inoculated groups, 2 T viride-inoculated groups, and 2 control (tent or pen) groups. One of each pair of sporetreated groups and the tent control group were exposed 7 times to sterilized fine feedyard dust (mean+/-SD particle diameter, <7.72+/-0.69 microm) for 4 hours in a specially constructed tent. Goats in the 4 fungal treatment groups were inoculated intratracheally 5 times with a fungal spore preparation (30 mL), whereas tent control goats were intratracheally inoculated with physiologic saline (0.9% NaCl) solution (30 mL). Pen control goats were not inoculated or exposed to dust. Goats received an IV challenge with equine RBCs to assess antibody responses to foreign antigens. Postmortem examinations were performed at study completion (day 68) to evaluate lung tissue lesions. 5 of 7 deaths occurred between days 18 and 45 and were attributed to fine dust exposures prior to fungal treatments. Fine dust inhalation induced similar lung lesions and precipitating antibodies among spore-treated goats. Following spore inoculations, dust-exposed goats had significantly more spores per gram of consolidated lung tissue than did their nonexposed counterparts. Fine dust inhalation appeared to decrease the ability of goats to successfully clear fungal spores from the lungs following intratracheal inoculation.

Transfer time to a specialist burn service and influence on burn mortality in Australia and New Zealand: A multi-centre, hospital based retrospective cohort study.

PubMed

Cassidy, T John; Edgar, Dale W; Phillips, Michael; Cameron, Peter; Cleland, Heather; Wood, Fiona M

2015-06-01

In Australia and New Zealand (ANZ), health care is provided for ∼26 million people dispersed across the eight million square kilometres of the two countries. Providing optimal care prior to and during transfer across such vast distances is challenging. Lengthening the time taken to definitive burn care has a negative impact on burn outcome. The aims of this study were to determine if transfer time and admission pathway influenced burn mortality and to identify the factors predicting burn mortality in ANZ. The study included all adult burn patient admission data from 15 of 17 burn services submitted to the Australian and New Zealand Burn Association bi-national registry (2010-2012). Multivariate logistic regression analyses were conducted to address the study aims. Of the 2892 patients, 69 (2.4%) died following burn. Time to admission and direct admission to a burn centre did not independently influence burn mortality except when patients with inhalation injury took >16 h to transfer to definitive care. The risk of death was increased 5.7 times in the presence of inhalation injury. Burn size and age amplified the risk of death while gender did not. In ANZ, pre-hospital transport systems and peripheral hospital stabilisation were not associated with an increased risk of death due to burn except when inhalation injury was present. The results of this study indicate that burn patients with inhalation injury should be stabilised and transferred to a burn service within 16 h of burn. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.

Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation

PubMed Central

Downie, Sue R; Salome, Cheryl M; Verbanck, Sylvia; Thompson, Bruce; Berend, Norbert; King, Gregory G

2007-01-01

Background Airway hyperresponsiveness is the ability of airways to narrow excessively in response to inhaled stimuli and is a key feature of asthma. Airway inflammation and ventilation heterogeneity have been separately shown to be associated with airway hyperresponsiveness. A study was undertaken to establish whether ventilation heterogeneity is associated with airway hyperresponsiveness independently of airway inflammation in subjects with asthma and to determine the effect of inhaled corticosteroids on this relationship. Methods Airway inflammation was measured in 40 subjects with asthma by exhaled nitric oxide, ventilation heterogeneity by multiple breath nitrogen washout and airway hyperresponsiveness by methacholine challenge. In 18 of these subjects with uncontrolled symptoms, measurements were repeated after 3 months of treatment with inhaled beclomethasone dipropionate. Results At baseline, airway hyperresponsiveness was independently predicted by airway inflammation (partial r2 = 0.20, p<0.001) and ventilation heterogeneity (partial r2 = 0.39, p<0.001). Inhaled corticosteroid treatment decreased airway inflammation (p = 0.002), ventilation heterogeneity (p = 0.009) and airway hyperresponsiveness (p<0.001). After treatment, ventilation heterogeneity was the sole predictor of airway hyperresponsiveness (r2 = 0.64, p<0.001). Conclusions Baseline ventilation heterogeneity is a strong predictor of airway hyperresponsiveness, independent of airway inflammation in subjects with asthma. Its persistent relationship with airway hyperresponsiveness following anti‐inflammatory treatment suggests that it is an important independent determinant of airway hyperresponsiveness. Normalisation of ventilation heterogeneity is therefore a potential goal of treatment that may lead to improved long‐term outcomes. PMID:17311839

Exposure to Particulate Hexavalent Chromium Exacerbates Allergic Asthma Pathology

PubMed Central

Schneider, Brent C.; Constant, Stephanie L.; Patierno, Steven R.; Jurjus, Rosalyn A.; Ceryak, Susan M.

2011-01-01

Airborne hexavalent chromate, Cr(VI), has been identified by the Environmental Protection Agency as a possible health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate chromates are produced in many different industrial settings, with high levels of aerosolized forms historically documented. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in workers exposed to certain inhaled particulate Cr(VI) compounds. However, a direct causal association between Cr(VI) and allergic asthma has not been established. We recently showed that inhaled particulate Cr(VI) induces an innate neutrophilic inflammatory response in BALB/c mice. In the current studies we investigated how the inflammation induced by inhaled particulate Cr(VI) might alter the pathology of an allergic asthmatic response. We used a well-established mouse model of allergic asthma. Groups of ovalbumin protein (OVA)-primed mice were challenged either with OVA alone, or with a combination of OVA and particulate zinc chromate, and various parameters associated with asthmatic responses were measured. Co-exposure to particulate Cr(VI) and OVA mediated a mixed form of asthma in which both eosinophils and neutrophils are present in airways, tissue pathology is markedly exacerbated, and airway hyperresponsiveness is significantly increased. Taken together these findings suggest that inhalation of particulate forms of Cr(VI) may augment the severity of ongoing allergic asthma, as well as alter its phenotype. Such findings may have implications for asthmatics in settings in which airborne particulate Cr(VI) compounds are present at high levels. PMID:22178736

Efficacy Projection of Obiltoxaximab for Treatment of Inhalational Anthrax across a Range of Disease Severity.

PubMed

Yamamoto, Brent J; Shadiack, Annette M; Carpenter, Sarah; Sanford, Daniel; Henning, Lisa N; O'Connor, Edward; Gonzales, Nestor; Mondick, John; French, Jonathan; Stark, Gregory V; Fisher, Alan C; Casey, Leslie S; Serbina, Natalya V

2016-10-01

Inhalational anthrax has high mortality even with antibiotic treatment, and antitoxins are now recommended as an adjunct to standard antimicrobial regimens. The efficacy of obiltoxaximab, a monoclonal antibody against anthrax protective antigen (PA), was examined in multiple studies conducted in two animal models of inhalational anthrax. A single intravenous bolus of 1 to 32 mg/kg of body weight obiltoxaximab or placebo was administered to New Zealand White rabbits (two studies) and cynomolgus macaques (4 studies) at disease onset (significant body temperature increase or detection of serum PA) following lethal challenge with aerosolized Bacillus anthracis spores. The primary endpoint was survival. The relationship between efficacy and disease severity, defined by pretreatment bacteremia and toxemia levels, was explored. In rabbits, single doses of 1 to 16 mg/kg obiltoxaximab led to 17 to 93% survival. In two studies, survival following 16 mg/kg obiltoxaximab was 93% and 62% compared to 0% and 0% for placebo (P = 0.0010 and P = 0.0013, respectively). Across four macaque studies, survival was 6.3% to 78.6% following 4 to 32 mg/kg obiltoxaximab. In two macaque studies, 16 mg/kg obiltoxaximab reduced toxemia and led to survival rates of 31%, 35%, and 47% versus 0%, 0%, and 6.3% with placebo (P = 0.0085, P = 0.0053, P = 0.0068). Pretreatment bacteremia and toxemia levels inversely correlated with survival. Overall, obiltoxaximab monotherapy neutralized PA and increased survival across the range of disease severity, indicating clinical benefit of toxin neutralization with obiltoxaximab in both early and late stages of inhalational anthrax. Copyright © 2016 Yamamoto et al.

Estimation of inhalation flow profile using audio-based methods to assess inhaler medication adherence.

PubMed

Taylor, Terence E; Lacalle Muls, Helena; Costello, Richard W; Reilly, Richard B

2018-01-01

Asthma and chronic obstructive pulmonary disease (COPD) patients are required to inhale forcefully and deeply to receive medication when using a dry powder inhaler (DPI). There is a clinical need to objectively monitor the inhalation flow profile of DPIs in order to remotely monitor patient inhalation technique. Audio-based methods have been previously employed to accurately estimate flow parameters such as the peak inspiratory flow rate of inhalations, however, these methods required multiple calibration inhalation audio recordings. In this study, an audio-based method is presented that accurately estimates inhalation flow profile using only one calibration inhalation audio recording. Twenty healthy participants were asked to perform 15 inhalations through a placebo Ellipta™ DPI at a range of inspiratory flow rates. Inhalation flow signals were recorded using a pneumotachograph spirometer while inhalation audio signals were recorded simultaneously using the Inhaler Compliance Assessment device attached to the inhaler. The acoustic (amplitude) envelope was estimated from each inhalation audio signal. Using only one recording, linear and power law regression models were employed to determine which model best described the relationship between the inhalation acoustic envelope and flow signal. Each model was then employed to estimate the flow signals of the remaining 14 inhalation audio recordings. This process repeated until each of the 15 recordings were employed to calibrate single models while testing on the remaining 14 recordings. It was observed that power law models generated the highest average flow estimation accuracy across all participants (90.89±0.9% for power law models and 76.63±2.38% for linear models). The method also generated sufficient accuracy in estimating inhalation parameters such as peak inspiratory flow rate and inspiratory capacity within the presence of noise. Estimating inhaler inhalation flow profiles using audio based methods may be clinically beneficial for inhaler technique training and the remote monitoring of patient adherence.

Estimation of inhalation flow profile using audio-based methods to assess inhaler medication adherence

PubMed Central

Lacalle Muls, Helena; Costello, Richard W.; Reilly, Richard B.

2018-01-01

Asthma and chronic obstructive pulmonary disease (COPD) patients are required to inhale forcefully and deeply to receive medication when using a dry powder inhaler (DPI). There is a clinical need to objectively monitor the inhalation flow profile of DPIs in order to remotely monitor patient inhalation technique. Audio-based methods have been previously employed to accurately estimate flow parameters such as the peak inspiratory flow rate of inhalations, however, these methods required multiple calibration inhalation audio recordings. In this study, an audio-based method is presented that accurately estimates inhalation flow profile using only one calibration inhalation audio recording. Twenty healthy participants were asked to perform 15 inhalations through a placebo Ellipta™ DPI at a range of inspiratory flow rates. Inhalation flow signals were recorded using a pneumotachograph spirometer while inhalation audio signals were recorded simultaneously using the Inhaler Compliance Assessment device attached to the inhaler. The acoustic (amplitude) envelope was estimated from each inhalation audio signal. Using only one recording, linear and power law regression models were employed to determine which model best described the relationship between the inhalation acoustic envelope and flow signal. Each model was then employed to estimate the flow signals of the remaining 14 inhalation audio recordings. This process repeated until each of the 15 recordings were employed to calibrate single models while testing on the remaining 14 recordings. It was observed that power law models generated the highest average flow estimation accuracy across all participants (90.89±0.9% for power law models and 76.63±2.38% for linear models). The method also generated sufficient accuracy in estimating inhalation parameters such as peak inspiratory flow rate and inspiratory capacity within the presence of noise. Estimating inhaler inhalation flow profiles using audio based methods may be clinically beneficial for inhaler technique training and the remote monitoring of patient adherence. PMID:29346430

The inhalation characteristics of patients when they use different dry powder inhalers.

PubMed

Azouz, Wahida; Chetcuti, Philip; Hosker, Harold S R; Saralaya, Dinesh; Stephenson, John; Chrystyn, Henry

2015-02-01

The characteristics of each inhalation maneuver when patients use dry powder inhalers (DPIs) are important, because they control the quality of the emitted dose. We have measured the inhalation profiles of asthmatic children [CHILD; n=16, mean forced expiratory volume in 1 sec (FEV1) 79% predicted], asthmatic adults (ADULT; n=53, mean predicted FEV1 72%), and chronic obstructive pulmonary disease (COPD; n=29, mean predicted FEV1 42%) patients when they inhaled through an Aerolizer, Diskus, Turbuhaler, and Easyhaler using their "real-life" DPI inhalation technique. These are low-, medium-, medium/high-, and high-resistance DPIs, respectively. The inhalation flow against time was recorded to provide the peak inhalation flow (PIF; in L/min), the maximum pressure change (ΔP; in kPa), acceleration rates (ACCEL; in kPa/sec), time to maximum inhalation, the length of each inhalation (in sec), and the inhalation volume (IV; in liters) of each inhalation maneuver. PIF, ΔP, and ACCEL values were consistent with the order of the inhaler's resistance. For each device, the inhalation characteristics were in the order ADULT>COPD>CHILD for PIF, ΔP, and ACCEL (p<0.001). The results showed a large variability in inhalation characteristics and demonstrate the advantages of ΔP and ACCEL rather than PIFs. Overall inhaled volumes were low, and only one patient achieved an IV >4 L and ΔP >4 kPa. The large variability of these inhalation characteristics and their range highlights that if inhalation profiles were used with compendial in vitro dose emission measurements, then the results would provide useful information about the dose patients inhale during routine use. The inhalation characteristics highlight that adults with asthma have greater inspiratory capacity than patients with COPD, whereas children with asthma have the lowest. The significance of the inhaled volume to empty doses from each device requires investigation.

A method for calculating the gas volume proportions and inhalation temperature of inert gas mixtures allowing reaching normothermic or hypothermic target body temperature in the awake rat.

PubMed

Abraini, Jacques H; David, Hélène N; Blatteau, Jean-Éric; Risso, Jean Jacques; Vallée, Nicolas

2017-01-01

The noble gases xenon (Xe) and helium (He) are known to possess neuroprotective properties. Xe is considered the golden standard neuroprotective gas. However, Xe has a higher molecular weight and lower thermal conductivity and specific heat than those of nitrogen, the main diluent of oxygen (O2) in air, conditions that could impair or at least reduce the intrinsic neuroprotective properties of Xe by increasing the critical care patient's respiratory workload and body temperature. In contrast, He has a lower molecular weight and higher thermal conductivity and specific heat than those of nitrogen, but is unfortunately far less potent than Xe at providing neuroprotection. Therefore, combining Xe with He could allow obtaining, depending on the gas inhalation temperature and composition, gas mixtures with neutral or hypothermic properties, the latter being advantageous in term of neuroprotection. However, calculating the thermal properties of a mixture, whatever the substances - gases, metals, rubbers, etc . - is not trivial. To answer this question, we provide a graphical method to assess the volume proportions of Xe, He and O2 that a gas mixture should contain, and the inhalation temperature to which it should be administered to allow a clinician to maintain the patient at a target body temperature.

Obiltoxaximab Prevents Disseminated Bacillus anthracis Infection and Improves Survival during Pre- and Postexposure Prophylaxis in Animal Models of Inhalational Anthrax.

PubMed

Yamamoto, Brent J; Shadiack, Annette M; Carpenter, Sarah; Sanford, Daniel; Henning, Lisa N; Gonzales, Nestor; O'Connor, Edward; Casey, Leslie S; Serbina, Natalya V

2016-10-01

The Centers for Disease Control and Prevention recommend adjunctive antitoxins when systemic anthrax is suspected. Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax in combination with antibiotics and for prophylaxis when alternative therapies are not available. The impact of toxin neutralization with obiltoxaximab during pre- and postexposure prophylaxis was explored, and efficacy results that supported the prophylaxis indication are presented here. New Zealand White rabbits and cynomolgus macaques received obiltoxaximab as a single intramuscular or intravenous dose of 2 to 16 mg/kg of body weight at various times relative to Bacillus anthracis aerosol spore challenge. The primary endpoint was survival, and effect of treatment timing was explored. In rabbits, obiltoxaximab administration 9 h postchallenge singly or combined with a 5-day levofloxacin regimen protected 89% to 100% of animals compared to 33% with levofloxacin monotherapy. In cynomolgus macaques, a single intramuscular dose of 16 mg/kg obiltoxaximab led to 100% survival when given 1 to 3 days preexposure and 83% to 100% survival when given 18 to 24 h postexposure and prior to systemic bacteremia onset. Obiltoxaximab administration after bacteremia onset resulted in lower (25% to 50%) survival rates reflective of treatment setting. Prophylactic administration of obiltoxaximab before spore challenge or to spore-challenged animals before systemic bacterial dissemination is efficacious in promoting survival, ameliorating toxemia, and inhibiting bacterial spread to the periphery. Copyright © 2016 Yamamoto et al.

Using Telemetry Data to Refine Endpoints for New Zealand White Rabbits Challenged with Bacillus anthracis.

PubMed

Dawson, David G; Bower, Kristin A; Burnette, Candace N; Holt, Rebecca K; Swearengen, James R; Dabisch, Paul A; Scorpio, Angelo

2017-11-01

We used a continuous-monitoring digital telemetry system to investigate temperature response in New Zealand White rabbits after inhalation or subcutaneous challenge with Bacillus anthracis. Two spore preparations of B. anthracis Ames A2084 were evaluated by using a nose-only inhalation model, and 2 strains, B. anthracis Ames A2084 and B. anthracis UT500, were evaluated in a subcutaneous model. Animal body temperature greater than 3 SD above the mean baseline temperature was considered a significant increase in body temperature (SIBT). All rabbits that exhibited SIBT after challenge by either route of infection or bacterial strain eventually died or were euthanized due to infection, and all rabbits that died or were euthanized due to infection exhibited SIBT during the course of disease. The time at onset of SIBT preceded clinical signs of disease in 94% of the rabbits tested by as long as 2 days. In addition, continuous temperature monitoring facilitated discrimination between the 2 B. anthracis strains with regard to the time interval between SIBT and death. These data suggest that for the New Zealand White rabbit anthrax model, SIBT is a reliable indicator of infection, is predictive of experimental outcome in the absence of treatment, and is measurable prior to the appearance of more severe signs of disease. The use of digital telemetry to monitor infectious disease course in animal models of anthrax can potentially be used in conjunction with other clinical score metrics to refine endpoint euthanasia criteria.

Obiltoxaximab Prevents Disseminated Bacillus anthracis Infection and Improves Survival during Pre- and Postexposure Prophylaxis in Animal Models of Inhalational Anthrax

PubMed Central

Yamamoto, Brent J.; Shadiack, Annette M.; Carpenter, Sarah; Sanford, Daniel; Henning, Lisa N.; Gonzales, Nestor; O'Connor, Edward; Casey, Leslie S.

2016-01-01

The Centers for Disease Control and Prevention recommend adjunctive antitoxins when systemic anthrax is suspected. Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax in combination with antibiotics and for prophylaxis when alternative therapies are not available. The impact of toxin neutralization with obiltoxaximab during pre- and postexposure prophylaxis was explored, and efficacy results that supported the prophylaxis indication are presented here. New Zealand White rabbits and cynomolgus macaques received obiltoxaximab as a single intramuscular or intravenous dose of 2 to 16 mg/kg of body weight at various times relative to Bacillus anthracis aerosol spore challenge. The primary endpoint was survival, and effect of treatment timing was explored. In rabbits, obiltoxaximab administration 9 h postchallenge singly or combined with a 5-day levofloxacin regimen protected 89% to 100% of animals compared to 33% with levofloxacin monotherapy. In cynomolgus macaques, a single intramuscular dose of 16 mg/kg obiltoxaximab led to 100% survival when given 1 to 3 days preexposure and 83% to 100% survival when given 18 to 24 h postexposure and prior to systemic bacteremia onset. Obiltoxaximab administration after bacteremia onset resulted in lower (25% to 50%) survival rates reflective of treatment setting. Prophylactic administration of obiltoxaximab before spore challenge or to spore-challenged animals before systemic bacterial dissemination is efficacious in promoting survival, ameliorating toxemia, and inhibiting bacterial spread to the periphery. PMID:27431219

Methacholine challenge test: diagnostic characteristics in asthmatic patients receiving controller medications.

PubMed

Sumino, Kaharu; Sugar, Elizabeth A; Irvin, Charles G; Kaminsky, David A; Shade, Dave; Wei, Christine Y; Holbrook, Janet T; Wise, Robert A; Castro, Mario

2012-07-01

The methacholine challenge test (MCT) is commonly used to assess airway hyperresponsiveness, but the diagnostic characteristics have not been well studied in asthmatic patients receiving controller medications after the use of high-potency inhaled corticosteroids became common. We investigated the ability of the MCT to differentiate participants with a physician's diagnosis of asthma from nonasthmatic participants. We conducted a cohort-control study in asthmatic participants (n= 126) who were receiving regular controller medications and nonasthmatic control participants (n= 93) to evaluate the sensitivity and specificity of the MCT. The overall sensitivity was 77% and the specificity was 96% with a threshold PC(20) (the provocative concentration of methacholine that results in a 20% drop in FEV(1)) of 8 mg/mL. The sensitivity was significantly lower in white than in African American participants (69% vs 95%, P= .015) and higher in atopic compared with nonatopic (82% vs 52%, P= .005). Increasing the PC(20) threshold from 8 to 16 mg/mL did not noticeably improve the performance characteristics of the test. African American race, presence of atopy, and lower percent predicted FEV(1) were associated with a positive test result. The utility of the MCT to rule out a diagnosis of asthma depends on racial and atopic characteristics. Clinicians should take into account the reduced sensitivity of the MCT in white and nonatopic asthmatic patients when using this test for the diagnosis of asthma. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Indoleamine 2,3-dioxygenase-dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model.

PubMed

Taher, Yousef A; Piavaux, Benoit J A; Gras, Reneé; van Esch, Betty C A M; Hofman, Gerard A; Bloksma, Nanne; Henricks, Paul A J; van Oosterhout, Antoon J M

2008-04-01

The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in immune suppression and tolerance induction. We examined (1) whether IDO activity is required during tolerance induction by allergen immunotherapy or for the subsequent suppressive effects on asthma manifestations and (2) whether tryptophan depletion or generation of its downstream metabolites is involved. Ovalbumin (OVA)-sensitized and OVA-challenged BALB/c mice that display increased airway responsiveness to methacholine, serum OVA-specific IgE levels, bronchoalveolar eosinophilia, and TH2 cytokine levels were used as a model of allergic asthma. Sensitized mice received subcutaneous optimal (1 mg) or suboptimal (100 microg) OVA immunotherapy. Inhibition of IDO by 1-methyl-DL-tryptophan during immunotherapy, but not during inhalation challenge, partially reversed the suppressive effects of immunotherapy on airway eosinophilia and TH2 cytokine levels, whereas airway hyperresponsiveness and serum OVA-specific IgE levels remained suppressed. Administration of tryptophan during immunotherapy failed to abrogate its beneficial effects toward allergic airway inflammation. Interestingly, administration of tryptophan or its metabolites, kynurenine, 3-hydroxykynurenine, and xanthurenic acid, but not 3-hydroxyanthranilinic acid, quinolinic acid, and kynurenic acid, during suboptimal immunotherapy potentiated the reduction of eosinophilia. These effects coincided with reduced TH2 cytokine levels in bronchoalveolar lavage fluid, but no effects on IgE levels were detected. During immunotherapy, the tryptophan metabolites kynurenine, 3-hydroxykynurenine, and xanthurenic acid generated through IDO contribute to tolerance induction regarding TH2-dependent allergic airway inflammation.

Subchronic exposures to fungal bioaerosols promotes allergic pulmonary inflammation in naïve mice.

PubMed

Nayak, A P; Green, B J; Lemons, A R; Marshall, N B; Goldsmith, W T; Kashon, M L; Anderson, S E; Germolec, D R; Beezhold, D H

2016-06-01

Epidemiological surveys indicate that occupants of mold contaminated environments are at increased risk of respiratory symptoms. The immunological mechanisms associated with these responses require further characterization. The aim of this study was to characterize the immunotoxicological outcomes following repeated inhalation of dry Aspergillus fumigatus spores aerosolized at concentrations potentially encountered in contaminated indoor environments. Aspergillus fumigatus spores were delivered to the lungs of naïve BALB/cJ mice housed in a multi-animal nose-only chamber twice a week for a period of 13 weeks. Mice were evaluated at 24 and 48 h post-exposure for histopathological changes in lung architecture, recruitment of specific immune cells to the airways, and serum antibody responses. Germinating A. fumigatus spores were observed in lungs along with persistent fungal debris in the perivascular regions of the lungs. Repeated exposures promoted pleocellular infiltration with concomitant epithelial mucus hypersecretion, goblet cell metaplasia, subepithelial fibrosis and enhanced airway hyperreactivity. Cellular infiltration in airways was predominated by CD4(+) T cells expressing the pro-allergic cytokine IL-13. Furthermore, our studies show that antifungal T cell responses (IFN-γ(+) or IL-17A(+) ) co-expressed IL-13, revealing a novel mechanism for the dysregulated immune response to inhaled fungi. Total IgE production was augmented in animals repeatedly exposed to A. fumigatus. Repeated inhalation of fungal aerosols resulted in significant pulmonary pathology mediated by dynamic shifts in specific immune populations and their cytokines. These studies provide novel insights into the immunological mechanisms and targets that govern the health outcomes that result from repeated inhalation of fungal bioaerosols in contaminated environments. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Subchronic exposures to fungal bioaerosols promotes allergic pulmonary inflammation in naïve mice

PubMed Central

Nayak, Ajay P.; Green, Brett J.; Lemons, Angela R.; Marshall, Nikki B.; Goldsmith, W. Travis; Kashon, Michael L.; Anderson, Stacey E.; Germolec, Dori R.; Beezhold, Donald H.

2016-01-01

Background Epidemiological surveys indicate that occupants of mold contaminated environments are at increased risk of respiratory symptoms. The immunological mechanisms associated with these responses require further characterization. Objective The aim of this study was to characterize the immunotoxicological outcomes following repeated inhalation of dry Aspergillus fumigatus spores aerosolized at concentrations potentially encountered in contaminated indoor environments. Methods A. fumigatus spores were delivered to the lungs of naïve BALB/cJ mice housed in a multi-animal nose-only chamber twice a week for a period of 13 weeks. Mice were evaluated at 24 and 48 hours post-exposure for histopathological changes in lung architecture, recruitment of specific immune cells to the airways, and serum antibody responses. Result Germinating A. fumigatus spores were observed in lungs along with persistent fungal debris in the perivascular regions of the lungs. Repeated exposures promoted pleocellular infiltration with concomitant epithelial mucus hypersecretion, goblet cell metaplasia, subepithelial fibrosis and enhanced airway hyperreactivity. Cellular infiltration in airways was predominated by CD4+ T cells expressing the pro-allergic cytokine IL-13. Furthermore, our studies show that antifungal T cell responses (IFN-γ+ or IL-17A+) co-expressed IL-13, revealing a novel mechanism for the dysregulated immune response to inhaled fungi. Total IgE production was augmented in animals repeatedly exposed to A. fumigatus. Conclusions & Clinical Relevance Repeated inhalation of fungal aerosols resulted in significant pulmonary pathology mediated by dynamic shifts in specific immune populations and their cytokines. These studies provide novel insights into the immunological mechanisms and targets that govern the health outcomes that result from repeated inhalation of fungal bioaerosols in contaminated environments. PMID:26892490

Type I interferon and pattern recognition receptor signaling following particulate matter inhalation

PubMed Central

2012-01-01

Background Welding, a process that generates an aerosol containing gases and metal-rich particulates, induces adverse physiological effects including inflammation, immunosuppression and cardiovascular dysfunction. This study utilized microarray technology and subsequent pathway analysis as an exploratory search for markers/mechanisms of in vivo systemic effects following inhalation. Mice were exposed by inhalation to gas metal arc – stainless steel (GMA-SS) welding fume at 40 mg/m3 for 3 hr/d for 10 d and sacrificed 4 hr, 14 d and 28 d post-exposure. Whole blood cells, aorta and lung were harvested for global gene expression analysis with subsequent Ingenuity Pathway Analysis and confirmatory qRT-PCR. Serum was collected for protein profiling. Results The novel finding was a dominant type I interferon signaling network with the transcription factor Irf7 as a central component maintained through 28 d. Remarkably, these effects showed consistency across all tissues indicating a systemic type I interferon response that was complemented by changes in serum proteins (decreased MMP-9, CRP and increased VCAM1, oncostatin M, IP-10). In addition, pulmonary expression of interferon α and β and Irf7 specific pattern recognition receptors (PRR) and signaling molecules (Ddx58, Ifih1, Dhx58, ISGF3) were induced, an effect that showed specificity when compared to other inflammatory exposures. Also, a canonical pathway indicated a coordinated response of multiple PRR and associated signaling molecules (Tlr7, Tlr2, Clec7a, Nlrp3, Myd88) to inhalation of GMA-SS. Conclusion This methodological approach has the potential to identify consistent, prominent and/or novel pathways and provides insight into mechanisms that contribute to pulmonary and systemic effects following toxicant exposure. PMID:22776377

Type I interferon and pattern recognition receptor signaling following particulate matter inhalation.

PubMed

Erdely, Aaron; Antonini, James M; Salmen-Muniz, Rebecca; Liston, Angie; Hulderman, Tracy; Simeonova, Petia P; Kashon, Michael L; Li, Shengqiao; Gu, Ja K; Stone, Samuel; Chen, Bean T; Frazer, David G; Zeidler-Erdely, Patti C

2012-07-09

Welding, a process that generates an aerosol containing gases and metal-rich particulates, induces adverse physiological effects including inflammation, immunosuppression and cardiovascular dysfunction. This study utilized microarray technology and subsequent pathway analysis as an exploratory search for markers/mechanisms of in vivo systemic effects following inhalation. Mice were exposed by inhalation to gas metal arc - stainless steel (GMA-SS) welding fume at 40 mg/m3 for 3 hr/d for 10 d and sacrificed 4 hr, 14 d and 28 d post-exposure. Whole blood cells, aorta and lung were harvested for global gene expression analysis with subsequent Ingenuity Pathway Analysis and confirmatory qRT-PCR. Serum was collected for protein profiling. The novel finding was a dominant type I interferon signaling network with the transcription factor Irf7 as a central component maintained through 28 d. Remarkably, these effects showed consistency across all tissues indicating a systemic type I interferon response that was complemented by changes in serum proteins (decreased MMP-9, CRP and increased VCAM1, oncostatin M, IP-10). In addition, pulmonary expression of interferon α and β and Irf7 specific pattern recognition receptors (PRR) and signaling molecules (Ddx58, Ifih1, Dhx58, ISGF3) were induced, an effect that showed specificity when compared to other inflammatory exposures. Also, a canonical pathway indicated a coordinated response of multiple PRR and associated signaling molecules (Tlr7, Tlr2, Clec7a, Nlrp3, Myd88) to inhalation of GMA-SS. This methodological approach has the potential to identify consistent, prominent and/or novel pathways and provides insight into mechanisms that contribute to pulmonary and systemic effects following toxicant exposure.

Vaccination against nicotine alters the distribution of nicotine delivered via cigarette smoke inhalation to rats

PubMed Central

Pravetoni, M; Keyler, DE; Raleigh, MD; Harris, AC; LeSage, MG; Mattson, CK; Pettersson, S; Pentel, PR

2011-01-01

Preclinical models of nicotine vaccine pharmacology have relied on i.v. or s.c. administration of nicotine. Models using cigarette smoke inhalation might more accurately simulate nicotine exposure in smokers. Nicotine vaccine effects were examined in rats using two cigarette smoke exposure models: a 10 minute nose-only exposure (NSE) producing serum nicotine levels equivalent to the nicotine boost from 1 cigarette in a smoker, and a two hour whole-body exposure (WBE) producing serum nicotine levels similar to those associated with regular midday smoking. Vaccination prior to 10 min smoke NSE reduced nicotine distribution to brain by 90%, comparable to its effect on nicotine administered i.v. Vaccination prior to 2 hr smoke WBE reduced nicotine distribution to brain by 35%. The nicotine concentration in broncheoalveolar lavage (BAL) fluid obtained after 2 hr WBE was increased by 230% in vaccinated rats but was also increased in rats passively immunized with a nicotine-specific monoclonal antibody, and so was likely due to transfer of antibody from serum rather than local production at the pulmonary mucosa. Nicotine-specific IgA was not detectable in BAL fluid, but titers in serum were appreciable at 21–25% of the IgG titer and could contribute to vaccine efficacy. Both vaccination and passive immunization are effective in reducing nicotine distribution to brain in rats when nicotine is delivered via inhaled cigarette smoke. These data validate results previously obtained in rodents for nicotine vaccines using i.v. or s.c. nicotine dosing and provide a quantitative method for studying aspects of nicotine exposure which are unique to cigarette smoke inhalation. PMID:21333633

Occupational allergy to aquarium fish food: red midge larva, freshwater shrimp, and earthworm. A clinical and immunological study.

PubMed

Meseguer Arce, J; Villajos, I M Sánchez-Guerrero; Iraola, V; Carnés, J; Fernández Caldas, E

2013-01-01

Chironomids seem to be the main cause of occupational allergy to aquarium fish food. The aim of this study was to investigate the pattern of occupational sensitization to 3 different arthropod species used as components of aquarium fish food. The study sample comprised 8 workers from a fish food packing department. The control group comprised 40 atopic patients (20 of whom were allergic to mites). We performed prick tests with extracts of red midge larva (Chironomus thummi), freshwater shrimp (Gammarus species), earthworm (Tubifex species), and other arthropod species and a battery of common inhalant allergens. We measured peak expiratory flow rate (PEFR) and specific immunoglobulin (Ig) E and performed a methacholine challenge test, nasal challenge test, and immunoblotting. Cross-reactivity analyses were completed using immunoblotting and CAP inhibition. Prick test results were positive to red midge larvae in 7 patients (87.5%), Gammarus in 5 (62.5%), Tubifex in 3 (37.5%), and mites in 6 (75%). In the mite-allergic controls, 30% had positive prick test results to red midge larvae. PEFR decreased > or = 20% during the packing process in all patients, and in 1 patient it indicated a dual asthmatic response. Methacholine challenge test results were positive in all participants. Nasal challenge tests were performed in 4 patients, and the results were positive. Specific IgE to red midge larvae was detected in 62.5%, Gammarus in 50%, and Tubifex in 16%. Bands of approximately 14-15 kDa and 31 kDa were observed in Gammarus and red midge larvae extracts. Cross-reactivity assays demonstrated that Gammarus totally inhibited red midge larvae, while Tubifex did so partially. Dermatophagoides pteronyssinus showed very low inhibitory capacity. Aquarium fish food arthropods are potent allergens with an elevated prevalence of sensitization and variable degree of crossreactivity. This is the first report of occupational allergy to Tubifex. More data are necessary to identify and characterize the responsible allergens.

Change of tumor vascular reactivity during tumor growth and postchemotherapy observed by near-infrared spectroscopy

NASA Astrophysics Data System (ADS)

Lee, Songhyun; Jeong, Hyeryun; Seong, Myeongsu; Kim, Jae Gwan

2017-12-01

Breast cancer is one of the most common cancers in females. To monitor chemotherapeutic efficacy for breast cancer, medical imaging systems such as x-ray mammography, computed tomography, magnetic resonance imaging, and ultrasound imaging have been used. Currently, it can take up to 3 to 6 weeks to see the tumor response from chemotherapy by monitoring tumor volume changes. We used near-infrared spectroscopy (NIRS) to predict breast cancer treatment efficacy earlier than tumor volume changes by monitoring tumor vascular reactivity during inhalational gas interventions. The results show that the amplitude of oxy-hemoglobin changes (vascular reactivity) during hyperoxic gas inhalation is well correlated with tumor growth and responded one day earlier than tumor volume changes after chemotherapy. These results may imply that NIRS with respiratory challenges can be useful in early detection of tumor and in the prediction of tumor response to chemotherapy.

Response localization of the pharmacological agents histamine and salbutamol along the respiratory system by forced oscillations in asthmatic subjects.

PubMed

Wouters, E F; Polko, A H; Visser, B F

1989-01-01

The bronchodilating effect of 1 mg and 0.4 mg salbutamol on the impedance of the respiratory system was studied in 25 asthmatic subjects after histamine-induced bronchoconstriction. Histamine caused an increase of respiratory resistance (Rrs) at lower frequencies and a frequency dependence of Rrs. Respiratory reactance (Xrs) decreased at all frequencies after histamine challenge. These changes can be explained by peripheral airway obstruction. Impedance measurements performed 5 min after inhalation of 1 mg and 0.4 mg salbutamol showed a decrease of Rrs values at lower frequencies, a disappearance of the frequency dependence of Rrs, and a significant increase of Xrs values. No significant differences in absolute changes of Rrs and Xrs are observed between the salbutamol regimens. These changes after inhalation of salbutamol can be explained by supposing a predominant action on the peripheral airways.

Effectiveness of Nurse-Driven Inhaler Education on Inhaler Proficiency and Compliance Among Obstructive Lung Disease Patients: A Quasi-Experimental Study.

PubMed

Al-Kalaldeh, Mahmoud; El-Rahman, Mona Abd; El-Ata, Amal

2016-06-01

Background Health education on proper inhaler usage is the most feasible and accessible strategy to increase inhaler effectiveness. Purpose To assess the impact of nurse-driven inhaler education on the compliance and proficiency of using inhalers among inhaler users. Methods This single-center, quasi-experimental study included the implementation of an individualized 60-min educational session on inhalers use. Health education and pretest and posttest outcomes were assessed by the Inhaler Proficiency Schedule and Patient Reported Behaviour tools. Results One hundred and twenty-one participants joined the study. At pretest, participants showed inadequate knowledge of general inhaler use. No previous training had been received by participants and difficulty with use and complications from using the inhalers were reported. At posttest, participants reported improvement in inhaler proficiency scores from 5.72 to 8.60 ( t = 17.99, df = 220, p < 0.001). Likewise, they showed a significant reduction towards the noncompliant behaviors from 15.21 to 11.19 ( t = 16.388, df = 238, p < 0.001). Conclusions Nurse-driven inhaler education yielded positive outcomes in both inhaler proficiency and compliance. The patients' assessment of using inhalers is crucial to determine the patients' educational deficits.

Checklists for the Assessment of Correct Inhalation Therapy.

PubMed

Knipel, V; Schwarz, S; Magnet, F S; Storre, J H; Criée, C P; Windisch, W

2017-02-01

Introduction  For the long-term treatment of obstructive lung diseases inhalation therapy with drugs being delivered directly to the lungs as an aerosol has become the method of choice. However, patient-related mistakes in inhalation techniques are frequent and recognized to be associated with reduced disease control. Since the assessment of patient-mistakes in inhalation has yet not been standardized, the present study was aimed at developing checklists for the assessment of correct inhalation. Methods  Checklists were developed in German by an expert panel of pneumologists and professionally translated into English following back-translation procedures. The checklists comparably assessed three major steps of inhalation: 1) inhalation preparation, 2) inhalation routine, and 3) closure of inhalation. Results  Checklists for eight frequently used inhalers were developed: Aerolizer, Breezhaler, Diskus (Accuhaler), metered-dose inhaler, Handihaler, Novolizer, Respimat, Turbohaler. Each checklist consists of ten items: three for inhalation preparation, six for inhalation routine, and one for closure of inhalation. Discussion  Standardized checklists for frequently used inhalers are available in German and English. These checklists can be used for clinical routines or for clinical trials. All checklists can be downloaded free of charge for non-profit application from the homepage of the German Airway League (Deutsche Atemwegsliga e. V.): www.atemwegsliga.de. © Georg Thieme Verlag KG Stuttgart · New York.

Airborne Nanostructured Particles and Occupational Health

NASA Astrophysics Data System (ADS)

Maynard, Andrew D.; Kuempel, Eileen D.

2005-12-01

Nanotechnology is leading to the development in many field, of new materials and devices in many fields that demonstrate nanostructure-dependent properties. However, concern has been expressed that these same properties may present unique challenges to addressing potential health impact. Airborne particles associated with engineered nanomaterials are of particular concern, as they can readily enter the body through inhalation. Research into the potential occupational health risks associated with inhaling engineered nanostructured particles is just beginning. However, there is a large body of data on occupational and environmental aerosols, which is applicable to developing an initial assessment of potential risk and risk reduction strategies. Epidemiological and pathological studies of occupational and environmental exposures to airborne particles and fibers provide information on the aerosol-related lung diseases and conditions that have been observed in humans. Toxicological studies provide information on the specific disease mechanisms, dose-response relationships, and the particle characteristics that influence toxicity, including the size, surface area, chemistry or reactivity, solubility, and shape. Potential health risk will depend on the magnitude and nature of exposures to airborne nanostructured particles, and on the release, dispersion, transformation and control of materials in the workplace. Aerosol control methods have not been well-characterized for nanometer diameter particles, although theory and limited experimental data indicate that conventional ventilation, engineering control and filtration approaches should be applicable in many situations. Current information supports the development of preliminary guiding principles on working with engineered nanomaterials. However critical research questions remain to be answered before the potential health risk of airborne nanostructured particles in the workplace can be fully addressed.

Review of toluene action: clinical evidence, animal studies and molecular targets

PubMed Central

Cruz, Silvia L.; Rivera-García, María Teresa; Woodward, John J.

2014-01-01

It has long been known that individuals will engage in voluntary inhalation of volatile solvents for their rewarding effects. However, research into the neurobiology of these agents has lagged behind that of more commonly used drugs of abuse such as psychostimulants, alcohol and nicotine. This imbalance has begun to shift in recent years as the serious effects of abused inhalants, especially among children and adolescents, on brain function and behavior have become appreciated and scientifically documented. In this review, we discuss the physicochemical and pharmacological properties of toluene, a representative member of a large class of organic solvents commonly used as inhalants. This is followed by a brief summary of the clinical and pre-clinical evidence showing that toluene and related solvents produce significant effects on brain structures and processes involved in the rewarding aspects of drugs. This is highlighted by tables highlighting toluene’s effect on behaviors (reward, motor effects, learning, etc.) and cellular proteins (e.g. voltage and ligand-gated ion channels) closely associated the actions of abused substances. These sections demonstrate not only the significant progress that has been made in understanding the neurobiological basis for solvent abuse but also reveal the challenges that remain in developing a coherent understanding of this often overlooked class of drugs of abuse. PMID:25360325

Environmental Justice Aspects of Exposure to PM2.5 Emissions from Electric Vehicle Use in China.

PubMed

Ji, Shuguang; Cherry, Christopher R; Zhou, Wenjun; Sawhney, Rapinder; Wu, Ye; Cai, Siyi; Wang, Shuxiao; Marshall, Julian D

2015-12-15

Plug-in electric vehicles (EVs) in China aim to improve sustainability and reduce environmental health impacts of transport emissions. Urban use of EVs rather than conventional vehicles shifts transportation's air pollutant emissions from urban areas (tailpipes) to predominantly rural areas (power plants), changing the geographic distribution of health impacts. We model PM2.5-related health impacts attributable to urban EV use for 34 major cities. Our investigation focuses on environmental justice (EJ) by comparing pollutant inhalation versus income among impacted counties. We find that EVs could increase EJ challenge in China: most (~77%, range: 41-96%) emission inhalation attributable to urban EVs use is distributed to predominately rural communities whose incomes are on average lower than the cities where EVs are used. Results vary dramatically across cities depending on urban income and geography. Discriminant analysis reveals that counties with low income and high inhalation of urban EV emissions have comparatively higher agricultural employment rates, higher mortality rates, more children in the population, and lower education levels. We find that low-emission electricity sources such as renewable energy can help mitigate EJ issues raised here. Findings here are not unique to EVs, but instead are relevant for nearly all electricity-consuming technologies in urban areas.

Drug consumption among medical students in São Paulo, Brazil: influences of gender and academic year.

PubMed

Oliveira, Lucio Garcia de; Barroso, Lucia Pereira; Wagner, Gabriela Arantes; Ponce, Julio de Carvalho; Malbergier, André; Stempliuk, Vladimir de Andrade; Andrade, Arthur Guerra de

2009-09-01

To analyze alcohol, tobacco and other drug use among medical students. Over a five-year period (1996-2001), we evaluated 457 students at the Universidade de São Paulo School of Medicine, located in São Paulo, Brazil. The students participated by filling out an anonymous questionnaire on drug use (lifetime, previous 12 months and previous 30 days). The influence that gender and academic year have on drug use was also analyzed. During the study period, there was an increase in the use of illicit drugs, especially inhalants and amphetamines, among the medical students evaluated. Drug use (except that of marijuana and inhalants) was comparable between the genders, and academic year was an important influencing factor. Increased inhalant use was observed among the medical students, especially among males and students in the early undergraduate years. This is suggestive of a specific behavioral pattern among medical students. Our findings corroborate those of previous studies. Inhalant use is on the rise among medical students at the Universidade de São Paulo School of Medicine. Because of the negative health effects of illicit drug use, further studies are needed in order to deepen the understanding of this phenomenon and to facilitate the development of preventive measures.

Hierarchical pulmonary target nanoparticles via inhaled administration for anticancer drug delivery.

PubMed

Chen, Rui; Xu, Liu; Fan, Qin; Li, Man; Wang, Jingjing; Wu, Li; Li, Weidong; Duan, Jinao; Chen, Zhipeng

2017-11-01

Inhalation administration, compared with intravenous administration, significantly enhances chemotherapeutic drug exposure to the lung tissue and may increase the therapeutic effect for pulmonary anticancer. However, further identification of cancer cells after lung deposition of inhaled drugs is necessary to avoid side effects on normal lung tissue and to maximize drug efficacy. Moreover, as the action site of the major drug was intracellular organelles, drug target to the specific organelle is the final key for accurate drug delivery. Here, we designed a novel multifunctional nanoparticles (MNPs) for pulmonary antitumor and the material was well-designed for hierarchical target involved lung tissue target, cancer cell target, and mitochondrial target. The biodistribution in vivo determined by UHPLC-MS/MS method was employed to verify the drug concentration overwhelmingly increasing in lung tissue through inhaled administration compared with intravenous administration. Cellular uptake assay using A549 cells proved the efficient receptor-mediated cell endocytosis. Confocal laser scanning microscopy observation showed the location of MNPs in cells was mitochondria. All results confirmed the intelligent material can progressively play hierarchical target functions, which could induce more cell apoptosis related to mitochondrial damage. It provides a smart and efficient nanocarrier platform for hierarchical targeting of pulmonary anticancer drug. So far, this kind of material for pulmonary mitochondrial-target has not been seen in other reports.

Detection of butane gas inhalation at 16days after hypoxic encephalopathy: A case report.

PubMed

Sato, Takako; Nishioka, Hiroshi; Tsuboi, Kento; Katagi, Munehiro; Miki, Akihiro; Saito, Takashi; Abe, Shuntaro; Nomura, Masakatsu; Kitagawa, Misa; Tsuchihashi, Hitoshi; Suzuki, Koichi

2017-11-01

In Japan, there are increasing reports of death by poisoning following butane abuse. To determine the specific cause of death in such cases, it is important to confirm the presence of fuel gas components in the body, although careful analysis is required because of their volatile properties. In most reported cases, the subject died suddenly during or immediately after butane aspiration. Thus, the butane concentration in the samples from the deceased should be relatively high. Herein, we present a case of an 18-year-old man found with cardiopulmonary arrest, who then exhibited hypoxic encephalopathy for 16days in a hospital. At autopsy, we detected hypoxic encephalopathy, pneumonia, and ischemia-reperfusion injury of the myocardium, while the cause of cardiac arrest remained unclear. Toxicological analysis was then performed for fuel gas components in several specimens collected at autopsy. Results showed that n-butane and isobutane were detected in the adipose tissue at 16days after inhalation, indicating a role of butane gas inhalation as the cause of death. These data suggest that adipose tissue may be the most appropriate analysis sample to be collected at postmortem in cases where involvement of volatile and fat-soluble gas inhalation is suspected. Copyright © 2017 Elsevier B.V. All rights reserved.

The Rule of Five for Non-Oral Routes of Drug Delivery: Ophthalmic, Inhalation and Transdermal

PubMed Central

Choy, Young Bin; Prausnitz, Mark R.

2011-01-01

The Rule of Five predicts suitability of drug candidates, but was developed primarily using orally administered drugs. Here, we test whether the Rule of Five predicts drugs for delivery via non-oral routes, specifically ophthalmic, inhalation and transdermal. We assessed 111 drugs approved by FDA for those routes of administration and found that >98% of current non-oral drugs have physicochemical properties within the limits of the Rule of Five. However, given the inherent bias in the dataset, this analysis was not able to assess whether drugs with properties outside those limits are poor candidates. Indeed, further analysis indicates that drugs well outside the Rule of Five limits, including hydrophilic macromolecules, can be delivered by inhalation. In contrast, drugs currently administered across skin fall within more stringent limits than predicted by the Rule of Five, but new transdermal delivery technologies may make these constraints obsolete by dramatically increasing skin permeability. The Rule of Five does appear to apply well to ophthalmic delivery. We conclude that although current non-oral drugs mostly have physicochemical properties within the Rule of Five thresholds, the Rule of Five should not be used to predict non-oral drug candidates, especially for inhalation and transdermal routes. PMID:20967491

A new automated multiple allergen simultaneous test-chemiluminescent assay (MAST-CLA) using an AP720S analyzer.

PubMed

Lee, Sungsil; Lim, Hwan Sub; Park, Jungyong; Kim, Hyon Suk

2009-04-01

In the diagnosis of atopic diseases, allergen detection is a crucial step. Multiple allergen simultaneous test-chemiluminescent assay (MAST-CLA) is a simple and noninvasive method for in vitro screening of allergen-specific IgE antibodies. The Korean Inhalant Panel test on 20 patients and Food Panel test on 19 patients were performed using the conventional manual MAST-CLA kit and the new automated MAST-CLA method (automated AP720S system for the Optigen Assay; Hitachi Chemical Diagnostics, Inc., USA) simultaneously. The results were evaluated for positive reactivity and concordance. The results of inhalant panel gave a relatively higher class level result than the food panel. The 8 patients out of 20 (40%) of the inhalation panel, and 9 patients out of 18 (47.4%) of the food panel showed 100% concordance between the 2 systems. Eighteen patients (90%) of the Inhalation Panel and sixteen patients (84.2%) of the Food Panel showed more than 91% concordance. These results suggest that the MAST-CLA assay using the new, automated AP720S analyzer performs well, showing a high concordance rate with conventional MAST-CLA. Compared to manual MAST-CLA, the automated AP720S system has a shorter assay time and uses a smaller serum volume (500 microl) along with other conveniences.

Sinonasal inhalation of dornase alfa administered by vibrating aerosol to cystic fibrosis patients: a double-blind placebo-controlled cross-over trial.

PubMed

Mainz, Jochen G; Schien, Claudia; Schiller, Isabella; Schädlich, Katja; Koitschev, Assen; Koitschev, Christiane; Riethmüller, Joachim; Graepler-Mainka, Uta; Wiedemann, Bärbel; Beck, James F

2014-07-01

Chronic rhinosinusitis significantly impairs CF patients' quality of life and overall health. The Pari-Sinus™ device delivers vibrating aerosol effectively to paranasal sinuses. After a small pilot study to assess sinonasal inhalation of dornase alfa and placebo (isotonic saline) on potential sinonasal outcome measures, we present the subsequent prospective double-blind placebo-controlled crossover-trial. 23 CF patients were randomised to inhale either dornase alfa or isotonic saline for 28 days with the Pari-Sinus™ and after 28 days (wash-out) crossed over to the alternative treatment. The primary outcome parameter was primary nasal symptom score in the disease-specific quality of life Sino-Nasal Outcome-Test-20 (SNOT-20: nasal obstruction/sneezing/runny nose/thick nasal discharge/reduced smelling). Primary nasal symptoms improved significantly with dornase alfa compared with no treatment, while small improvements with isotonic saline did not reach significance. SNOT-20 overall scores improved significantly after dornase alfa compared with isotonic saline (p=0.017). Additionally, sinonasal dornase alfa but not isotonic saline significantly improved pulmonary function (FEF75-25: p=0.021). Vibrating sinonasal inhalation of dornase alfa reduces rhinosinusitis symptoms in CF. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Electrical Insulation Fire Characteristics : Volume 2. Toxicity.

DOT National Transportation Integrated Search

1978-12-01

The purpose of this research was to determine the relative inhalation toxicity of the thermal degradation products or gaseous pyrolysis of selected types of electrical wiring insulations. The specific materials to be evaluated were supplied by the Bo...

Inhaled corticosteroids in chronic obstructive pulmonary disease: a pro–con perspective

PubMed Central

Babu, K Suresh; Kastelik, Jack A; Morjaria, Jaymin B

2014-01-01

Current guidelines limit regular use of inhaled corticosteroids (ICS) to a specific subgroup of patients with chronic obstructive pulmonary disease (COPD) in whom the forced expiratory volume in 1 s is <60% of predicted and who have frequent exacerbations. In these patients, there is evidence that ICS reduce the frequency of exacerbations and improve lung function and quality of life. However, a review of the literature suggests that the evidence available may be interpreted to favour or contradict these observations. It becomes apparent that COPD is a heterogeneous condition. Clinicians therefore need to be aware of the heterogeneity as well as having an understanding of how ICS may be used in the context of the specific subgroups of patients with COPD. This review argues for and against the use of ICS in COPD by providing an in-depth analysis of the currently available evidence. PMID:25099256

Pulmonary drug delivery. Part II: The role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications

PubMed Central

Labiris, N R; Dolovich, M B

2003-01-01

Research in the area of pulmonary drug delivery has gathered momentum in the last several years, with increased interest in using the lung as a means of delivering drugs systemically. Advances in device technology have led to the development of more efficient delivery systems capable of delivering larger doses and finer particles into the lung. As more efficient pulmonary delivery devices and sophisticated formulations become available, physicians and health professionals will have a choice of a wide variety of device and formulation combinations that will target specific cells or regions of the lung, avoid the lung's clearance mechanisms and be retained within the lung for longer periods. It is now recognized that it is not enough just to have inhalation therapy available for prescribing; physicians and other healthcare providers need a basic understanding of aerosol science, inhaled formulations, delivery devices, and bioequivalence of products to prescribe these therapies optimally. PMID:14616419

Mouse models to unravel the role of inhaled pollutants on allergic sensitization and airway inflammation

PubMed Central

2010-01-01

Air pollutant exposure has been linked to a rise in wheezing illnesses. Clinical data highlight that exposure to mainstream tobacco smoke (MS) and environmental tobacco smoke (ETS) as well as exposure to diesel exhaust particles (DEP) could promote allergic sensitization or aggravate symptoms of asthma, suggesting a role for these inhaled pollutants in the pathogenesis of asthma. Mouse models are a valuable tool to study the potential effects of these pollutants in the pathogenesis of asthma, with the opportunity to investigate their impact during processes leading to sensitization, acute inflammation and chronic disease. Mice allow us to perform mechanistic studies and to evaluate the importance of specific cell types in asthma pathogenesis. In this review, the major clinical effects of tobacco smoke and diesel exhaust exposure regarding to asthma development and progression are described. Clinical data are compared with findings from murine models of asthma and inhalable pollutant exposure. Moreover, the potential mechanisms by which both pollutants could aggravate asthma are discussed. PMID:20092634

The Effects of Inhaled Nickel Nanoparticles on Murine Endothelial Progenitor Cells

NASA Astrophysics Data System (ADS)

Liberda, Eric N.

Introduction. Particulate air pollution, specifically nickel found on or in particulate matter, has been associated with an increased risk of mortality in human population studies and can cause increases in vascular inflammation, generate reactive oxygen species, alter vasomotor tone, and potentiate atherosclerosis in murine exposures. With the discovery of endothelial progenitor cells (EPCs), a door has been opened which may explain these observed cardiovascular effects associated with inhaled air particles and nickel exposure. In order to further quantify the effects of inhaled nickel nanoparticles and attempt to elucidate how the observed findings from other studies may occur, several whole body inhalation exposure experiments to nickel nanoparticles were performed. Methods. Following whole body exposure to approximately 500mug/m3 of nickel nanoparticles for 5 hrs, bone marrow EPCs from C57BL/6 mice were isolated. EPCs were harvested for their RNA or used in a variety of assays including chemotaxis, tube formation, and proliferation. Gene expression was assessed for important receptors involved in EPC mobilization and homing using RT-PCR methods. EPCs, circulating endothelial progenitor cells, circulating endothelial cells (CECs), and endothelial microparticles (EMPs) were quantified on a BD FACSCalibur to examine endothelial damage and repair associated with the inhalation exposure. Plasma proteins were assessed using the 2D DIGE proteomic approach and commercially available ELISAs. Results and Conclusions. Exposure to inhaled nickel nanoparticles significantly increased both bone marrow EPCs as well as their levels in circulation. CECs were significantly upregulated suggesting that endothelial damage occurred due to the exposure. There was no significant difference in EMPs between the two groups. Tube formation and chemotaxis, but not proliferation, of bone marrow EPCs was impaired in the nickel nanoparticle exposed group. This decrease in EPC function coincided with downregulation of receptors for EPC mobilization and homing. Antioxidant plasma proteins were upregulated post-exposure and transferrin was downregulated. In conclusion, these results indicate that inhalation exposure to Ni nanoparticles below the current OSHA permissible exposure limit for Ni compounds can lead to alterations in bone marrow progenitor cells that may ultimately lead to the development of various cardiovascular diseases.

BioSim (trademark) BG Non-Biological Aerosol Simulant

DTIC Science & Technology

2004-11-17

39.5 1.36 1,1- difluoroethane HFA 152a – Not used for pharmaceutical inhalers , is used for personal products Boiling point (-13o F) 63 (psig... 1 BIOSIMTM BG NON-BIOLOGICAL AEROSOL SIMULANT David S. Alburty, Kelly L. Brown, Jennifer L. Dannehl and Andrew E. Page Midwest...BioSafey Level 1 regulations. All of these materials of biological origin pose challenging logistics problems including safety issues, cost

Changes in cross-sectional airway areas induced by methacholine, histamine, and LTC4 in asthmatic subjects.

PubMed

Molfino, N A; Slutsky, A S; Hoffstein, V; McClean, P A; Rebuck, A S; Drazen, J M; Zamel, N

1992-09-01

To examine whether leukotrienes, histamine, and methacholine have different sites of bronchoconstrictor action, we studied 8 stable asthmatic subjects (mean age +/- SD, 26 +/- 5 yr) on 3 different days. On each day, a randomized challenge with LTC4, methacholine, or histamine was performed until the dose that provoked a fall of 20% in FEV1 (PC20) was obtained. Complete and partial flow-volume curves as well as area-distance profiles generated by the acoustic reflection technique (ART) at a fixed lung volume were obtained in all subjects before and after each inhalation challenge. No significant differences were found in pulmonary function or baseline cross-sectional airway areas for the different study days. The three agonists provoked significant (p less than 0.05) bronchoconstriction at the level of the main bronchi when identical falls of FEV1 were achieved. Similarly, equal reductions of V30p were elicited by the three agonists. However, LTC4 and methacholine induced additional tracheal constriction but histamine inhalation did not. These differences in the degree of tracheal constriction were statistically significant (p less than 0.05; ANOVA). These results may be explained by distinct pharmacologic properties of the agents used and may have relevance in the understanding of the pathophysiology of asthma.

Practical aspects of inhaler use in the management of chronic obstructive pulmonary disease in the primary care setting.

PubMed

Yawn, Barbara P; Colice, Gene L; Hodder, Rick

2012-01-01

Sustained bronchodilation using inhaled medications in moderate to severe chronic obstructive pulmonary disease (COPD) grades 2 and 3 (Global Initiative for Chronic Obstructive Lung Disease guidelines) has been shown to have clinical benefits on long-term symptom control and quality of life, with possible additional benefits on disease progression and longevity. Aggressive diagnosis and treatment of symptomatic COPD is an integral and pivotal part of COPD management, which usually begins with primary care physicians. The current standard of care involves the use of one or more inhaled bronchodilators, and depending on COPD severity and phenotype, inhaled corticosteroids. There is a wide range of inhaler devices available for delivery of inhaled medications, but suboptimal inhaler use is a common problem that can limit the clinical effectiveness of inhaled therapies in the real-world setting. Patients' comorbidities, other physical or mental limitations, and the level of inhaler technique instruction may limit proper inhaler use. This paper presents information that can overcome barriers to proper inhaler use, including issues in device selection, steps in correct technique for various inhaler devices, and suggestions for assessing and monitoring inhaler techniques. Ensuring proper inhaler technique can maximize drug effectiveness and aid clinical management at all grades of COPD.

Practical aspects of inhaler use in the management of chronic obstructive pulmonary disease in the primary care setting

PubMed Central

Yawn, Barbara P; Colice, Gene L; Hodder, Rick

2012-01-01

Sustained bronchodilation using inhaled medications in moderate to severe chronic obstructive pulmonary disease (COPD) grades 2 and 3 (Global Initiative for Chronic Obstructive Lung Disease guidelines) has been shown to have clinical benefits on long-term symptom control and quality of life, with possible additional benefits on disease progression and longevity. Aggressive diagnosis and treatment of symptomatic COPD is an integral and pivotal part of COPD management, which usually begins with primary care physicians. The current standard of care involves the use of one or more inhaled bronchodilators, and depending on COPD severity and phenotype, inhaled corticosteroids. There is a wide range of inhaler devices available for delivery of inhaled medications, but suboptimal inhaler use is a common problem that can limit the clinical effectiveness of inhaled therapies in the real-world setting. Patients’ comorbidities, other physical or mental limitations, and the level of inhaler technique instruction may limit proper inhaler use. This paper presents information that can overcome barriers to proper inhaler use, including issues in device selection, steps in correct technique for various inhaler devices, and suggestions for assessing and monitoring inhaler techniques. Ensuring proper inhaler technique can maximize drug effectiveness and aid clinical management at all grades of COPD. PMID:22888221

Teaching inhaler use in chronic obstructive pulmonary disease patients.

PubMed

Lareau, Suzanne C; Hodder, Richard

2012-02-01

To review barriers to the successful use of inhalers in patients with chronic obstructive pulmonary disease (COPD), and the role of the nurse practitioner (NP) in facilitating optimum inhaler use. Review of the national and international scientific literature. Pharmacologic treatment of COPD patients comprises mainly inhaled medications. Incorrect use of inhalers is very common in these individuals. Some of the consequences of poor inhaler technique include reduced therapeutic dosing, medication adherence, and disease stability, which can lead to increased morbidity, decreased quality of life, and a high burden on the healthcare system. Knowledgeable evaluation and frequent reassessment of inhaler use coupled with education of patients, caregivers, and healthcare professionals can significantly improve the benefits COPD patients derive from inhaled therapy. Patient education is vital for correct use of inhalers and to ensure the effectiveness of inhaled medications. The NP has a critical role in assessing potential barriers to successful learning by the patient and improving inhaler technique and medication management. The NP can also facilitate success with inhaled medications by providing up-to-date inhaler education for other healthcare team members, who may then act as patient educators. ©2011 The Author(s) Journal compilation ©2011 American Academy of Nurse Practitioners.

Inhaled Asthma Medications

MedlinePlus

... metered – dose inhaler (MDI), which uses a chemical propellant to push the medication out of the inhaler. ... powder inhalers (DPIs) deliver medication without using chemical propellants, but they require a strong and fast inhalation. ...

Empowering family physicians to impart proper inhaler teaching to patients with chronic obstructive pulmonary disease and asthma

PubMed Central

Leung, Janice M; Bhutani, Mohit; Leigh, Richard; Pelletier, Dan; Good, Cathy; Sin, Don D

2015-01-01

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) and asthma depend on inhalers for management, but critical errors committed during inhaler use can limit drug effectiveness. Outpatient education in inhaler technique remains inconsistent due to limited resources and inadequate provider knowledge. OBJECTIVE: To determine whether a simple, two-session inhaler education program can improve physician attitudes toward inhaler teaching in primary care practice. METHODS: An inhaler education program with small-group hands-on device training was instituted for family physicians (FP) in British Columbia and Alberta. Sessions were spaced one to three months apart. All critical errors were corrected in the first session. Questionnaires surveying current inhaler teaching practices and attitudes toward inhaler teaching were distributed to physicians before and after the program. RESULTS: Forty-one (60%) of a total 68 participating FPs completed both before and after program questionnaires. Before the program, only 20 (49%) reported providing some form of inhaler teaching in their practices, and only four (10%) felt fully competent to teach patients inhaler technique. After the program, 40 (98%) rated their inhaler teaching as good to excellent. Thirty-four (83%) reported providing inhaler teaching in their practices, either by themselves or by an allied health care professional they had personally trained. All stated they could teach inhaler technique within 5 min. Observation of FPs during the second session by certified respiratory educators found that none made critical errors and all had excellent technique. CONCLUSION: A physician inhaler education program can improve attitudes toward inhaler teaching and facilitate implementation in clinical practices. PMID:26436910

Performance of personal inhalable aerosol samplers in very slowly moving air when facing the aerosol source.

PubMed

Witschger, O; Grinshpun, S A; Fauvel, S; Basso, G

2004-06-01

While personal aerosol samplers have been characterized primarily based on wind tunnel tests conducted at relatively high wind speeds, modern indoor occupational environments are usually represented by very slow moving air. Recent surveys suggest that elevated levels of occupational exposure to inhalable airborne particles are typically observed when the worker, operating in the vicinity of the dust source, faces the source. Thus, the first objective of this study was to design and test a new, low cost experimental protocol for measuring the sampling efficiency of personal inhalable aerosol samplers in the vicinity of the aerosol source when the samplers operate in very slowly moving air. In this system, an aerosol generator, which is located in the centre of a room-sized non-ventilated chamber, continuously rotates and omnidirectionally disperses test particles of a specific size. The test and reference samplers are equally distributed around the source at the same distance from the centre and operate in parallel (in most of our experiments, the total number of simultaneously operating samplers was 15). Radial aerosol transport is driven by turbulent diffusion and some natural convection. For each specific particle size and the sampler, the aerosol mass concentration is measured by weighing the collection filter. The second objective was to utilize the new protocol to evaluate three widely used aerosol samplers: the IOM Personal Inhalable Sampler, the Button Personal Inhalable Aerosol Sampler and the 25 mm Millipore filter holder (closed-face C25 cassette). The sampling efficiencies of each instrument were measured with six particle fractions, ranging from 6.9 to 76.9 micro m in their mass median aerodynamic diameter. The Button Sampler efficiency data demonstrated a good agreement with the standard inhalable convention and especially with the low air movement inhalabilty curve. The 25 mm filter holder was found to considerably under-sample the particles larger than 10 micro m; its efficiency did not exceed 7% for particles of 40-100 micro m. The IOM Sampler facing the source was found to over-sample compared with the data obtained previously with a slowly rotating, freely suspended sampler in a low air movement environment. It was also found that the particle wall deposition in the IOM metallic cartridge was rather significant and particle size-dependent. For each sampler (IOM, Button and C25) the precision was characterized through the relative standard deviation (RSD) of the aerosol concentration obtained with identical samplers in a specific experiment. The average RSD was 14% for the IOM Sampler, 11% for the Button Sampler and 35% for the 25 mm filter cassette. A separate set of experiments, performed with the Simplified Torso showed that in very slowly moving air a personal sampler can be adequately evaluated even when it is not attached to a body but freely suspended (confirming the data reported previously).

Chemical-specific screening criteria for interpretation of biomonitoring data for volatile organic compounds (VOCs)--application of steady-state PBPK model solutions.

PubMed

Aylward, Lesa L; Kirman, Chris R; Blount, Ben C; Hays, Sean M

2010-10-01

The National Health and Nutrition Examination Survey (NHANES) generates population-representative biomonitoring data for many chemicals including volatile organic compounds (VOCs) in blood. However, no health or risk-based screening values are available to evaluate these data from a health safety perspective or to use in prioritizing among chemicals for possible risk management actions. We gathered existing risk assessment-based chronic exposure reference values such as reference doses (RfDs), reference concentrations (RfCs), tolerable daily intakes (TDIs), cancer slope factors, etc. and key pharmacokinetic model parameters for 47 VOCs. Using steady-state solutions to a generic physiologically-based pharmacokinetic (PBPK) model structure, we estimated chemical-specific steady-state venous blood concentrations across chemicals associated with unit oral and inhalation exposure rates and with chronic exposure at the identified exposure reference values. The geometric means of the slopes relating modeled steady-state blood concentrations to steady-state exposure to a unit oral dose or unit inhalation concentration among 38 compounds with available pharmacokinetic parameters were 12.0 microg/L per mg/kg-d (geometric standard deviation [GSD] of 3.2) and 3.2 microg/L per mg/m(3) (GSD=1.7), respectively. Chemical-specific blood concentration screening values based on non-cancer reference values for both oral and inhalation exposure range from 0.0005 to 100 microg/L; blood concentrations associated with cancer risk-specific doses at the 1E-05 risk level ranged from 5E-06 to 6E-02 microg/L. The distribution of modeled steady-state blood concentrations associated with unit exposure levels across VOCs may provide a basis for estimating blood concentration screening values for VOCs that lack chemical-specific pharmacokinetic data. The screening blood concentrations presented here provide a tool for risk assessment-based evaluation of population biomonitoring data for VOCs and are most appropriately applied to central tendency estimates for such datasets. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Poorly soluble particulates: searching for a unifying denominator of nanoparticles and fine particles for DNEL estimation.

PubMed

Pauluhn, Jürgen

2011-01-11

Under the new European chemicals regulation, REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) a Derived No-Effect Level (DNEL), i.e., the level of exposure above which humans should not be exposed, is defined. The focus of this paper is to develop a weight-of-evidence-based DNEL-approach for inhaled poorly soluble particles. Despite the common mode of action of inhaled insoluble, spherical particulate matter (PM), a unifying, most appropriate metric conferring pulmonary biopersistence and toxicity has yet not been demonstrated. Nonetheless, there is compelling evidence from repeated rat inhalation exposure studies suggesting that the particle displacement volume is the most prominent unifying denominator linking the pulmonary retained dose with toxicity. Procedures were developed to analyze and model the pulmonary toxicokinetics from short-term to long-term exposure. Six different types of poorly soluble nano- to submicron PMs were compared: ultrafine and pigmentary TiO₂, synthetic iron oxide (Fe₃O₄, magnetite), two aluminum oxyhydroxides (AlOOH, Boehmite) with primary isometric particles approximately of either 10 or 40 nm, and MWCNT. The specific agglomerate densities of these materials ranged from 0.1 g/cm³ (MWCNT) to 5 g/cm³ (Fe₃O₄). Along with all PM, due to their long retention half-times and associated biopersistence in the lung, even short-term inhalation studies may require postexposure periods of at least 3 months to reveal PM-specific dispositional and toxicological characteristics. This analysis provides strong evidence that pulmonary toxicity (sustained inflammation) is dependent on the volume-based cumulative lung exposure dose. Lung toxicity, evidenced by PMN in BAL occurred at lung doses exceeding 10-times the overload threshold. Furthermore, the conclusion is supported that repeated inhalation studies on rats should utilize an experimental window of cumulative volume loads of respirable PM in the range of 1 μl/lung (no-adverse-effect range); however, not exceeding ≈10 μl/lung that would lead to retention half-times increasing 1 year. This can be targeted best by computational toxicology, i.e., the modeling of particle deposition and lung retention biokinetics during the exposure and recovery periods. Inhalation studies exceeding that threshold volume may lead to meaningless findings difficult to extrapolate to any real-life scenario. In summary, this analysis supports a volume-based generic mass concentration of 0.5 μl PM(respirable)/m³ x agglomerate density, independent on nano- or submicron-sized properties, as a generic no-adverse effect level in both rats and humans. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Computer modeling of airway deposition distribution of Foster(®) NEXThaler(®) and Seretide(®) Diskus(®) dry powder combination drugs.

PubMed

Jókay, Ágnes; Farkas, Árpád; Füri, Péter; Horváth, Alpár; Tomisa, Gábor; Balásházy, Imre

2016-06-10

Asthma is a serious global health problem with rising prevalence and treatment costs. Due to the growing number of different types of inhalation devices and aerosol drugs, physicians often face difficulties in choosing the right medication for their patients. The main objectives of this study are (i) to elucidate the possibility and the advantages of the application of numerical modeling techniques in aerosol drug and device selection, and (ii) to demonstrate the possibility of the optimization of inhalation modes in asthma therapy with a numerical lung model by simulating patient-specific drug deposition distributions. In this study we measured inhalation parameter values of 25 healthy adult volunteers when using Foster(®) NEXThaler(®) and Seretide(®) Diskus(®). Relationships between emitted doses and patient-specific inhalation flow rates were established. Furthermore, individualized emitted particle size distributions were determined applying size distributions at measured flow rates. Based on the measured breathing parameter values, we calculated patient-specific drug deposition distributions for the active components (steroid and bronchodilator) of both drugs by the help of a validated aerosol lung deposition model adapted to therapeutic aerosols. Deposited dose fractions and deposition densities have been computed in the entire respiratory tract, in distinct anatomical regions of the airways and at the level of airway generations. We found that Foster(®) NEXThaler(®) deposits more efficiently in the lungs (average deposited steroid dose: 42.32±5.76% of the nominal emitted dose) than Seretide(®) Diskus(®) (average deposited steroid dose: 24.33±2.83% of the nominal emitted dose), but the variance of the deposition values of different individuals in the lung is significant. In addition, there are differences in the required minimal flow rates, therefore at certain patients Seretide(®) Diskus(®) or pMDIs could be a better choice. Our results show that validated computer deposition models could be useful tools in providing valuable deposition data and assisting health professionals in the personalized drug selection and delivery optimization. Patient-specific modeling could open a new horizon in the treatment of asthma towards a more effective personalized medicine in the future. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparative inhalation toxicity of multi-wall carbon nanotubes, graphene, graphite nanoplatelets and low surface carbon black.

PubMed

Ma-Hock, Lan; Strauss, Volker; Treumann, Silke; Küttler, Karin; Wohlleben, Wendel; Hofmann, Thomas; Gröters, Sibylle; Wiench, Karin; van Ravenzwaay, Bennard; Landsiedel, Robert

2013-06-17

Carbon nanotubes, graphene, graphite nanoplatelets and carbon black are seemingly chemically identical carbon-based nano-materials with broad technological applications. Carbon nanotubes and carbon black possess different inhalation toxicities, whereas little is known about graphene and graphite nanoplatelets. In order to compare the inhalation toxicity of the mentioned carbon-based nanomaterials, male Wistar rats were exposed head-nose to atmospheres of the respective materials for 6 hours per day on 5 consecutive days. Target concentrations were 0.1, 0.5, or 2.5 mg/m3 for multi-wall carbon nanotubes and 0.5, 2.5, or 10 mg/m3 for graphene, graphite nanoplatelets and low-surface carbon black. Toxicity was determined after end of exposure and after three-week recovery using broncho-alveolar lavage fluid and microscopic examinations of the entire respiratory tract. No adverse effects were observed after inhalation exposure to 10 mg/m3 graphite nanoplatelets or relatively low specific surface area carbon black. Increases of lavage markers indicative for inflammatory processes started at exposure concentration of 0.5 mg/m3 for multi-wall carbon nanotubes and 10 mg/m3 for graphene. Consistent with the changes in lavage fluid, microgranulomas were observed at 2.5 mg/m3 multi-wall carbon nanotubes and 10 mg/m3 graphene. In order to evaluate volumetric loading of the lung as the key parameter driving the toxicity, deposited particle volume was calculated, taking into account different methods to determine the agglomerate density. However, the calculated volumetric load did not correlate to the toxicity, nor did the particle surface burden of the lung. The inhalation toxicity of the investigated carbon-based materials is likely to be a complex interaction of several parameters. Until the properties which govern the toxicity are identified, testing by short-term inhalation is the best option to identify hazardous properties in order to avoid unsafe applications or select safer alternatives for a given application.

Inhalant Use and Inhalant Use Disorders in the United States

PubMed Central

Howard, Matthew O.; Bowen, Scott E.; Garland, Eric L.; Perron, Brian E.; Vaughn, Michael G.

2011-01-01

More than 22 million Americans age 12 and older have used inhalants, and every year more than 750,000 use inhalants for the first time. Despite the substantial prevalence and serious toxicities of inhalant use, it has been termed “the forgotten epidemic.” Inhalant abuse remains the least-studied form of substance abuse, although research on its epidemiology, neurobiology, treatment, and prevention has accelerated in recent years. This review examines current findings in these areas, identifies gaps in the research and clinical literatures pertaining to inhalant use, and discusses future directions for inhalant-related research and practice efforts. PMID:22003419

Gestational Toluene Exposure Effects on Spontaneous and Amphetamine-Induced Locomotor Behavior in Rats

PubMed Central

Mohammadi, Michael H.; Batis, Jeffery C.; Hannigan, John H.

2007-01-01

The abuse of volatile organic solvents (inhalants) continues to be a major health concern throughout the world. Toluene, which is found in many products such as glues and household cleaners, is among the most commonly abused organic solvents. The neurobehavioral teratogenic sequelae of solvent abuse (i.e., repeated, brief inhalation exposures to very high concentrations of solvents) have not been examined thoroughly. In a preclinical model of inhalant abuse, timed-pregnant Sprague-Dawley rats were exposed to 0, 8,000, or 12,000 parts per million (ppm) for 15 min twice daily from gestation day 8 (GD8) through GD20. In the first experiment, separate groups of offspring were observed individually in an open-field on postnatal day 22 (PN22), PN42 or PN63. In the second experiment, other offspring given identical prenatal toluene exposures were observed in an “open-field” following an acute i.p. injection of amphetamine (0, 0.56, 1.78 mg/kg) on PN28. Automated measurements of distance traveled and ambulatory time were recorded. Prenatal toluene exposure resulted in small alterations in spontaneous activity compared to non-exposed rats. Prenatal exposure to 12,000 ppm toluene resulted in significant hyposensitivity to the locomotor stimulatory effects of the amphetamine challenge in male but not female rats on PN28. The results demonstrate that prenatal exposure to abuse patterns of high concentrations of toluene through inhalation can alter spontaneous and amphetamine-induced locomotor behavior in rats. The expression of these effects also appears to depend upon the postnatal age of testing. These results imply that abuse of organic solvents during pregnancy in humans may also produce long-lasting effects on biobehavioral development. PMID:17112700

New insight into the assessment of asthma using xenon ventilation computed tomography.

PubMed

Jung, Jae-Woo; Kwon, Jae-Woo; Kim, Tae-Wan; Lee, So-Hee; Kim, Kyung-Mook; Kang, Hye-Ryun; Park, Heung-Woo; Lee, Chang-Hyun; Goo, Jin-Mo; Min, Kyung-Up; Cho, Sang-Heon

2013-08-01

Image analyses include computed tomography (CT), magnetic resonance imaging, and xenon ventilation CT, which is new modality to evaluate pulmonary functional imaging. To examine the usefulness of dual-energy xenon ventilation CT in asthmatic patients. A total of 43 patients 18 years or older who were nonsmokers were included in the study. Xenon CT images in wash-in and wash-out phases were obtained at baseline and after inhalation of methacholine and salbutamol. The degrees of ventilation defects and xenon trappings were evaluated through visual analysis. Ventilation defects and xenon trapping were significantly increased and decreased after methacholine challenge and salbutamol inhalation, respectively (P < .005). The ventilation abnormalities were not significantly related to the percentage of forced expiratory volume in 1 second (FEV1) or the ratio of FEV1 to forced vital capacity. Xenon trappings after salbutamol inhalation were negatively related to the scores of the asthma control test, wheezing, or night symptoms, with statistical significance (P < .05), whereas, FEV1 showed no significant correlation with symptom scores. Baseline FEV1 was significantly lower and dyspnea and wheezing were more severe in the non-full reversal group than in the full reversal group after salbutamol inhalation in xenon CT (P < .05). The degree of ventilation defects were positively correlated with FEV1 improvement after 3 months of treatment (P = .02). The results of this study suggest that xenon ventilation CT can be used as a new method to assess ventilation abnormalities in asthma, and these ventilation abnormalities can be used as novel parameters that reflect the status of asthma control and symptom severity. Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

[Did the patients with chronic obstructive pulmonary disease in Primary Care center Anton de Borja correctly utilize inhalers?].

PubMed

Represas-Carrera, Francisco Jesús

2015-01-01

To determine the percentage of patients with Pulmonary Obstructive Chronic Disease who doing of incorrect form the inhaler technique. Descriptive transversal study made in the Primary Care Center "Antón de Borja" of Rubi (in Barcelona) during the period between May and December 2013, where it was studied a representative sample of 200 patients. To assess the inhaler technique was performed a personal interview with the patient in which it was requested him to carry out a demonstration of how he was using his inhaler regularly evaluating his inhaler technique by means of the regulations established by Spanish Society of Pneumology and Thoracic Surgery. 43% of the patients carry out inhaler technique incorrectly. The percentage of inadequate use of inhalers of dry powder was 26%, of the pressurized cartridge 38% and the inhaler chamber 10%. 82% of patients ≥ 65 years who have prescribed a pressurized inhaler cartridge do not perform accompanied by an inhaler chamber. A high percentage of patients do not correctly carry out inhaler technique, pointing the rare use made of the inhaler chamber despite its proven efficacy and the high number of patients with pressurized inhaler cartridge. These results reflect the need for the implementation of an educational program in our Primary Care Center to teach patients to use inhaler devices. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Protection of non-human primates against glanders with a gold nanoparticle glycoconjugate vaccine.

PubMed

Torres, Alfredo G; Gregory, Anthony E; Hatcher, Christopher L; Vinet-Oliphant, Heather; Morici, Lisa A; Titball, Richard W; Roy, Chad J

2015-01-29

The Gram-negative Burkholderia mallei is a zoonotic pathogen and the causative agent of glanders disease. Because the bacteria maintain the potential to be used as a biothreat agent, vaccine strategies are required for human glanders prophylaxis. A rhesus macaque (Macaca mulatta) model of pneumonic (inhalational) glanders was established and the protective properties of a nanoparticle glycoconjugate vaccine composed of Burkholderia thailandensis LPS conjugated to FliC was evaluated. An aerosol challenge dose of ∼1×10(4) CFU B. mallei produced mortality in 50% of naïve animals (n=2/4), 2-3 days post-exposure. Although survival benefit was not observed by vaccination with a glycoconjugate glanders vaccine (p=0.42), serum LPS-specific IgG titers were significantly higher on day 80 in 3 vaccinated animals who survived compared with 3 vaccinated animals who died. Furthermore, B. mallei was isolated from multiple organs of both non-vaccinated survivors, but not from any organs of 3 vaccinated survivors at 30 days post-challenge. Taken together, this is the first time a candidate vaccine has been evaluated in a non-human primate aerosol model of glanders and represents the initial step for consideration in pre-clinical studies. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nanostructured Lipid Carriers as Multifunctional Nanomedicine Platform for Pulmonary Co-Delivery of Anticancer Drugs and siRNA

PubMed Central

Taratula, Oleh; Kuzmov, Andriy; Shah, Milin; Garbuzenko, Olga B.; Minko, Tamara

2013-01-01

We developed, synthesized, and tested a multifunctional nanostructured lipid nanocarrier-based system (NLCS) for efficient delivery of an anticancer drug and siRNA directly into the lungs by inhalation. The system contains: (1) nanostructured lipid carriers (NLC); (2) anticancer drug (doxorubicin or paclitaxel); (3) siRNA targeted to MRP1 mRNA as a suppressor of pump drug resistance; (4) siRNA targeted to BCL2 mRNA as a suppressor of nonpump cellular resistance and (5) a modified synthetic analog of luteinizing hormone-releasing hormone (LHRH) as a targeting moiety specific to the receptors that are overexpressed in the plasma membrane of lung cancer cells. The NLCS was tested in vitro using human lung cancer cells and in vivo utilizing mouse orthotopic model of human lung cancer. After inhalation, the proposed NLCS effectively delivered its payload into lung cancer cells leaving healthy lung tissues intact and also significantly decreasing the exposure of healthy organs when compared with intravenous injection. The NLCS showed enhanced antitumor activity when compared with intravenous treatment. The data obtained demonstrated high efficiency of proposed NLCS for tumor-targeted local delivery by inhalation of anticancer drugs and mixture of siRNAs specifically to lung cancer cells and, as a result, efficient suppression of tumor growth and prevention of adverse side effects on healthy organs. PMID:23648833

A method for calculating the gas volume proportions and inhalation temperature of inert gas mixtures allowing reaching normothermic or hypothermic target body temperature in the awake rat

PubMed Central

Abraini, Jacques H.; David, Hélène N.; Blatteau, Jean-Éric; Risso, Jean Jacques; Vallée, Nicolas

2017-01-01

The noble gases xenon (Xe) and helium (He) are known to possess neuroprotective properties. Xe is considered the golden standard neuroprotective gas. However, Xe has a higher molecular weight and lower thermal conductivity and specific heat than those of nitrogen, the main diluent of oxygen (O2) in air, conditions that could impair or at least reduce the intrinsic neuroprotective properties of Xe by increasing the critical care patient's respiratory workload and body temperature. In contrast, He has a lower molecular weight and higher thermal conductivity and specific heat than those of nitrogen, but is unfortunately far less potent than Xe at providing neuroprotection. Therefore, combining Xe with He could allow obtaining, depending on the gas inhalation temperature and composition, gas mixtures with neutral or hypothermic properties, the latter being advantageous in term of neuroprotection. However, calculating the thermal properties of a mixture, whatever the substances – gases, metals, rubbers, etc. – is not trivial. To answer this question, we provide a graphical method to assess the volume proportions of Xe, He and O2 that a gas mixture should contain, and the inhalation temperature to which it should be administered to allow a clinician to maintain the patient at a target body temperature. PMID:29152210

Inhalation Exposure Method for Illegal Drugs.

PubMed

Inomata, Akiko; Ogata, Akio; Tada, Yukie; Nagasawa, Akemichi; Yuzawa, Katsuhiro; Ando, Hiroshi; Kubo, Yoshikazu; Takahashi, Hiroshi; Kaihoko, Fujifumi; Tanaka, Kazuyoshi; Nakajima, Jun'ichi; Suzuki, Atsuko; Uemura, Nozomi; Moriyasu, Takako; Watanabe, Daisuke; Ishihara, Kei; Usami, Takashi; Kamei, Satoru; Kohno, Yasuaki

2017-01-01

We developed a new inhalation exposure method to evaluate effects of synthetic cannabimimetics that are being distributed as new, unregulated drugs in the Tokyo area. We selected the commercial product "SOUTOU" containing AB-CHMINACA and 5F-AMB as the test drug and dried marshmallow (Althaea officinalis) leaves as the negative control. A half cigarette packed with dried marshmallow leaves or SOUTOU was ignited, then mainstream smoke from each was delivered to five mice in an exposure box. After the cigarettes were fully consumed, neurobehavioral observations and a catalepsy test were performed at 15, 30 and 60 min after exposure. The effluent air from the exposure box was poured into impingers containing acetonitrile (first impinger) and dimethyl sulfoxide (second impinger). The resulting solutions were analyzed to assess decomposition of the synthetic cannabimimetics. Mice exposed to SOUTOU smoke showed many excitement behaviors and some suppressive behaviors at 15, 30 and 60 min. These clearly included cannabimimetic specific pharmacological actions. Negative control mice also showed some suppressive behaviors at 15 min but these were attenuated at later times, nearly disappearing at 60 min. In addition, the behavioral effects observed in controls were less pronounced than those in SOUTOU exposed mice. The inhalation exposure method developed in our study would be effective for determining cannabinoid specific pharmacological effects of illegal drugs, as well as for assessing the presence of active compound(s) by comparing the test substance with a negative control.

Visualization of tumor vascular reactivity in response to respiratory challenges by optical coherence tomography (Conference Presentation)

NASA Astrophysics Data System (ADS)

Kim, Hoon Sup; Lee, Songhyun; Lee, Kiri; Eom, Tae Joong; Kim, Jae G.

2016-02-01

We previously reported the potential of using vascular reactivity during respiratory challenges as a marker to predict the response of breast tumor to chemotherapy in a rat model by using a continuous wave near-infrared spectroscopy. However, it cannot visualize how the vascular reactivity from tumor vessel can predict the tumor response to its treatment. In this study, we utilized a spectral domain optical coherence tomography (SD-OCT) system to visualize vascular reactivity of both tumor and normal vasculature during respiratory challenges in a mouse model. We adapted intensity based Doppler variance algorithm to draw angiogram from the ear of mouse (8-week-old Balb/c nu/nu). Animals were anesthetized using 1.5% isoflurane, and the body temperature was maintained by a heating pad. Inhalational gas was switched from air (10min) to 100% oxygen (10min), and a pulse oximeter was used to monitor arterial oxygen saturation and heart rate. OCT angiograms were acquired 5 min after the onset of each gas. The vasoconstriction effect of hyperoxic gas on vasculature was shown by subtracting an en-face image acquired during 100% oxygen from the image acquired during air inhalation. The quantitative change in the vessel diameter was measured from the en-face OCT images of the individual blood vessels. The percentage of blood vessel diameter reduction varied from 1% to 12% depending on arterial, capillary, or venous blood vessel. The vascular reactivity change during breast tumor progression and post chemotherapy will be monitored by OCT angiography.

The chemo and the mona: inhalants, devotion and street youth in Mexico City.

PubMed

Gigengack, Roy

2014-01-01

This paper understands inhalant use--the deliberate inhalation of volatile solvents or glues with intentions of intoxication--as a socially and culturally constituted practice. It describes the inhalant use of young street people in Mexico City from their perspective ("the vicioso or inhalant fiend's point of view"). Even if inhalant use is globally associated with economic inequality and deprivation, there is a marked lack of ethnography. Incomprehension and indignation have blocked our understanding of inhalant use as a form of marginalised drug use. The current explanation models reduce inhalant consumption to universal factors and individual motives; separating the practice from its context, these models tend to overlook gustatory meanings and experiences. The paper is informed by long-term, on-going fieldwork with young street people in Mexico City. Fieldwork was done from 1990 through 2010, in regular periods of fieldwork and shorter visits, often with Mexican colleagues. We created extensive sets of fieldnotes, which were read and re-read. "Normalcy" is a striking feature of inhalant use in Mexico City. Street-wise inhabitants of popular neighbourhoods have knowledge about inhalants and inhalant users, and act accordingly. Subsequently, Mexico City's elaborate street culture of sniffing is discussed, that is, the range of inhalants used, how users classify the substances, and their techniques for sniffing. The paper also distinguishes three patterns of inhalant use, which more or less correlate with age. These patterns indicate embodiments of street culture: the formation within users of gusto, that is, an acquired appetite for inhalants, and of vicio, the inhalant fiends' devotion to inhalants. What emerges from the ethnographic findings is an elaborate street culture of sniffing, a complex configuration of shared perspectives and embodied practices, which are shaped by and shaping social exclusion. These findings are relevant to appreciate and address the inhalant fiends' acquired appetite and habit. Copyright © 2013 Elsevier B.V. All rights reserved.

DETERMINING INHALATION RISK -- TOOLS FOR ASSESSING HAZARD.

EPA Science Inventory

The Clean Air Act focuses on reduction of the potential for specific air pollutants to cause adverse health effects. Implementation of standards to control release of the 188 hazardous air pollutants (HAPs) requires the Environmental Protection Agency (EPA) to evaluate the healt...

Salmeterol inhaler using a non-chlorinated propellant, HFA134a: systemic pharmacodynamic activity in healthy volunteers.

PubMed Central

Kirby, S. M.; Smith, J.; Ventresca, G. P.

1995-01-01

BACKGROUND--Metered dose inhalers for the treatment of asthma use chlorofluorocarbons as propellants. These face an international ban due to their effect on the ozone layer. Salmeterol has been reformulated using the non-chlorinated propellant Glaxo inhalation grade HFA134a. METHODS--The safety, tolerability and systemic pharmacodynamic activity of the salmeterol/HFA134a inhaler, the current salmeterol inhaler, and placebo (HFA134a) were compared in 12 healthy volunteers in a double blind, randomised crossover study using a cumulative dosing design. RESULTS--Safety and tolerability were similar and the response was related to the dose over the range used (50-400 micrograms) with both salmeterol inhalers. The salmeterol/HFA134a inhaler showed no differences from the current inhaler for pulse rate, blood pressure, tremor, QTc interval, and plasma glucose levels. The salmeterol/HFA134a inhaler had significantly less effect on plasma potassium levels. CONCLUSIONS--In healthy volunteers the salmeterol/HFA134a inhaler is at least as safe and well tolerated as the current salmeterol inhaler, and has similar systemic pharmacodynamic activity. PMID:7638815

Toxicological aspects of fire.

PubMed

Stefanidou, M; Athanaselis, S

2004-08-01

Most fatalities from fires are not due to burns, but are a result of inhalation of toxic gases produced during combustion. Fire produces a complex toxic environment, involving flame, heat, oxygen depletion, smoke and toxic gases. As a wide variety of synthetic materials is used in buildings (insulation, furniture, carpeting, electric wiring covering, decorative items), the potential for poisoning from inhalation of products of combustion is continuously increasing. In the present review, the problems that are present in a fire event, the toxicology of the toxic substances and the specific chemical hazards to firefighters are described. Regulatory toxicology aspects are presented concerning the use of non-flammable building and furnishing materials to prevent fires and decrease of poisonings and deaths resulting from fires.

Inhalation Therapy in Horses.

PubMed

Cha, Mandy L; Costa, Lais R R

2017-04-01

This article discusses the benefits and limitations of inhalation therapy in horses. Inhalation drug therapy delivers the drug directly to the airways, thereby achieving maximal drug concentrations at the target site. Inhalation therapy has the additional advantage of decreasing systemic side effects. Inhalation therapy in horses is delivered by the use of nebulizers or pressured metered dose inhalers. It also requires the use of a muzzle or nasal mask in horses. Drugs most commonly delivered through inhalation drug therapy in horses include bronchodilators, antiinflammatories, and antimicrobials. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhalers and nebulizers: basic principles and preliminary measurements

NASA Astrophysics Data System (ADS)

Misik, Ondrej; Lizal, Frantisek; Asl, Vahid Farhikhteh; Belka, Miloslav; Jedelsky, Jan; Elcner, Jakub; Jicha, Miroslav

2018-06-01

Inhalers are hand-held devices which are used for administration of therapeutic aerosols via inhalation. Nebulizers are larger devices serving for home and hospital care using inhaled medication. This contribution describes the basic principles of dispersion of aerosol particles used in various types of inhalers and nebulizers, and lists the basic physical mechanisms contributing to the deposition of inhaled particles in the human airways. The second part of this article presents experimental setup, methodology and preliminary results of particle size distributions produced by several selected inhalers and nebulizers.

Practice makes perfect: self-reported adherence a positive marker of inhaler technique maintenance.

PubMed

Azzi, Elizabeth; Srour, Pamela; Armour, Carol; Rand, Cynthia; Bosnic-Anticevich, Sinthia

2017-04-24

Poor inhaler technique and non-adherence to treatment are major problems in the management of asthma. Patients can be taught how to achieve good inhaler technique, however maintenance remains problematic, with 50% of patients unable to demonstrate correct technique. The aim of this study was to determine the clinical, patient-related and/or device-related factors that predict inhaler technique maintenance. Data from a quality-controlled longitudinal community care dataset was utilized. 238 patients using preventer medications where included. Data consisted of patient demographics, clinical data, medication-related factors and patient-reported outcomes. Mixed effects logistic regression was used to identify predictors of inhaler technique maintenance at 1 month. The variables found to be independently associated with inhaler technique maintenance using logistic regression (Χ 2 (3,n = 238) = 33.24, p < 0.000) were inhaler technique at Visit 1 (OR 7.1), device type (metered dose inhaler and dry powder inhalers) (OR 2.2) and self-reported adherent behavior in the prior 7 days (OR 1.3). This research is the first to unequivocally establish a predictive relationship between inhaler technique maintenance and actual patient adherence, reinforcing the notion that inhaler technique maintenance is more than just a physical skill. Inhaler technique maintenance has an underlying behavioral component, which future studies need to investigate. BEHAVIORAL ELEMENT TO CORRECT LONG-TERM INHALER TECHNIQUES: Patients who consciously make an effort to perfect asthma inhaler technique will maintain their skills long-term. Elizabeth Azzi at the University of Sydney, Australia, and co-workers further add evidence that there is a strong behavioral component to patients retaining correct inhaler technique over time. Poor inhaler technique can limit asthma control, affecting quality of life and increasing the chances of severe exacerbations. Azzi's team followed 238 patients to determine the key predictors of inhaler technique maintenance from factors including age, asthma knowledge and perceived future risks. Correct inhaler technique at initial assessment was the strongest predictor of long-term success, but this was strengthened further when patients reported good adherence to their own medication regimen. This suggests that maintaining correct inhaler technique is more than just a physical skill. Careful guidance towards this 'practice makes perfect' approach may improve patients' long-term technique maintenance.

Analgesic use of inhaled methoxyflurane: Evaluation of its potential nephrotoxicity.

PubMed

Dayan, A D

2016-01-01

Methoxyflurane is a volatile, halogenated analgesic, self-administered in a controlled low dose from the Penthrox(®) inhaler for short-term pain relief. It was formerly used in significantly higher doses to produce anaesthesia, when it caused a specific type of dose-related renal tubular damage. The pathogenesis of the renal damage and clinical use of methoxyflurane are discussed here with evidence that a low but effective analgesic dose is not associated with the risk of renal adverse effects. The maximum dose employed to produce analgesia is limited to methoxyflurane 6 mL/day and 15 mL/week, producing a minimum alveolar concentration (MAC) of 0.59 MAC-hours. Renal damage is due to the metabolism of methoxyflurane and release of fluoride ions. Exposure of humans to methoxyflurane ≤2.0 MAC-hours, resulting in serum fluoride ≤40 µmol/L, has not been associated with renal tubular toxicity. The safety margin of analgesic use of methoxyflurane in the Penthrox ((®)) inhaler is at least 2.7- to 8-fold, based on methoxyflurane MAC-hours or serum fluoride level, with clinical experience suggesting it is higher. It is concluded from clinical experience in emergency medicine, surgical procedures and various experimental and laboratory investigations that the analgesic use of methoxyflurane in subanaesthetic doses in the Penthrox inhaler does not carry a risk of nephrotoxicity. © The Author(s) 2015.

In vivo evaluation of the potential neurotoxicity of aerosols released from mechanical stress of nano-TiO2 additived paints in mice chronically exposed by inhalation

NASA Astrophysics Data System (ADS)

Manixay, S.; Delaby, S.; Gaie-Levrel, F.; Wiart, M.; Motzkus, C.; Bencsik, A.

2017-06-01

Engineered Nanomaterials (ENM) provide technical and specific benefits due to their physical-chemical properties at the nanometer scale. For instance, many ENM are used to improve products in the building industry. Nanoscaled titanium dioxide (TiO2) is one of the most used ENM in this industry. Incorporated in different matrix, cement, glass, paints… TiO2 nanoparticles (NPs) provide the final product with anti-UV, air purification and self-cleaning properties, thanks to their photocatalytic activity. However, ageing processes of such products, as photocatalytic paints, during a mechanical stress have been shown to release TiO2 NPs from this matrix associated with sanding dust. Thus, workers who sand painted walls could be exposed to TiO2 NPs through inhalation. As inhalation may lead to a translocation of particulate matter to the brain via olfactory or trigeminal nerves, there is an urgent need for evaluating a potential neurotoxicity. In order to provide new knowledge on this topic, we developed a dedicated experimental set-up using a rodent model exposed via inhalation. The aerosol released from a mechanical stress of photocatalytic paints containing TiO2 NPs was characterized and coupled to an exposition chamber containing group of mice free to move and chronically exposed (2 hours per day for 5 days a week during 8 weeks).

The optimization of iloprost inhalation under moderate flow of oxygen therapy in severe pulmonary arterial hypertension.

PubMed

Nakayama, Kazuhiko; Emoto, Noriaki; Tamada, Naoki; Okano, Mitsumasa; Shinkura, Yuto; Yanaka, Kenichi; Onishi, Hiroyuki; Hiraishi, Mana; Yamada, Shinichiro; Tanaka, Hidekazu; Shinke, Toshiro; Hirata, Ken-Ichi

2018-01-01

Inhaled iloprost efficiently improves pulmonary hemodynamics, exercise capacity, and quality of life in patients with pulmonary arterial hypertension (PAH). However, the process of inhalation is laborious for patients suffering from resting dyspnea. We describe a 75-year-old man with idiopathic PAH and a low gas transfer. Investigations excluded significant parenchymal lung disease and airflow obstruction (presuming FEV1/FVC ration > 70%). The patient struggled to complete iloprost inhalation due to severe dyspnea and hypoxemia. As such, we optimized the methods of oxygen supply from the nasal cannula to the trans-inhalator during the inhalation. We successfully shortened the inhalation duration that effectively reduced the laborious efforts required of patients. We also recorded pulmonary hemodynamics during inhalation of nebulized iloprost. This revealed significant hemodynamic improvement immediately following inhalation but hemodynamics returned to baseline within 2 hours. We hope that this optimization will enable patients with severe PAH to undergo iloprost inhalation.

Inhibition of gap junction currents by the abused solvent toluene.

PubMed

Del Re, Angelo M; Woodward, John J

2005-05-09

Abused inhalants are a large class of compounds that are inhaled for their intoxicating and mood altering effects. They include chemicals with known therapeutic uses such as anesthetic gases as well as volatile organic solvents like toluene that are found in paint thinners and adhesives. Because of their widespread commercial use and availability, inhalants are often among the first drugs that children encounter and use of these compounds is often associated with adverse acute and long-term consequences. The cellular and molecular sites of action for abused inhalants is not well known although recent studies report that toluene and other organic solvents alter the activity of specific ligand- and voltage-gated ion channels that regulate cellular excitability. As part of an ongoing effort to define molecular sites of action for abused inhalants, this study examined the effect of toluene on the function of gap junction proteins endogenously expressed in human embryonic kidney (HEK 293) cells. Gap junctions allow cell-to-cell electrical communication as well as passage of small molecular weight substances and are critical for synchronizing cellular activity in certain tissues. Gap junction currents in HEK 293 cells were measured during brief voltage steps using patch-clamp electrophysiology and were blocked by known gap junction blockers confirming expression of connexin proteins in these cells. Toluene dose-dependently inhibited these conductances with threshold effects appearing at approximately 0.4 mM and near complete inhibition occurring at concentrations of 1 mM and higher. The estimated EC50 value for toluene inhibition of gap junction currents in HEK 293 cells was 0.57 mM. The results of these studies suggest that volatile solvents including toluene may produce some of their effects by disrupting inter-cellular communication mediated by gap junction proteins.

Depletion of liver glutathione levels in rats: a potential confound of nose-only inhalation.

PubMed

Fechter, Laurence D; Nelson-Miller, Alisa; Gearhart, Caroline

2008-07-01

Nose-only inhalation exposure chambers offer key advantages to whole-body systems, particularly when aerosol or mixed aerosol-vapor exposures are used. Specifically, nose-only chambers provide enhanced control over the route of exposure and dose by minimizing the deposition of particles either on the subjects skin/fur or on surfaces of a whole-body exposure system. In the current series of experiments, liver, brain, and lung total glutathione (GSH) levels were assessed following either nose-only or whole-body exposures to either jet fuel or to clean, filtered air. The data were compared to untreated control subjects. Acute nose-only inhalation exposures of rats resulted in a significant depletion of liver GSH levels both in subjects that were exposed to clean, filtered air as well as those exposed to JP-8 jet fuel and to a synthetic jet fuel. Glutathione levels were not altered in lung or brain tissue. Whole-body inhalation exposure had no effect on GSH levels in any tissue for any of the treatment groups. A second experiment demonstrated that the loss of GSH did not occur if rats were anaesthetized prior to and during nose-only exposure to clean, filtered air or to mixed hydrocarbons. These data appear to be consistent with studies demonstrating depletion in liver GSH levels among rats subjected to restraint stress. Finally, the depletion of GSH that was observed in liver following a single acute exposure was reduced following five daily exposures to clean, filtered air, suggesting the possibility of habituation to restraint in the nose-only exposure chamber. The finding that placement in a nose-only exposure chamber per se yields liver GSH depletion raises the possibility of an interaction between this mode of toxicant exposure and the toxicological effects of certain inhaled test substances.

A travel mode comparison of commuters' exposures to air pollutants in Barcelona

NASA Astrophysics Data System (ADS)

de Nazelle, Audrey; Fruin, Scott; Westerdahl, Dane; Martinez, David; Ripoll, Anna; Kubesch, Nadine; Nieuwenhuijsen, Mark

2012-11-01

Daily commutes may contribute disproportionately to overall daily inhalations of urban air contaminants. Understanding factors that explain variability of exposures during travel, and especially differences across transportation modes, is essential to accurately assess health impacts of traffic emissions and to develop effective mitigating measures. We evaluated exposures and inhaled doses of air pollution and assessed factors that contributed to their variability in different travel modes in Barcelona. Black carbon (BC), ultrafine particles (UFP), carbon monoxide (CO), fine particle mass (PM2.5) and carbon dioxide (CO2) were measured and compared across walk, bike, bus, and car modes for a total of 172 trips made on two different round trip routes. On average, the car mode experienced highest concentrations for all contaminants. In pairwise t-tests between concurrent mode runs, statistically significant differences were found for cars compared to walking and biking. Car-to-walk or car-to-bike concentration ratios ranged from 1.3 for CO2 to 25 for CO and were 2-3 for PM2.5, BC, and UFP. In multivariate analyses, travel mode explained the greatest variability in travel exposures, from 8% for PM2.5 to 70% for CO. Different modal patterns emerged when estimating daily inhaled dose, with active commuters' two to three times greater total inhalation volume during travel producing about equal UFP and BC daily inhaled doses to car commuters and 33-50% higher UFP and BC doses compared to bus commuters. These findings, however, are specific to the bike and pedestrian lanes in this study being immediately adjacent to the roadways measured. Dedicated bike or pedestrian routes away from traffic would lead to lower active travel doses.

Commuter exposure to inhalable, thoracic and alveolic particles in various transportation modes in Delhi.

PubMed

Kumar, Pramod; Gupta, N C

2016-01-15

A public health concern is to understand the linkages between specific pollution sources and adverse health impacts. Commuting can be viewed as one of the significant-exposure activity in high-vehicle density areas. This paper investigates the commuter exposure to inhalable, thoracic and alveolic particles in various transportation modes in Delhi, India. Air pollution levels are significantly contributed by automobile exhaust and also in-vehicle exposure can be higher sometime than ambient levels. Motorcycle, auto rickshaw, car and bus were selected to study particles concentration along two routes in Delhi between Kashmere Gate and Dwarka. The bus and auto rickshaw were running on compressed natural gas (CNG) while the car and motorcycle were operated on gasoline fuel. Aerosol spectrometer was employed to measure inhalable, thoracic and alveolic particles during morning and evening rush hours for five weekdays. From the study, we observed that the concentration levels of these particles were greatly influenced by transportation modes. Concentrations of inhalable particles were found higher during morning in auto rickshaw (332.81 ± 90.97 μg/m(3)) while the commuter of bus exhibited higher exposure of thoracic particles (292.23 ± 110.45 μg/m(3)) and car commuters were exposed to maximum concentrations of alveolic particles (222.37 ± 26.56 μg/m(3)). We observed that in evening car commuters experienced maximum concentrations of all sizes of particles among the four commuting modes. Interestingly, motorcycle commuters were exposed to lower levels of inhalable and thoracic particles during morning and evening hours as compared to other modes of transport. The mean values were found greater than the median values for all the modes of transport suggesting that positive skewed distributions are characteristics of naturally occurring phenomenon. Copyright © 2015 Elsevier B.V. All rights reserved.

An outbreak of occupational asthma due to chromium and cobalt.

PubMed

Walters, G I; Moore, V C; Robertson, A S; Burge, C B S G; Vellore, A-D; Burge, P S

2012-10-01

Five metal turners employed by an aerospace manufacturer presented to the Birmingham Chest Clinic occupational lung disease unit. Four cases of occupational asthma (OA) due to chromium salt (3) and cobalt (1) were diagnosed by serial peak-expiratory flow measurements and specific inhalation challenge testing. To measure the extent of the outbreak and to provide epidemiological data to ascertain the aetiology. Participants answered a detailed, self-administered questionnaire, designed to detect occupational lung disease. Urine chromium and cobalt excretion, spirometry and exhaled nitric oxide measurements were taken. Those with possible, probable or definite non-OA or OA, after questionnaire, were invited to undertake two-hourly peak flow measurements and received specialist follow-up. A total of 62 workers (95% of workforce) participated. Sixty-one per cent of employees were working in higher metalworking fluid (MWF) exposure areas. Ninety per cent of workers had urinary chromium excretion indicating occupational exposure. Sixty-six per cent of workers reported active respiratory symptoms, although there were no significant differences between exposure groups. Two further workers with probable OA were identified and had significantly higher urinary chromium and cobalt concentration than asymptomatic controls. Eighteen cases of occupational rhinitis (OR) were identified, with significantly raised urinary chromium concentration compared with asymptomatic controls. Chromium salt and cobalt can be responsible for OA and OR in workers exposed to MWF aerosols. Onset of symptoms in those with positive specific challenges followed change in MWF brand. Workers with OA had increased urinary concentrations of chromium and cobalt, and those with OR had increased urinary concentrations of chromium.

Occupational rhinitis and bronchial asthma due to artichoke (Cynara scolymus).

PubMed

Miralles, Juan-Carlos; García-Sells, Javier; Bartolomé, Borja; Negro, José-María

2003-07-01

The artichoke is a perennial horticultural plant that belongs to the Compositae family. To present case studies of 2 vegetable warehouse workers who developed occupational rhinitis and bronchial asthma by sensitization to artichoke. Skin prick tests with common inhalants and foods were performed. Specific IgE to artichoke, Parietaria judaica pollen, and Olea europaea pollen extracts was measured by a specific IgE enzyme immunosorbent assay kit. Molecular mass of the allergens was studied by the sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) immunoblotting technique. Patients underwent a nasal challenge test, and one patient provided peak expiratory flow rate (PEFR) measurements in her workplace. In both patients, results of skin prick tests to artichoke were positive. Levels of specific IgE for artichoke were 0.68 kU/L in patient 1 and 2.14 kU/L in patient 2. The protein composition of the artichoke extract, studied by SDS-PAGE, showed that most bands ranged from 30 to 14 kDa. The IgE-binding bands with the serum samples of patient 1 showed apparent molecular masses of 56, 48, 38, 31, 27, 25, 16, and 15 kDa; however, the serum samples of patient 2 showed IgE bands of 21 and 19 kDa. Western blotting of artichoke extract showed a complete inhibition of IgE-binding bands when serum samples were preincubated with P. judaica pollen extract. Nasal challenge with artichoke extract triggered a peak nasal inspiratory flow decrease of 81% and 85% in patient 1 and patient 2, respectively. Finally, patient 1 recorded a PEFR decrease of up to 36% after exposure to artichoke in her workplace. SDS-PAGE immunoblotting inhibition performed for the artichoke extract showed a total disappearance of the specific IgE binding bands when serum samples were previously incubated with P. judaica pollen extract, thus establishing the existence of a serologic cross-reactivity between artichoke and P. judaica pollen.

Biodistribution and PET Imaging of pharmacokinetics of manganese in mice using Manganese-52

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wooten, A. Lake; Aweda, Tolulope A.; Lewis, Benjamin C.

Manganese is essential to life, and humans typically absorb sufficient quantities of this element from a normal healthy diet; however, chronic, elevated ingestion or inhalation of manganese can be neurotoxic, potentially leading to manganism. Although imaging of large amounts of accumulated Mn(II) is possible by MRI, quantitative measurement of the biodistribution of manganese, particularly at the trace level, can be challenging. In this study, we produced the positron-emitting radionuclide 52Mn (t 1/2 = 5.6 d) by proton bombardment (E p<15 MeV) of chromium metal, followed by solid-phase isolation by cation-exchange chromatography. An aqueous solution of [ 52Mn]MnCl 2 was nebulizedmore » into a closed chamber with openings through which mice inhaled the aerosol, and a separate cohort of mice received intravenous (IV) injections of [ 52Mn]MnCl 2. Ex vivo biodistribution was performed at 1 h and 1 d post-injection/inhalation (p.i.). In both trials, we observed uptake in lungs and thyroid at 1 d p.i. Manganese is known to cross the blood-brain barrier, as confirmed in our studies following IV injection (0.86%ID/g, 1 d p.i.) and following inhalation of aerosol, (0.31%ID/g, 1 d p.i.). Uptake in salivary gland and pancreas were observed at 1 d p.i. (0.5 and 0.8%ID/g), but to a much greater degree from IV injection (6.8 and 10%ID/g). In a separate study, mice received IV injection of an imaging dose of [ 52Mn]MnCl 2, followed by in vivo imaging by positron emission tomography (PET) and ex vivo biodistribution. The results from this study supported many of the results from the biodistribution-only studies. In this work, we have confirmed results in the literature and contributed new results for the biodistribution of inhaled radiomanganese for several organs. In conclusion, our results could serve as supporting information for environmental and occupational regulations, for designing PET studies utilizing 52Mn, and/or for predicting the biodistribution of manganese-based MR contrast agents.« less

Validity of using a 3-dimensional PET scanner during inhalation of 15O-labeled oxygen for quantitative assessment of regional metabolic rate of oxygen in man

NASA Astrophysics Data System (ADS)

Hori, Yuki; Hirano, Yoshiyuki; Koshino, Kazuhiro; Moriguchi, Tetsuaki; Iguchi, Satoshi; Yamamoto, Akihide; Enmi, Junichiro; Kawashima, Hidekazu; Zeniya, Tsutomu; Morita, Naomi; Nakagawara, Jyoji; Casey, Michael E.; Iida, Hidehiro

2014-09-01

Use of 15O labeled oxygen (15O2) and positron emission tomography (PET) allows quantitative assessment of the regional metabolic rate of oxygen (CMRO2) in vivo, which is essential to understanding the pathological status of patients with cerebral vascular and neurological disorders. The method has, however, been challenging, when a 3D PET scanner is employed, largely attributed to the presence of gaseous radioactivity in the trachea and the inhalation system, which results in a large amount of scatter and random events in the PET assessment. The present study was intended to evaluate the adequacy of using a recently available commercial 3D PET scanner in the assessment of regional cerebral radioactivity distribution during an inhalation of 15O2. Systematic experiments were carried out on a brain phantom. Experiments were also performed on a healthy volunteer following a recently developed protocol for simultaneous assessment of CMRO2 and cerebral blood flow, which involves sequential administration of 15O2 and C15O2. A particular intention was to evaluate the adequacy of the scatter-correction procedures. The phantom experiment demonstrated that errors were within 3% at the practically maximum radioactivity in the face mask, with the greatest radioactivity in the lung. The volunteer experiment demonstrated that the counting rate was at peak during the 15O gas inhalation period, within a verified range. Tomographic images represented good quality over the entire FOV, including the lower part of the cerebral structures and the carotid artery regions. The scatter-correction procedures appeared to be important, particularly in the process to compensate for the scatter originating outside the FOV. Reconstructed images dramatically changed if the correction was carried out using inappropriate procedures. This study demonstrated that accurate reconstruction could be obtained when the scatter compensation was appropriately carried out. This study also suggested the feasibility of using a state-of-the-art 3D PET scanner in the quantitative PET imaging during inhalation of 15O labeled oxygen.

Biodistribution and PET Imaging of pharmacokinetics of manganese in mice using Manganese-52

DOE PAGES

Wooten, A. Lake; Aweda, Tolulope A.; Lewis, Benjamin C.; ...

2017-03-17

Manganese is essential to life, and humans typically absorb sufficient quantities of this element from a normal healthy diet; however, chronic, elevated ingestion or inhalation of manganese can be neurotoxic, potentially leading to manganism. Although imaging of large amounts of accumulated Mn(II) is possible by MRI, quantitative measurement of the biodistribution of manganese, particularly at the trace level, can be challenging. In this study, we produced the positron-emitting radionuclide 52Mn (t 1/2 = 5.6 d) by proton bombardment (E p<15 MeV) of chromium metal, followed by solid-phase isolation by cation-exchange chromatography. An aqueous solution of [ 52Mn]MnCl 2 was nebulizedmore » into a closed chamber with openings through which mice inhaled the aerosol, and a separate cohort of mice received intravenous (IV) injections of [ 52Mn]MnCl 2. Ex vivo biodistribution was performed at 1 h and 1 d post-injection/inhalation (p.i.). In both trials, we observed uptake in lungs and thyroid at 1 d p.i. Manganese is known to cross the blood-brain barrier, as confirmed in our studies following IV injection (0.86%ID/g, 1 d p.i.) and following inhalation of aerosol, (0.31%ID/g, 1 d p.i.). Uptake in salivary gland and pancreas were observed at 1 d p.i. (0.5 and 0.8%ID/g), but to a much greater degree from IV injection (6.8 and 10%ID/g). In a separate study, mice received IV injection of an imaging dose of [ 52Mn]MnCl 2, followed by in vivo imaging by positron emission tomography (PET) and ex vivo biodistribution. The results from this study supported many of the results from the biodistribution-only studies. In this work, we have confirmed results in the literature and contributed new results for the biodistribution of inhaled radiomanganese for several organs. In conclusion, our results could serve as supporting information for environmental and occupational regulations, for designing PET studies utilizing 52Mn, and/or for predicting the biodistribution of manganese-based MR contrast agents.« less

Effects of gestational ethanol inhalation on hippocampal function in rats.

EPA Science Inventory

Recent legislation has increased national emphasis on the development of renewable fuels as alternatives to petroleum fuels. The toxicity of gasoline-ethanol blended fuels to the developing nervous system is of specific concern. The hippocampus, a brain region involved in spatial...

VASCULAR RESPONSE TO TRAFFIC-DERIVED INHALATION IN HUMANS

EPA Science Inventory

By coordinating closely with Center Projects 1-3, we will determine whether specific aspects of traffic-derived exposure (primary vs. secondary organics, particulate vs. gases, spark-ignition vs. diesel engine vs. a mixture) enhance the human vascular response to pollutants. W...

Budesonide ameliorates lung function of the cigarette smoke-exposed rats through reducing matrix metalloproteinase-1 content

PubMed Central

Sun, Jiawei; Zhang, Ping; Zhang, Bin; Li, Kang; Li, Zhu; Li, Junhong; Zhang, Yongjian; Sun, Wuzhuang

2015-01-01

Objectives: This study was conducted to investigate an effect of inhaled budesonide on cigarette smoke-exposed lungs with a possible mechanism involved in the event. Methods: Rats were exposed to air (control) and cigarette smoke (smoking) in presence and absence of budesonide. Inflammatory cell count in bronchoalveolar lavage fluid (BALF), lung function testing, mean liner intercept (MLI) in lung tissue, mean alveolar number (MAN) and a ratio of bronchial wall thickness and external diameter (BWT/D) were determined in the grouped rats, respectively. Contents of matrix metalloproteinase (MMP)-1, MMP-2 and tissue inhibitor of metalloproteinase (TIMP)-2 productions in BALF were examined as well. Results: There were significant changes in the above assessments in the smoking rats as compared to those in the control rats (all P < 0.01 and 0.05). Budesonide inhalation significantly decreased the numbers of the BALF cells and partly reversed lung function decline in the challenged rats (P < 0.01 and 0.05). However, this corticosteroid did not influence pathological changes in fine structures of the tobacco smoke-exposed lungs. Treatment with budesonide resulted in an obvious decrease in the MMP-1 but not MMP-2 and TIMP-2 productions (P < 0.05). Conclusion: Inhaled budesonide mitigates the ongoing inflammatory process in the smoked lungs and ameliorates declining lung function through reducing MMP-1 content. PMID:26191209

Budesonide ameliorates lung function of the cigarette smoke-exposed rats through reducing matrix metalloproteinase-1 content.

PubMed

Sun, Jiawei; Zhang, Ping; Zhang, Bin; Li, Kang; Li, Zhu; Li, Junhong; Zhang, Yongjian; Sun, Wuzhuang

2015-01-01

This study was conducted to investigate an effect of inhaled budesonide on cigarette smoke-exposed lungs with a possible mechanism involved in the event. Rats were exposed to air (control) and cigarette smoke (smoking) in presence and absence of budesonide. Inflammatory cell count in bronchoalveolar lavage fluid (BALF), lung function testing, mean liner intercept (MLI) in lung tissue, mean alveolar number (MAN) and a ratio of bronchial wall thickness and external diameter (BWT/D) were determined in the grouped rats, respectively. Contents of matrix metalloproteinase (MMP)-1, MMP-2 and tissue inhibitor of metalloproteinase (TIMP)-2 productions in BALF were examined as well. There were significant changes in the above assessments in the smoking rats as compared to those in the control rats (all P<0.01 and 0.05). Budesonide inhalation significantly decreased the numbers of the BALF cells and partly reversed lung function decline in the challenged rats (P<0.01 and 0.05). However, this corticosteroid did not influence pathological changes in fine structures of the tobacco smoke-exposed lungs. Treatment with budesonide resulted in an obvious decrease in the MMP-1 but not MMP-2 and TIMP-2 productions (P<0.05). Inhaled budesonide mitigates the ongoing inflammatory process in the smoked lungs and ameliorates declining lung function through reducing MMP-1 content.

How to match the optimal currently available inhaler device to an individual child with asthma or recurrent wheeze.

PubMed

van Aalderen, Wim M; Garcia-Marcos, Luis; Gappa, Monika; Lenney, Warren; Pedersen, Søren; Dekhuijzen, Richard; Price, David

2015-01-08

Inhaled medications are the cornerstone of treatment in early childhood wheezing and paediatric asthma. A match between patient and device and a correct inhalation technique are crucial for good asthma control. The aim of this paper is to propose an inhaler strategy that will facilitate an inhaler choice most likely to benefit different groups of children. The main focus will be on pressurised metered dose inhalers and dry powder inhalers. In this paper we will discuss (1) practical difficulties with the devices and with inhaled therapy and (2) the optimal location for deposition of medicines in the lungs, and (3) we will propose a practical and easy way to make the best match between the inhaler device and the individual patient. We hope that this paper will contribute to an increased likelihood of treatment success and improved adherence to therapy.

Understanding how long‐acting β2‐adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma – an update

PubMed Central

Giembycz, Mark A

2016-01-01

In moderate‐to‐severe asthma, adding an inhaled long‐acting β2‐adenoceptor agonist (LABA) to an inhaled corticosteroid (ICS) provides better disease control than simply increasing the dose of ICS. Acting on the glucocorticoid receptor (GR, gene NR3C1), ICSs promote anti‐inflammatory/anti‐asthma gene expression. In vitro, LABAs synergistically enhance the maximal expression of many glucocorticoid‐induced genes. Other genes, including dual‐specificity phosphatase 1(DUSP1) in human airways smooth muscle (ASM) and epithelial cells, are up‐regulated additively by both drug classes. Synergy may also occur for LABA‐induced genes, as illustrated by the bronchoprotective gene, regulator of G‐protein signalling 2 (RGS2) in ASM. Such effects cannot be produced by either drug alone and may explain the therapeutic efficacy of ICS/LABA combination therapies. While the molecular basis of synergy remains unclear, mechanistic interpretations must accommodate gene‐specific regulation. We explore the concept that each glucocorticoid‐induced gene is an independent signal transducer optimally activated by a specific, ligand‐directed, GR conformation. In addition to explaining partial agonism, this realization provides opportunities to identify novel GR ligands that exhibit gene expression bias. Translating this into improved therapeutic ratios requires consideration of GR density in target tissues and further understanding of gene function. Similarly, the ability of a LABA to interact with a glucocorticoid may be suboptimal due to low β2‐adrenoceptor density or biased β2‐adrenoceptor signalling. Strategies to overcome these limitations include adding‐on a phosphodiesterase inhibitor and using agonists of other Gs‐coupled receptors. In all cases, the rational design of ICS/LABA, and derivative, combination therapies requires functional knowledge of induced (and repressed) genes for therapeutic benefit to be maximized. PMID:27646470

Advanced Development of the rF1V and rBV A/B Vaccines: Progress and Challenges

PubMed Central

Hart, Mary Kate; Saviolakis, George A.; Welkos, Susan L.; House, Robert V.

2012-01-01

The development of vaccines for microorganisms and bacterial toxins with the potential to be used as biowarfare and bioterrorism agents is an important component of the US biodefense program. DVC is developing two vaccines, one against inhalational exposure to botulinum neurotoxins A1 and B1 and a second for Yersinia pestis, with the ultimate goal of licensure by the FDA under the Animal Rule. Progress has been made in all technical areas, including manufacturing, nonclinical, and clinical development and testing of the vaccines, and in assay development. The current status of development of these vaccines, and remaining challenges are described in this chapter. PMID:22028978

Feasibility and impact of a computer-guided consultation on guideline-based management of COPD in general practice.

PubMed

Angus, Robert M; Thompson, Elizabeth B; Davies, Lisa; Trusdale, Ann; Hodgson, Chris; McKnight, Eddie; Davies, Andrew; Pearson, Mike G

2012-12-01

Applying guidelines is a universal challenge that is often not met. Intelligent software systems that facilitate real-time management during a clinical interaction may offer a solution. To determine if the use of a computer-guided consultation that facilitates the National Institute for Health and Clinical Excellence-based chronic obstructive pulmonary disease (COPD) guidance and prompts clinical decision-making is feasible in primary care and to assess its impact on diagnosis and management in reviews of COPD patients. Practice nurses, one-third of whom had no specific respiratory training, undertook a computer-guided review in the usual consulting room setting using a laptop computer with the screen visible to them and to the patient. A total of 293 patients (mean (SD) age 69.7 (10.1) years, 163 (55.6%) male) with a diagnosis of COPD were randomly selected from GP databases in 16 practices and assessed. Of 236 patients who had spirometry, 45 (19%) did not have airflow obstruction and the guided clinical history changed the primary diagnosis from COPD in a further 24 patients. In the 191 patients with confirmed COPD, the consultations prompted management changes including 169 recommendations for altered prescribing of inhalers (addition or discontinuation, inhaler dose or device). In addition, 47% of the 55 current smokers were referred for smoking cessation support, 12 (6%) for oxygen assessment, and 47 (24%) for pulmonary rehabilitation. Computer-guided consultations are practicable in general practice. Primary care COPD databases were confirmed to contain a significant proportion of incorrectly assigned patients. They resulted in interventions and the rationalisation of prescribing in line with recommendations. Only in 22 (12%) of those fully assessed was no management change suggested. The introduction of a computer-guided consultation offers the prospect of comprehensive guideline quality management.

Managing Agitation Associated with Schizophrenia and Bipolar Disorder in the Emergency Setting.

PubMed

Zeller, Scott L; Citrome, Leslie

2016-03-01

Patient agitation represents a significant challenge in the emergency department (ED), a setting in which medical staff are working under pressure dealing with a diverse range of medical emergencies. The potential for escalation into aggressive behavior, putting patients, staff, and others at risk, makes it imperative to address agitated behavior rapidly and efficiently. Time constraints and limited access to specialist psychiatric support have in the past led to the strategy of "restrain and sedate," which was believed to represent the optimal approach; however, it is increasingly recognized that more patient-centered approaches result in improved outcomes. The objective of this review is to raise awareness of best practices for the management of agitation in the ED and to consider the role of new pharmacologic interventions in this setting. The Best practices in Evaluation and Treatment of Agitation (BETA) guidelines address the complete management of agitation, including triage, diagnosis, interpersonal calming skills, and medicine choices. Since their publication in 2012, there have been further developments in pharmacologic approaches for dealing with agitation, including both new agents and new modes of delivery, which increase the options available for both patients and physicians. Newer modes of delivery that could be useful in rapidly managing agitation include inhaled, buccal/sublingual and intranasal formulations. To date, the only formulation administered via a non-intramuscular route with a specific indication for agitation associated with bipolar or schizophrenia is inhaled loxapine. Non-invasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and healthcare providers. Management of agitation in the ED should encompass a patient-centered approach, incorporating non-pharmacologic approaches if feasible. Where pharmacologic intervention is necessary, a cooperative approach using non-invasive medications should be employed where possible.

Correlation between anthrax lethal toxin neutralizing antibody levels and survival in guinea pigs and nonhuman primates vaccinated with the AV7909 anthrax vaccine candidate.

PubMed

Savransky, Vladimir; Shearer, Jeffry D; Gainey, Melicia R; Sanford, Daniel C; Sivko, Gloria S; Stark, Gregory V; Li, Na; Ionin, Boris; Lacy, Michael J; Skiadopoulos, Mario H

2017-09-05

The anthrax vaccine candidate AV7909 is being developed as a next generation vaccine for a post-exposure prophylaxis (PEP) indication against anthrax. AV7909 consists of the Anthrax Vaccine Adsorbed (AVA, BioThrax®) bulk drug substance adjuvanted with the immunostimulatory oligodeoxynucleotide (ODN) compound, CPG 7909. The addition of CPG 7909 to AVA enhances both the magnitude and the kinetics of antibody responses in animals and human subjects, making AV7909 a suitable next-generation vaccine for use in a PEP setting. The studies described here provide initial information on AV7909-induced toxin-neutralizing antibody (TNA) levels associated with the protection of animals from lethal Bacillus anthracis challenge. Guinea pigs or nonhuman primates (NHPs) were immunized on Days 0 and 28 with various dilutions of AV7909, AVA or a saline or Alhydrogel+CPG 7909 control. Animals were challenged via the inhalational route with a lethal dose of aerosolized B. anthracis (Ames strain) spores and observed for clinical signs of disease and mortality. The relationship between pre-challenge serum TNA levels and survival following challenge was determined in order to calculate a threshold TNA level associated with protection. Immunisation with AV7909 induced a rapid, highly protective TNA response in guinea pigs and NHPs. Surprisingly, the TNA threshold associated with a 70% probability of survival for AV7909 immunized animals was substantially lower than the threshold which has been established for the licensed AVA vaccine. The results of this study suggest that the TNA threshold of protection against anthrax could be modified by the addition of an immune stimulant such as CPG 7909 and that the TNA levels associated with protection may be vaccine-specific. Copyright © 2017. Published by Elsevier Ltd.

Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice.

PubMed

Crosby, Jeff R; Zhao, Chenguang; Jiang, Chong; Bai, Dong; Katz, Melanie; Greenlee, Sarah; Kawabe, Hiroshi; McCaleb, Michael; Rotin, Daniela; Guo, Shuling; Monia, Brett P

2017-11-01

Epithelial sodium channel (ENaC, Scnn1) hyperactivity in the lung leads to airway surface dehydration and mucus accumulation in cystic fibrosis (CF) patients and in mice with CF-like lung disease. We identified several potent ENaC specific antisense oligonucleotides (ASOs) and tested them by inhalation in mouse models of CF-like lung disease. The inhaled ASOs distributed into lung airway epithelial cells and decreased ENaC expression by inducing RNase H1-dependent degradation of the targeted Scnn1a mRNA. Aerosol delivered ENaC ASO down-regulated mucus marker expression and ameliorated goblet cell metaplasia, inflammation, and airway hyper-responsiveness. Lack of systemic activity of ASOs delivered via the aerosol route ensures the safety of this approach. Our results demonstrate that antisense inhibition of ENaC in airway epithelial cells could be an effective and safe approach for the prevention and reversal of lung symptoms in CF and potentially other inflammatory diseases of the lung. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Effects of mild processing pressures on the performance of dry powder inhaler formulations for inhalation therapy. 1: Budesonide and lactose.

PubMed

Marek, Steve R; Donovan, Martin J; Smyth, Hugh D C

2011-05-01

Batch-to-batch variability, whereby distinct batches of dry powder inhaler formulations, though manufactured with identical components and specifications, may exhibit significant variations in aerosol performance, is a major obstacle to consistent and reproducible drug delivery for inhalation therapy. This variability may arise from processing or manufacturing effects that have yet to be investigated. This study focused on the potential effects of mild compression forces experienced during powder manufacture and transport (such as during the filling of, or storage in, a hopper) on the flowability and aerosol performance of a lactose-based dry powder inhaler formulation. Different grades of inhalation lactose were subjected to typical compression forces by either placing a weight of known mass on the sample or by using a Texture Analyzer to apply a constant force while measuring the distance of compaction. Powder flowability was evaluated with a rotating drum apparatus by imaging the avalanching of the powder over time. The average avalanche angle and avalanche time were used to determine the flowability of each sample, both before and after compression treatment. Aerosol performance of treated and untreated lactose/budesonide blends (2% (w/w)) was assessed in dispersion studies using a next generation impactor. At compression forces in excess of 5 kPa, the flowability of milled lactose was decreased relative to the untreated sample. Compression of lactose prior to blending caused a decrease in in vitro aerosol dispersion performance. However, dispersion performance was unchanged when compression occurred subsequent to drug blending. In contrast, inhalation grade sieved lactose, differing from the milled grade with a lower concentration of lactose fines (<10 μm) and larger overall particle sizes, exhibited no statistical differences in either flowability or dispersion performance across all experimental treatments. Thus, the compression of the lactose fines onto the surfaces of the larger lactose particles due to mild processing pressures is hypothesized to be the cause of these observed performance variations. It was shown that simulations of storage and transport in an industrial scale hopper can induce significant variations in formulation performance, and it is speculated that this could be a source of batch-to-batch variations. Copyright © 2011 Elsevier B.V. All rights reserved.

Computationally efficient analysis of particle transport and deposition in a human whole-lung-airway model. Part II: Dry powder inhaler application.

PubMed

Kolanjiyil, Arun V; Kleinstreuer, Clement; Sadikot, Ruxana T

2017-05-01

Pulmonary drug delivery is becoming a favored route for administering drugs to treat both lung and systemic diseases. Examples of lung diseases include asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD) as well as respiratory distress syndrome (ARDS) and pulmonary fibrosis. Special respiratory drugs are administered to the lungs, using an appropriate inhaler device. Next to the pressurized metered-dose inhaler (pMDI), the dry powder inhaler (DPI) is a frequently used device because of the good drug stability and a minimal need for patient coordination. Specific DPI-designs and operations greatly affect drug-aerosol formation and hence local lung deposition. Simulating the fluid-particle dynamics after use of a DPI allows for the assessment of drug-aerosol deposition and can also assist in improving the device configuration and operation. In Part I of this study a first-generation whole lung-airway model (WLAM) was introduced and discussed to analyze particle transport and deposition in a human respiratory tract model. In the present Part II the drug-aerosols are assumed to be injected into the lung airways from a DPI mouth-piece, forming the mouth-inlet. The total as well as regional particle depositions in the WLAM, as inhaled from a DPI, were successfully compared with experimental data sets reported in the open literature. The validated modeling methodology was then employed to study the delivery of curcumin aerosols into lung airways using a commercial DPI. Curcumin has been implicated to possess high therapeutic potential as an antioxidant, anti-inflammatory and anti-cancer agent. However, efficacy of curcumin treatment is limited because of the low bioavailability of curcumin when ingested. Hence, alternative drug administration techniques, e.g., using inhalable curcumin-aerosols, are under investigation. Based on the present results, it can be concluded that use of a DPI leads to low lung deposition efficiencies because large amounts of drugs are deposited in the oral cavity. Hence, the output of a modified DPI has been evaluated to achieve improved drug delivery, especially needed when targeting the smaller lung airways. This study is the first to utilize CF-PD methodology to simulate drug-aerosol transport and deposition under actual breathing conditions in a whole lung model, using a commercial dry-powder inhaler for realistic inlet conditions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Is the 'blue' colour convention for inhaled reliever medications important? A UK-based survey of healthcare professionals and patients with airways disease.

PubMed

Fletcher, Monica; Scullion, Jane; White, John; Thompson, Bronwen; Capstick, Toby

2016-11-03

In many countries, short-acting β 2 -agonist inhalers have traditionally been coloured blue. This inhaled therapy has also conventionally been known as a 'reliever' by patients and healthcare professionals (HCPs), in comparison with 'preventer' medications (inhaled steroids). With the rapidly changing market in inhaled therapy for COPD and asthma and growing numbers of devices, there has been some concern that the erosion of traditional colour conventions is leading to patients (and HCPs) becoming confused about the role of different therapies. In order to assess whether there was concern over the perceived changing colour conventions, the UK Inhaler Group carried out a large online survey of patients and HCPs. The aim was to determine how patients and HCPS identify and describe inhaled drugs, and how this might impact on use of medicines and safety. The results of the survey highlighted the importance of the term 'blue inhaler' for patients with only 11.3% never referring to the colour when referring to their inhaler. For HCPs, 95% felt colour conventions were important when referring to reliever medication. In addition, HCPs appear to refer to inhalers mainly by colour when talking to patients. Our conclusions were that the concept of a 'blue inhaler' remains important to patients and healthcare professionals. These results add to the debate about the need to formalise the colour coding of inhaled therapies, in particular using the colour blue for inhalers for rapid relief of symptoms, as this convention may be an important measure and contributor to patient safety. Our survey should provide impetus for all interested parties to discuss and agree a formal industry-wide approach to colour coding of inhaled therapies for the benefit of patients and carers and HCPs.

Thoracic and respirable particle definitions for human health risk assessment.

PubMed

Brown, James S; Gordon, Terry; Price, Owen; Asgharian, Bahman

2013-04-10

Particle size-selective sampling refers to the collection of particles of varying sizes that potentially reach and adversely affect specific regions of the respiratory tract. Thoracic and respirable fractions are defined as the fraction of inhaled particles capable of passing beyond the larynx and ciliated airways, respectively, during inhalation. In an attempt to afford greater protection to exposed individuals, current size-selective sampling criteria overestimate the population means of particle penetration into regions of the lower respiratory tract. The purpose of our analyses was to provide estimates of the thoracic and respirable fractions for adults and children during typical activities with both nasal and oral inhalation, that may be used in the design of experimental studies and interpretation of health effects evidence. We estimated the fraction of inhaled particles (0.5-20 μm aerodynamic diameter) penetrating beyond the larynx (based on experimental data) and ciliated airways (based on a mathematical model) for an adult male, adult female, and a 10 yr old child during typical daily activities and breathing patterns. Our estimates show less penetration of coarse particulate matter into the thoracic and gas exchange regions of the respiratory tract than current size-selective criteria. Of the parameters we evaluated, particle penetration into the lower respiratory tract was most dependent on route of breathing. For typical activity levels and breathing habits, we estimated a 50% cut-size for the thoracic fraction at an aerodynamic diameter of around 3 μm in adults and 5 μm in children, whereas current ambient and occupational criteria suggest a 50% cut-size of 10 μm. By design, current size-selective sample criteria overestimate the mass of particles generally expected to penetrate into the lower respiratory tract to provide protection for individuals who may breathe orally. We provide estimates of thoracic and respirable fractions for a variety of breathing habits and activities that may benefit the design of experimental studies and interpretation of particle size-specific health effects.

Thoracic and respirable particle definitions for human health risk assessment

PubMed Central

2013-01-01

Background Particle size-selective sampling refers to the collection of particles of varying sizes that potentially reach and adversely affect specific regions of the respiratory tract. Thoracic and respirable fractions are defined as the fraction of inhaled particles capable of passing beyond the larynx and ciliated airways, respectively, during inhalation. In an attempt to afford greater protection to exposed individuals, current size-selective sampling criteria overestimate the population means of particle penetration into regions of the lower respiratory tract. The purpose of our analyses was to provide estimates of the thoracic and respirable fractions for adults and children during typical activities with both nasal and oral inhalation, that may be used in the design of experimental studies and interpretation of health effects evidence. Methods We estimated the fraction of inhaled particles (0.5-20 μm aerodynamic diameter) penetrating beyond the larynx (based on experimental data) and ciliated airways (based on a mathematical model) for an adult male, adult female, and a 10 yr old child during typical daily activities and breathing patterns. Results Our estimates show less penetration of coarse particulate matter into the thoracic and gas exchange regions of the respiratory tract than current size-selective criteria. Of the parameters we evaluated, particle penetration into the lower respiratory tract was most dependent on route of breathing. For typical activity levels and breathing habits, we estimated a 50% cut-size for the thoracic fraction at an aerodynamic diameter of around 3 μm in adults and 5 μm in children, whereas current ambient and occupational criteria suggest a 50% cut-size of 10 μm. Conclusions By design, current size-selective sample criteria overestimate the mass of particles generally expected to penetrate into the lower respiratory tract to provide protection for individuals who may breathe orally. We provide estimates of thoracic and respirable fractions for a variety of breathing habits and activities that may benefit the design of experimental studies and interpretation of particle size-specific health effects. PMID:23575443

Acute cyanide poisoning in prehospital care: new challenges, new tools for intervention.

PubMed

Guidotti, Tee

2006-01-01

Effective management of cyanide poisoning from chemical terrorism, inhalation of fire smoke, and other causes constitutes a critical challenge for the prehospital care provider. The ability to meet the challenge of managing cyanide poisoning in the prehospital setting may be enhanced by the availability of the cyanide antidote hydroxocobalamin, currently under development for potential introduction in the United States. This paper discusses the causes, recognition, and management of acute cyanide poisoning in the prehospital setting with emphasis on the emerging profile of hydroxocobalamin, an antidote that may have a risk:benefit ratio suitable for empiric, out-of-hospital treatment of the range of causes of cyanide poisoning. If introduced in the U.S., hydroxocobalamin may enhance the role of the U.S. prehospital responder in providing emergency care in a cyanide incident.

Prediction of obeche wood-induced asthma by specific skin prick testing.

PubMed

Hannu, T; Lindström, I; Palmroos, P; Kuuliala, O; Sauni, R

2013-09-01

It has previously been shown that a positive skin prick test (SPT) result is a good predictor of a positive specific inhalation challenge (SIC) in patients with occupational asthma (OA) related to wheat or rye flours. This association has not been previously studied in OA attributable to obeche wood. To describe a clinical series of patients with OA induced by obeche wood. To investigate if the SPT result can be used as a predictor for the outcome of SIC tests. OA was diagnosed according to patient history, lung function examinations and SIC tests, as well as the determination of obeche SPTs. We analysed sensitivity, specificity and positive (PPV) and negative predictive values (NPV) at different wheal sizes of the SPTs and drew receiver-operating characteristic plots using the SIC test result as the gold standard. Obeche wood SIC tests were performed on 34 symptomatic workers. Of these, 27 workers had a positive test result and were diagnosed as having OA. The minimal cut-off value with a PPV of 100% was an SPT wheal of 3.5 mm from obeche wood. This means that all workers with a wheal size of ≥ 3.5 mm from obeche wood had a positive SIC. Positive SPT results in symptomatic workers were good predictors of a positive SIC. SIC with obeche wood may be unnecessary in strongly sensitized workers.

Inhalant Use, Abuse, and Dependence among Adolescent Patients: Commonly Comorbid Problems.

ERIC Educational Resources Information Center

Sakai, Joseph T.; Hall, Shannon K.; Mikulich-Gilbertson, Susan K.; Crowley, Thomas J.

2004-01-01

Objective: Little is known about adolescents with DSM-IV-defined inhalant abuse and dependence. The aim of this study was to compare comorbidity among (1) adolescents with inhalant use disorders, (2) adolescents who reported using inhalants without inhalant use disorder, and (3) other adolescent patients drawn from an adolescent drug and alcohol…

Effectiveness of Various Methods of Teaching Proper Inhaler Technique.

PubMed

Axtell, Samantha; Haines, Seena; Fairclough, Jamie

2017-04-01

To compare the effectiveness of 4 different instructional interventions in training proper inhaler technique. Randomized, noncrossover trial. Health fair and indigent clinic. Inhaler-naive adult volunteers who spoke and read English. Subjects were assigned to complete the following: (1) read a metered dose inhaler (MDI) package insert pamphlet, (2) watch a Centers for Disease Control and Prevention (CDC) video demonstrating MDI technique, (3) watch a YouTube video demonstrating MDI technique, or (4) receive direct instruction of MDI technique from a pharmacist. Inhaler use competency (completion of all 7 prespecified critical steps). Of the 72 subjects, 21 (29.2%) demonstrated competent inhaler technique. A statistically significant difference between pharmacist direct instruction and the remaining interventions, both combined ( P < .0001) and individually ( P ≤ .03), was evident. No statistically significant difference was detected among the remaining 3 intervention groups. Critical steps most frequently omitted or improperly performed were exhaling before inhalation and holding of breath after inhalation. A 2-minute pharmacist counseling session is more effective than other interventions in successfully educating patients on proper inhaler technique. Pharmacists can play a pivotal role in reducing the implications of improper inhaler use.

A cross-sectional observational study to assess inhaler technique in Saudi hospitalized patients with asthma and chronic obstructive pulmonary disease

PubMed Central

Ammari, Maha Al; Sultana, Khizra; Yunus, Faisal; Ghobain, Mohammed Al; Halwan, Shatha M. Al

2016-01-01

Objectives: To assess the proportion of critical errors committed while demonstrating the inhaler technique in hospitalized patients diagnosed with asthma and chronic obstructive pulmonary disease (COPD). Methods: This cross-sectional observational study was conducted in 47 asthmatic and COPD patients using inhaler devices. The study took place at King Abdulaziz Medical City, Riyadh, Saudi Arabia between September and December 2013. Two pharmacists independently assessed inhaler technique with a validated checklist. Results: Seventy percent of patients made at least one critical error while demonstrating their inhaler technique, and the mean number of critical errors per patient was 1.6. Most patients used metered dose inhaler (MDI), and 73% of MDI users and 92% of dry powder inhaler users committed at least one critical error. Conclusion: Inhaler technique in hospitalized Saudi patients was inadequate. Health care professionals should understand the importance of reassessing and educating patients on a regular basis for inhaler technique, recommend the use of a spacer when needed, and regularly assess and update their own inhaler technique skills. PMID:27146622

Use of Respimat® Soft Mist™ Inhaler in COPD patients

PubMed Central

Anderson, Paula

2006-01-01

Events of the past decade have stimulated development of new drug formulations and delivery devices that have improved the efficiency, ease of use, and environmental impact of inhaled drug therapy. Respimat® Soft Mist™ Inhaler is a novel, multidose, propellant-free, hand-held, liquid inhaler that represents a new category of inhaler devices. The aerosol cloud generated by Respimat contains a higher fraction of fine particles than most pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs), and the aerosol spray exits the inhaler more slowly and for a longer duration than with pMDIs. This translates into higher lung drug deposition and lower oropharyngeal deposition, making it possible to give lower nominal doses of delivered drugs without lowering efficacy. In clinical trials in patients with COPD, bronchodilator drugs delivered from Respimat were equally effective at half of the dose delivered from a pMDI. In one study of inhaler preference, Respimat was preferred over the pMDI by patients with COPD and other obstructive lung diseases. Respimat is a valuable addition to the range of inhaler devices available to the patient with COPD. PMID:18046862

Current challenges in the development of vaccines for pneumonic plague

PubMed Central

Smiley, Stephen T

2008-01-01

Inhalation of Yersinia pestis bacilli causes pneumonic plague, a rapidly progressing and exceptionally virulent disease. Extensively antibiotic-resistant Y. pestis strains exist and we currently lack a safe and effective pneumonic plague vaccine. These facts raise concern that Y. pestis may be exploited as a bioweapon. Here, I review the history and status of plague vaccine research and advocate that pneumonic plague vaccines should strive to prime both humoral and cellular immunity. PMID:18324890

Immune Serum Produced by DNA Vaccination Protects Hamsters against Lethal Respiratory Challenge with Andes Virus

DTIC Science & Technology

2008-02-01

responses in the hantavirus cardiopulmonary syndrome. J. Infect. Dis. 182:43–48. 3. Butler, J. C., and C. J. Peters. 1994. Hantaviruses and hantavirus ...November 2007 Hantavirus pulmonary syndrome (HPS) is a highly pathogenic disease (40% case fatality rate) carried by rodents chronically infected with...certain viruses within the genus Hantavirus of the family Bunyaviridae. The primary mode of transmission to humans is thought to be inhalation of excreta

Acetalated Dextran Microparticulate Vaccine Formulated via Coaxial Electrospray Preserves Toxin Neutralization and Enhances Murine Survival Following Inhalational Bacillus Anthracis Exposure.

PubMed

Gallovic, Matthew D; Schully, Kevin L; Bell, Matthew G; Elberson, Margaret A; Palmer, John R; Darko, Christian A; Bachelder, Eric M; Wyslouzil, Barbara E; Keane-Myers, Andrea M; Ainslie, Kristy M

2016-10-01

Subunit formulations are regarded as the safest type of vaccine, but they often contain a protein-based antigen that can result in significant challenges, such as preserving antigenicity during formulation and administration. Many studies have demonstrated that encapsulation of protein antigens in polymeric microparticles (MPs) via emulsion techniques results in total IgG antibody titers comparable to alum formulations, however, the antibodies themselves are non-neutralizing. To address this issue, a coaxial electrohydrodynamic spraying (electrospray) technique is used to formulate a microparticulate-based subunit anthrax vaccine under conditions that minimize recombinant protective antigen (rPA) exposure to harsh solvents and high shear stress. rPA and the adjuvant resiquimod are encapsulated either in separate or the same acetalated dextran MPs. Using a murine model, the electrospray formulations lead to higher IgG2a subtype titers as well as comparable total IgG antibody titers and toxin neutralization relative to the FDA-approved vaccine (BioThrax). BioThrax provides no protection against a lethal inhalational challenge of the highly virulent Ames Bacillus anthracis anthrax strain, whereas 50% of the mice vaccinated with separately encapsulated electrospray MPs survive. Overall, this study demonstrates the potential use of electrospray for encapsulating protein antigens in polymeric MPs. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bioavailability and Efficacy of Levofloxacin against Francisella tularensis in the Common Marmoset (Callithrix jacchus)▿

PubMed Central

Nelson, Michelle; Lever, Mark S.; Dean, Rachel E.; Pearce, Peter C.; Stevens, Daniel J.; Simpson, Andrew J. H.

2010-01-01

Pharmacokinetic and efficacy studies with levofloxacin were performed in the common marmoset (Callithrix jacchus) model of inhalational tularemia. Plasma levofloxacin pharmacokinetics were determined in six animals in separate single-dose and multidose studies. Plasma drug concentrations were analyzed using liquid chromatography-tandem mass spectrometry-electrospray ionization. On day 7 of a twice-daily dosing regimen of 40 mg/kg, the levofloxacin half-life, maximum concentration, and area under the curve in marmoset plasma were 2.3 h, 20.9 μg/ml, and 81.4 μg/liter/h, respectively. An efficacy study was undertaken using eight treated and two untreated control animals. Marmosets were challenged with a mean of 1.5 × 102 CFU of Francisella tularensis by the airborne route. Treated animals were administered 16.5 mg/kg levofloxacin by mouth twice daily, based on the pharmacokinetic parameters, beginning 24 h after challenge. Control animals had a raised core body temperature by 57 h postchallenge and died from infection by day 5. All of the other animals survived, remained afebrile, and lacked overt clinical signs. No bacteria were recovered from the organs of these animals at postmortem after culling at day 24 postchallenge. In conclusion, postexposure prophylaxis with orally administered levofloxacin was efficacious against acute inhalational tularemia in the common marmoset. The marmoset appears to be an appropriate animal model for the evaluation of postexposure therapies. PMID:20625157

Prevalence of sensitization to the predatory mite Amblyseius cucumeris as a new occupational allergen in horticulture.

PubMed

Groenewoud, G C M; de Graaf in 't Veld, C; vVan Oorschot-van Nes, A J; de Jong, N W; Vermeulen, A M; van Toorenenbergen, A W; Burdorf, A; de Groot, H; Gerth van Wijk, R

2002-07-01

Protection against thrips, a common pest in bell pepper horticulture is effectively possible without pesticides by using the commercially available predatory mite Amblyzeius cucumeris (Ac). The prevalence of sensitization to Ac among exposed greenhouse employees and its clinical relevance was studied. Four hundred and seventytwo employees were asked to fill in a questionnaire and were tested on location. Next to RAST, skin prick tests (SPTs) were performed with common inhalant allergens, the storage mite Tyrophagus putrescentiae (Tp) which serves as a temporary food source during the cultivation process and Ac. Furthermore, nasal challenge tests with Ac were carried out in 23 sensitized employees. SPTs positive to Ac were found in 109 employees (23%). Work-related symptoms were reported by 76.1%. Sensitization to Tp was found in 62 employees of whom 48 were also sensitized to Ac. Immunoglobulin (Ig)E-mediated allergy to inhalant allergens appeared to be an important risk factor for sensitization to Ac. Employees with rhinitis symptoms showed a significantly higher response to all Ac doses during the nasal challenge test compared with employees without rhinitis symptoms. The predatory mite Ac is a new occupational allergen in horticulture which can cause an IgE-mediated allergy in exposed employees. It is biologically active on the mucous membranes of the nose and therefore clinically relevant for the development of work-related symptoms.

G Protein βγ-Subunit Signaling Mediates Airway Hyperresponsiveness and Inflammation in Allergic Asthma

PubMed Central

Grunstein, Judith S.; McDonough, Joseph; Kreiger, Portia A.; Josephson, Maureen B.; Choi, John K.; Grunstein, Michael M.

2012-01-01

Since the Gβγ subunit of Gi protein has been importantly implicated in regulating immune and inflammatory responses, this study investigated the potential role and mechanism of action of Gβγ signaling in regulating the induction of airway hyperresponsiveness (AHR) in a rabbit model of allergic asthma. Relative to non-sensitized animals, OVA-sensitized rabbits challenged with inhaled OVA exhibited AHR, lung inflammation, elevated BAL levels of IL-13, and increased airway phosphodiesterase-4 (PDE4) activity. These proasthmatic responses were suppressed by pretreatment with an inhaled membrane-permeable anti-Gβγ blocking peptide, similar to the suppressive effect of glucocorticoid pretreatment. Extended mechanistic studies demonstrated that: 1) corresponding proasthmatic changes in contractility exhibited in isolated airway smooth muscle (ASM) sensitized with serum from OVA-sensitized+challenged rabbits or IL-13 were also Gβγ-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to Gβγ-induced direct stimulation of the non-receptor tyrosine kinase, c-Src, resulting in downstream activation of ERK1/2 and its consequent transcriptional upregulation of PDE4. Collectively, these data are the first to identify that a mechanism involving Gβγ-induced direct activation of c-Src, leading to ERK1/2-mediated upregulation of PDE4 activity, plays a decisive role in regulating the induction of AHR and inflammation in a rabbit model of allergic airway disease. PMID:22384144

Development of a bolus injection system for regional deposition studies of nanoparticles in the human respiratory system

NASA Astrophysics Data System (ADS)

Koujalagi, V.; Ramesh, S. L.; Gunarathne, G. P. P.; Semple, S.; Ayres, J. G.

2009-02-01

This study presents the work carried out in developing a precision bolus injection system in order to understand the regional deposition of nanoparticles (NP) in human lung. A real-time control system has been developed that is capable of storing graphite NP, assessing human breathing pattern and delivering a bolus of the stored NP at a pre-determined instance of the inhalation phase of breathing. This will form the basis for further development of a system to deliver radioactive nanoparticles to enable 3-dimensional lung imaging using techniques such as positron emission tomography (PET). The system may then be used to better understand the actual regional deposition in human lung, which could validate or challenge the current computational lung models such as that published by the International Commission for Radiation Protection (ICRP-1994). A dose related response to inhaled PM can possibly be shown, which can be used to review the current workplace exposure limits (WELs).

Inhalation Exposures to Particulate Matter and Carbon Monoxide during Ethiopian Coffee Ceremonies in Addis Ababa: A Pilot Study

PubMed Central

Keil, Chris; Kassa, Hailu; Brown, Alexander; Kumie, Abera; Tefera, Worku

2010-01-01

The unique Ethiopian cultural tradition of the coffee ceremony increases inhalation exposures to combustion byproducts. This pilot study evaluated exposures to particulate matter and carbon monoxide in ten Addis Ababa homes during coffee ceremonies. For coffee preparers the geometric mean (57 μg/m3) and median (72 μg/m3) contributions to an increase in a 24-hour time-weighted average exposure were above World Health Organization (WHO) guidelines. At 40% of the study sites the contribution to the 24-hour average exposure was greater than twice the WHO guideline. Similar exposure increases existed for ceremony participants. Particulate matter concentrations may be related to the use of incense during the ceremony. In nearly all homes the WHO guideline for a 60-minute exposure to carbon monoxide was exceeded. Finding control measures to reduce these exposures will be challenging due to the deeply engrained nature of this cultural practice and the lack of availability of alternative fuels. PMID:20886061

Occupational asthma and contact dermatitis in a spray painter after introduction of an aziridine cross-linker.

PubMed Central

Leffler, C T; Milton, D K

1999-01-01

A 23-year-old spray painter developed contact dermatitis and respiratory difficulty characterized by small airways obstruction shortly after the polyfunctional aziridine cross-linker CX-100 began to be used in his workplace as a paint activator. The symptoms resolved after he was removed from the workplace and was treated with inhaled and topical steroids. Painters may have an increased risk of asthma due to exposure to a variety of agents, such as isocyanates, alkyd resins, and chromates. This case illustrates the importance of using appropriate work practices and personal protective equipment to minimize exposure. Occupational asthma is diagnosed by a history of work-related symptoms and exposure to known causative agents. The diagnosis is confirmed by serial pulmonary function testing or inhalational challenge testing. The risk of asthma attributable to occupational exposures is probably underappreciated due to underreporting and to inappropriate use of narrow definitions of exposure in epidemiologic studies of attributable risk. Images Figure 1 PMID:10379008

Inhalation exposures to particulate matter and carbon monoxide during Ethiopian coffee ceremonies in Addis Ababa: a pilot study.

PubMed

Keil, Chris; Kassa, Hailu; Brown, Alexander; Kumie, Abera; Tefera, Worku

2010-01-01

The unique Ethiopian cultural tradition of the coffee ceremony increases inhalation exposures to combustion byproducts. This pilot study evaluated exposures to particulate matter and carbon monoxide in ten Addis Ababa homes during coffee ceremonies. For coffee preparers the geometric mean (57 μg/m³) and median (72 μg/m³) contributions to an increase in a 24-hour time-weighted average exposure were above World Health Organization (WHO) guidelines. At 40% of the study sites the contribution to the 24-hour average exposure was greater than twice the WHO guideline. Similar exposure increases existed for ceremony participants. Particulate matter concentrations may be related to the use of incense during the ceremony. In nearly all homes the WHO guideline for a 60-minute exposure to carbon monoxide was exceeded. Finding control measures to reduce these exposures will be challenging due to the deeply engrained nature of this cultural practice and the lack of availability of alternative fuels.

Inhalation Injuries

MedlinePlus

... breathe in toxic substances, such as smoke (from fires), chemicals, particle pollution, and gases. Inhalation injuries can ... of thermal injuries. Over half of deaths from fires are due to inhalation injuries. Symptoms of inhalation ...

EFFECTS OF TUMORS ON INHALED PHARMACOLOGIC DRUGS: I. FLOW PATTTERNS

EPA Science Inventory

ABSTRACT

Lung carcinomas are now the most common form of cancer. Clinical data suggest that tumors are found preferentially in upper airways, perhaps specifically at carina within bifurcations. The disease can be treated by aerosolized pharmacologic drugs. To enhance their...

Child-Specific Exposure Factors Handbook (2002, Interim Report)

EPA Science Inventory

Children are often more heavily exposed to environmental toxicants than adults. They consume more food and water and have higher inhalation rates per pound of body weight than adults. Young children play close to the ground and come into contact with contaminated soil outdoors ...

MODELING INHALATION AND MULTIMEDIA MULTIPATHWAY HUMAN EXPOSURES TO ENVIRONMENTAL POLLUTANTS

EPA Science Inventory

Estimation of exposures of children and adults to air toxics or multimedia pollutants require careful consideration of sources and concentrations of pollutants that may be present in different media, as well as various routes and pathways of exposures associated with age-specif...

Occupational asthma due to methyl methacrylate and cyanoacrylates.

PubMed Central

Lozewicz, S; Davison, A G; Hopkirk, A; Burge, P S; Boldy, D A; Riordan, J F; McGivern, D V; Platts, B W; Davies, D; Newman Taylor, A J

1985-01-01

Five patients had asthma provoked by cyanoacrylates and one by methyl methacrylate, possibly because of the development of a specific hypersensitivity response. Acrylates have wide domestic as well as industrial uses, and inhalation of vapour emitted during their use can cause asthma. PMID:4071461

Inhalation Exposure and Lung Dose Analysis of Multi-mode Complex Ambient Aerosols

EPA Science Inventory

Rationale: Ambient aerosols are complex mixture of particles with different size, shape and chemical composition. Although they are known to cause health hazard, it is not fully understood about causal mechanisms and specific attributes of particles causing the effects. Internal ...

Do air cleaners make a difference in treating allergic disease in homes?

PubMed

Reisman, R E

2001-12-01

The purpose of this review is to objectively critique available data regarding the clinical benefits of room air cleaners and to provide physicians and patients with a reasonable recommendation of their utility in treatment of inhalant allergic disease. Data were obtained from published studies and reviews. The specific reviewed studies met the following criteria: 1) selection of patients with clinical allergic disease confirmed by detection of allergen-specific immunoglobulin E; 2) use of an effective air filter; 3) clinical and laboratory evaluation of results; and 4) measurement of the results of air filtration on environmental allergen or airborne particulate levels. The studies were conducted in a double-blind manner. Conclusions of two previous reviews are also incorporated in this paper. The results of the published studies and summary reviews show minimal, if any, effectiveness of room air cleaners in treatment of allergic respiratory disease. Room air cleaners should not be recommended for people with inhalant allergic disease.

Child-Specific Exposure Factors Handbook (Final Report) ...

EPA Pesticide Factsheets

The National Center for Environmental Assessment Staff (NCEA) have prepared this handbook to provide information on various physiological and behavioral factors commonly used in assessing children’s exposure to environmental chemicals. Children have different exposure circumstances than do adults. Understanding these differences is key for evaluating potential for environmental hazards from pollutants. They consume more of certain foods and water and have higher inhalation rates per unit of body weight than adults. Young children play close to the ground and come into contact with contaminated soil outdoors and with contaminated dust on surfaces and carpets indoors. Ingestion of human milk may be another potential pathway of exposure for infants and young children. The Child-Specific Exposure Factors Handbook provides a summary of statistical data on various exposure factors used in assessing children exposures. These factors include: drinking water consumption; soil ingestion and mouthing behavior; inhalation rates; dermal factors including skin surface area and soil adherence factors; consumption of retail and home-grown foods; breast milk intake; body weight; and activity pattern data.

A Survey of Inhalant Use Disorders among Delinquent Youth: Prevalence, Clinical Features, and Latent Structure of DSM-IV Diagnostic Criteria

PubMed Central

Howard, Matthew O; Perron, Brian E

2009-01-01

Background Inhalant use is among the most pernicious and poorly understood forms of adolescent substance use. Many youth in the juvenile justice system have used inhalants, but little is known about inhalant use disorders (IUDs) in antisocial youth populations. The purpose of this study was to examine the prevalence, clinical features, and latent structure of DSM-IV IUDs in a state population of antisocial youth. Methods Cross-sectional survey conducted in 2003. Of 740 youth residing in Missouri State Division of Youth Services' (MDYS) residential treatment facilities at the time the study was conducted, 723 (97.7%) completed interviews. Eighty-seven percent were male, with a mean age of 15.5 (SD = 1.2). Nearly 4 in 10 youth (38.5%; n = 279) reported lifetime inhalant use. Youth ranged from very mildly to severely antisocial. Results Of 279 inhalant users, 52 (18.6%) met DSM-IV inhalant abuse criteria and 79 (28.3%) met inhalant dependence criteria. Five of 10 IUD criteria were met by > 10% of the total sample. Latent class analyses demonstrated a substantial concordance between DSM-IV-defined IUDs and an empirically-derived classification based on responses to DSM-IV IUD diagnostic criteria. Conclusion IUDs and constituent criteria were prevalent among youth in the juvenile justice system. Two groups of problem inhalant users were identified, symptomatic users-DSM-IV inhalant abuse and highly symptomatic users-DSM-IV inhalant dependence, which differed primarily in severity of inhalant-related problems. Inhalant screening, prevention and treatment efforts in juvenile justice settings are rarely delivered, but critically needed. PMID:19267939

Fiber inhalability and head deposition in rats and humans. ...

EPA Pesticide Factsheets

Due to their dimensions and long durability, inhaled asbestos fibers clear slowly from lung airways. Retained fibers may injure the epithelium, interact with macrophages, or translocate to the interstitium to result in various respiratory diseases. Therefore, calculations of fiber inhalability, deposition, and retention in respiratory tract regions of both rats and humans are crucial, both to assess the health risk of fiber exposures and to facilitate inferences from rat inhalation studies. Rat inhalation experiments are underway at the EPA and NIEHS. A model of fiber inhalability and initial deposition in the human and rat nasal cavity was developed. Existing models for particles were extended to fibers by replacing particle diameter with an equivalent fiber diameter. Since fiber inhalability into the respiratory tract and deposition in the extra thoracic airways depended mainly on its inertia, equivalent impaction diameters were derived and substituted in expressions for spherical particle diameter to determine fiber inhalability and nasal losses. Fiber impaction diameter depended strongly on its orientation in the air. Highest inhalability was obtained when fibers were aligned perpendicular to the flow streamlines in the inhaled air. However, detailed calculations of fiber transport in slow moving air such as that in the atmosphere and in lung airways showed that fibers stayed primarily aligned (parallel) to the flow. Therefore, for inhalability calculations,

Evaluation of a novel educational strategy, including inhaler-based reminder labels, to improve asthma inhaler technique.

PubMed

Basheti, Iman A; Armour, Carol L; Bosnic-Anticevich, Sinthia Z; Reddel, Helen K

2008-07-01

To evaluate the feasibility, acceptability and effectiveness of a brief intervention about inhaler technique, delivered by community pharmacists to asthma patients. Thirty-one pharmacists received brief workshop education (Active: n=16, CONTROL: n=15). Active Group pharmacists were trained to assess and teach dry powder inhaler technique, using patient-centered educational tools including novel Inhaler Technique Labels. Interventions were delivered to patients at four visits over 6 months. At baseline, patients (Active: 53, CONTROL: 44) demonstrated poor inhaler technique (mean+/-S.D. score out of 9, 5.7+/-1.6). At 6 months, improvement in inhaler technique score was significantly greater in Active cf. CONTROL patients (2.8+/-1.6 cf. 0.9+/-1.4, p<0.001), and asthma severity was significantly improved (p=0.015). Qualitative responses from patients and pharmacists indicated a high level of satisfaction with the intervention and educational tools, both for their effectiveness and for their impact on the patient-pharmacist relationship. A simple feasible intervention in community pharmacies, incorporating daily reminders via Inhaler Technique Labels on inhalers, can lead to improvement in inhaler technique and asthma outcomes. Brief training modules and simple educational tools, such as Inhaler Technique Labels, can provide a low-cost and sustainable way of changing patient behavior in asthma, using community pharmacists as educators.

Ease-of-use preference for the ELLIPTA® dry powder inhaler over a commonly used single-dose capsule dry powder inhaler by inhalation device-naïve Japanese volunteers aged 40 years or older.

PubMed

Komase, Yuko; Asako, Akimoto; Kobayashi, Akihiro; Sharma, Raj

2014-01-01

In patients receiving inhaled medication, dissatisfaction with and difficulty in using the inhaler can affect treatment adherence. The incidence of handling errors is typically higher in the elderly than in younger people. The aim of the study was to assess inhaler preference for and handling errors with the ELLIPTA® dry powder inhaler (DPI), (GSK), compared with the established BREEZHALER™, a single-dose capsule DPI (Novartis), in inhalation device-naïve Japanese volunteers aged ≥40 years. In this open-label, nondrug interventional, crossover DPI preference study comparing the ELLIPTA DPI and BREEZHALER, 150 subjects were randomized to handle the ELLIPTA or BREEZHALER DPIs until the point of inhalation, without receiving verbal or demonstrative instruction (first attempt). Subjects then crossed over to the other inhaler. Preference was assessed using a self-completed questionnaire. Inhaler handling was assessed by a trained assessor using a checklist. Subjects did not inhale any medication in the study, so efficacy and safety were not measured. The ELLIPTA DPI was preferred to the BREEZHALER by 89% of subjects (odds ratio [OR] 70.14, 95% confidence interval [CI] 33.69-146.01; P-value not applicable for this inhaler) for ease of use, by 63% of subjects (OR 2.98, CI 1.87-4.77; P<0.0001) for ease of determining the number of doses remaining in the inhaler, by 91% for number of steps required, and by 93% for time needed for handling the inhaler. The BREEZHALER was preferred to the ELLIPTA DPI for comfort of the mouthpiece by 64% of subjects (OR 3.16, CI 1.97-5.06; P<0.0001). The incidence of handling errors (first attempt) was 11% with ELLIPTA and 68% with BREEZHALER; differences in incidence were generally similar when analyzed by age (< or ≥65 years) or sex. These data, obtained in an inhalation device-naïve population, suggest that the ELLIPTA DPI is preferred to an established alternative based on its ease-of-use features and is associated with fewer handling errors.

Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry

EPA Pesticide Factsheets

EPA's methodology for estimation of inhalation reference concentrations (RfCs) as benchmark estimates of the quantitative dose-response assessment of chronic noncancer toxicity for individual inhaled chemicals.

Feasibility of haloperidol-anchored albumin nanoparticles loaded with doxorubicin as dry powder inhaler for pulmonary delivery.

PubMed

Varshosaz, Jaleh; Hassanzadeh, Farshid; Mardani, Amin; Rostami, Mahboubeh

2015-03-01

Haloperidol (Hal) is a ligand that can target sigma 2 receptors over-expressed in non-small cell lung cancer. Hal targeted nanoparticles of bovine serum albumin (BSA) were prepared for pulmonary delivery of doxorubicin (DOX). The conjugation was confirmed by Fourier transform infrared spectroscopy (FTIR) and (1)H nuclear magnetic resonance ((1)H NMR) spectroscopic methods. Nanoparticles were prepared by desolvation method from BSA-Hal and were loaded with DOX. They were characterized for their morphology, particle size, zeta potential, drug loading and release efficiency. The optimized nanoparticles were spray-dried using trehalose, l-leucin and mannitol as dry powder inhaler (DPI) in different inlet temperatures between 80 and 120°C. The obtained nanocomposites were characterized for their aerodynamic diameter, specific surface area (cm(2)/g) and fine particle fraction (FPF) by a Cascade Impactor device. The optimized nanoparticles showed particle size of 218 nm, zeta potential of -25.4 mV, drug entrapment efficiency of 89% and release efficiency of 56% until 2 h. After spray drying of these nanoparticles, the best results were obtained from mannitol with an inlet temperature of 80°C which produced a mean aerodynamic diameter of 4.58 μm, FPF of 66% and specific surface area of 6302.99 cm(2)/g. The obtained results suggest that the designed DPI could be a suitable inhaler for targeted delivery of DOX in pulmonary delivery.

INFLUENCE OF INHALATION INJURY ON ENERGY EXPENDITURE IN SEVERELY BURNED CHILDREN

PubMed Central

Przkora, Rene; Fram, Ricki Y.; Herndon, David N.; Suman, Oscar E.; Mlcak, Ronald P.

2014-01-01

Objective Determine the effect of inhalation injury on burn-induced hypermetabolism in children. Design Prospective study comparing hypermetabolism (i.e., resting energy expenditure and oxygen consumption) in burned children with and without inhalation injury during acute hospitalization. Setting Single pediatric burn center. Patients Eighty-six children (1–18 years) with ≥ 40% total body surface area burns were stratified to two groups: no inhalation injury and inhalation injury. Interventions None. Main Measurements and Results Inhalation injury was diagnosed based on bronchoscopic evaluation. At admission, PaO2:FiO2 ratios (an index of respiratory distress) were significantly higher in patients with no inhalation injury than in patient with inhalation injury. No differences were detected in resting energy expenditure or percent of the predicted basal metabolic rate between groups. Additionally, oxygen consumption did not significantly differ between groups. Conclusions Inhalation injury does not augment the burn-induced hypermetabolic stress response in children, as reflected by resting energy expenditure and oxygen consumption. PMID:24893760

Occupational asthma due to chrome and nickel electroplating

PubMed Central

Bright, P.; Burge, P. S.; O'Hickey, S. P.; Gannon, P. F.; Robertson, A. S.; Boran, A.

1997-01-01

BACKGROUND: Exposure to chromium during electroplating is a recognised though poorly characterised cause of occupational asthma. The first series of such patients referred to a specialist occupational lung disease clinic is reported. METHODS: The diagnosis of occupational asthma was made from a history of asthma with rest day improvement and confirmed by specific bronchial provocation testing with potassium dichromate and nickel chloride. RESULTS: Seven workers had been exposed to chrome and nickel fumes from electroplating for eight months to six years before asthma developed. One subject, although exposed for 11 years without symptoms, developed asthma after a single severe exposure during a ventilation failure. This was the only subject who had never smoked. The diagnosis was confirmed by specific bronchial challenges. Two workers had isolated immediate reactions, one a late asthmatic reaction, and four a dual response following exposure to nebulised potassium dichromate at 1-10 mg/ml. Two of the four subjects were also challenged with nebulised nickel chloride at 0.1-10 mg/ml. Two showed isolated late asthmatic reactions, in one at 0.1 mg/ml, where nickel was probably the primary sensitising agent. Four workers carried out two hourly measurements of peak expiratory flow over days at and away from work. All were scored as having occupational asthma using OASYS-2. Breathing zone air monitoring was carried out in 60 workers from four decorative and two hard chrome plating shops from workers with similar jobs to those sensitised. No measurement exceeded the current occupational exposure standard for chromate or nickel, the mean levels of chromate exposure for jobs similar to those of the affected workers were 9-15 micrograms/m3. CONCLUSION: Chrome used in electroplating is a potential cause of occupational asthma. Sensitivity to chrome in electroplaters may occur in situations where exposure levels are likely to be within the current exposure standards. There may be cross reactivity with nickel. Inhalation challenge with nebulised potassium dichromate solution is helpful in making the specific diagnosis where doubt exists. 


 PMID:9039236

Comparison of peak inspiratory flow rate via the Breezhaler®, Ellipta® and HandiHaler® dry powder inhalers in patients with moderate to very severe COPD: a randomized cross-over trial.

PubMed

Altman, Pablo; Wehbe, Luis; Dederichs, Juergen; Guerin, Tadhg; Ament, Brian; Moronta, Miguel Cardenas; Pino, Andrea Valeria; Goyal, Pankaj

2018-06-14

The chronic and progressive nature of chronic obstructive pulmonary disease (COPD) requires self-administration of inhaled medication. Dry powder inhalers (DPIs) are increasingly being used for inhalation therapy in COPD. Important considerations when selecting DPIs include inhalation effort required and flow rates achieved by patients. Here, we present the comparison of the peak inspiratory flow rate (PIF) values achieved by COPD patients, with moderate to very severe airflow limitation, through the Breezhaler®, the Ellipta® and the HandiHaler® inhalers. The effects of disease severity, age and gender on PIF rate were also evaluated. This randomized, open-label, multicenter, cross-over, Phase IV study recruited patients with moderate to very severe airflow limitation (Global Initiative for Obstructive Lung Disease 2014 strategy), aged ≥40 years and having a smoking history of ≥10 pack years. No active drug or placebo was administered during the study. The inhalation profiles were recorded using inhalers fitted with a pressure tap and transducer at the wall of the mouthpiece. For each patient, the inhalation with the highest PIF value, out of three replicate inhalations per device, was selected for analysis. A paired t-test was performed to compare mean PIFs between each combination of devices. In total, 97 COPD patients were enrolled and completed the study. The highest mean PIF value (L/min ± SE) was observed with the Breezhaler® (108 ± 23), followed by the Ellipta® (78 ± 15) and the HandiHaler® (49 ± 9) inhalers and the lowest mean pressure drop values were recorded with the Breezhaler® inhaler, followed by the Ellipta® inhaler and the HandiHaler® inhaler, in the overall patient population. A similar trend was consistently observed in patients across all subgroups of COPD severity, within all age groups and for both genders. Patients with COPD were able to inhale with the least inspiratory effort and generate the highest mean PIF value through the Breezhaler® inhaler when compared with the Ellipta® and the HandiHaler® inhalers. These results were similar irrespective of patients' COPD severity, age or gender. The trial was registered with ClinicalTrials.gov NCT02596009 on 4 November 2015.

Supraventricular tachycardia after fenoterol inhalation: report of two cases.

PubMed

Hung, Yu-Fa; Yang, Winnie; Chang, Mei-Ling

2003-01-01

Supraventricular tachycardia (SVT) following fenoterol inhalation in metered-dose inhaler (MDI) has never been reported. We report two cases of SVT after fenoterol inhalation in MDI. Case one was a 4-year-old boy who had asthma since early childhood. Paroxysmal supraventricular tachycardia (PSVT) was found after fenoterol inhalation (MDI), which returned to normal sinus rhythm following adenosine injection. The other one was a 9-year-old male who also had asthma since early childhood. He suffered from attacks of PSVT four times after fenoterol inhalation within one year. After verapamil injection and vagal maneuvers, PSVT was converted to normal sinus rhythm. There were no other episodes of SVT after discontinuing usage of fenoterol inhalation for 2 years in the follow-up. We report these two cases to remind pediatricians that cardiac arrhythmias should be evaluated following fenoterol inhalation (MDI).

"...you would probably want to do it. Cause that's what made them popular": Exploring perceptions of inhalant utility among young adolescent nonusers and occasional users.

PubMed

Siegel, Jason T; Alvaro, Eusebio M; Patel, Neil; Crano, William D

2009-01-01

With an eye toward future primary prevention efforts, this study explores perceptions of inhalant utility among young adolescents in the United States. The study makes use of data gathered via nine focus groups conducted in Tucson, Arizona in 2004 (N = 47, mean age = 13.2 years). Three main themes emerged concerning the perceived utility of inhalant use: (1) Inhalant use as a means of mental escape, (2) Inhalant use as a social tool, and (3) Inhalant use as a parental relations tool. Additionally, participants discussed an interaction hypothesis regarding inhalant use and popularity. Implications for future research are suggested and limitations described.

49 CFR 172.400 - General labeling requirements.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 172.411 1.6 EXPLOSIVES 1.6 172.411 2.1 FLAMMABLE GAS 172.417 2.2 NONFLAMMABLE GAS 172.415 2.3 POISON...)) POISON INHALATION HAZARD 172.429 6.1(other than material poisonous by inhalation) POISON 172.430 6.1 (inhalation hazard, Zone A or B) POISON INHALATION HAZARD 172.429 6.1 (other than inhalation hazard, Zone A or...

49 CFR 172.400 - General labeling requirements.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 172.411 1.6 EXPLOSIVES 1.6 172.411 2.1 FLAMMABLE GAS 172.417 2.2 NONFLAMMABLE GAS 172.415 2.3 POISON...)) POISON INHALATION HAZARD 172.429 6.1(other than material poisonous by inhalation) POISON 172.430 6.1 (inhalation hazard, Zone A or B) POISON INHALATION HAZARD 172.429 6.1 (other than inhalation hazard, Zone A or...

49 CFR 172.400 - General labeling requirements.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 172.411 1.6 EXPLOSIVES 1.6 172.411 2.1 FLAMMABLE GAS 172.417 2.2 NONFLAMMABLE GAS 172.415 2.3 POISON...)) POISON INHALATION HAZARD 172.429 6.1(other than material poisonous by inhalation) POISON 172.430 6.1 (inhalation hazard, Zone A or B) POISON INHALATION HAZARD 172.429 6.1 (other than inhalation hazard, Zone A or...

49 CFR 172.400 - General labeling requirements.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 172.411 1.6 EXPLOSIVES 1.6 172.411 2.1 FLAMMABLE GAS 172.417 2.2 NONFLAMMABLE GAS 172.415 2.3 POISON...)) POISON INHALATION HAZARD 172.429 6.1(other than material poisonous by inhalation) POISON 172.430 6.1 (inhalation hazard, Zone A or B) POISON INHALATION HAZARD 172.429 6.1 (other than inhalation hazard, Zone A or...

49 CFR 172.400 - General labeling requirements.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 172.411 1.6 EXPLOSIVES 1.6 172.411 2.1 FLAMMABLE GAS 172.417 2.2 NONFLAMMABLE GAS 172.415 2.3 POISON...)) POISON INHALATION HAZARD 172.429 6.1(other than material poisonous by inhalation) POISON 172.430 6.1 (inhalation hazard, Zone A or B) POISON INHALATION HAZARD 172.429 6.1 (other than inhalation hazard, Zone A or...

Objective Assessment of Patient Inhaler User Technique Using an Audio-Based Classification Approach.

PubMed

Taylor, Terence E; Zigel, Yaniv; Egan, Clarice; Hughes, Fintan; Costello, Richard W; Reilly, Richard B

2018-02-01

Many patients make critical user technique errors when using pressurised metered dose inhalers (pMDIs) which reduce the clinical efficacy of respiratory medication. Such critical errors include poor actuation coordination (poor timing of medication release during inhalation) and inhaling too fast (peak inspiratory flow rate over 90 L/min). Here, we present a novel audio-based method that objectively assesses patient pMDI user technique. The Inhaler Compliance Assessment device was employed to record inhaler audio signals from 62 respiratory patients as they used a pMDI with an In-Check Flo-Tone device attached to the inhaler mouthpiece. Using a quadratic discriminant analysis approach, the audio-based method generated a total frame-by-frame accuracy of 88.2% in classifying sound events (actuation, inhalation and exhalation). The audio-based method estimated the peak inspiratory flow rate and volume of inhalations with an accuracy of 88.2% and 83.94% respectively. It was detected that 89% of patients made at least one critical user technique error even after tuition from an expert clinical reviewer. This method provides a more clinically accurate assessment of patient inhaler user technique than standard checklist methods.

Effect of Mouse Strain in a Model of Chemical-induced Respiratory Allergy

PubMed Central

Nishino, Risako; Fukuyama, Tomoki; Watanabe, Yuko; Kurosawa, Yoshimi; Ueda, Hideo; Kosaka, Tadashi

2014-01-01

The inhalation of many types of chemicals is a leading cause of allergic respiratory diseases, and effective protocols are needed for the detection of environmental chemical–related respiratory allergies. In our previous studies, we developed a method for detecting environmental chemical–related respiratory allergens by using a long-term sensitization–challenge protocol involving BALB/c mice. In the current study, we sought to improve our model by characterizing strain-associated differences in respiratory allergic reactions to the well-known chemical respiratory allergen glutaraldehyde (GA). According to our protocol, BALB/c, NC/Nga, C3H/HeN, C57BL/6N, and CBA/J mice were sensitized dermally with GA for 3 weeks and then challenged with intratracheal or inhaled GA at 2 weeks after the last sensitization. The day after the final challenge, all mice were euthanized, and total serum IgE levels were assayed. In addition, immunocyte counts, cytokine production, and chemokine levels in the hilar lymph nodes (LNs) and bronchoalveolar lavage fluids (BALF) were also assessed. In conclusion, BALB/c and NC/Nga mice demonstrated markedly increased IgE reactions. Inflammatory cell counts in BALF were increased in the treated groups of all strains, especially BALB/c, NC/Nga, and CBA/J strains. Cytokine levels in LNs were increased in all treated groups except for C3H/HeN and were particularly high in BALB/c and NC/Nga mice. According to our results, we suggest that BALB/c and NC/Nga are highly susceptible to respiratory allergic responses and therefore are good candidates for use in our model for detecting environmental chemical respiratory allergens. PMID:25048268

Efficacy and Immunogenicity of Single-Dose AdVAV Intranasal Anthrax Vaccine Compared to Anthrax Vaccine Absorbed in an Aerosolized Spore Rabbit Challenge Model

PubMed Central

Krishnan, Vyjayanthi; Andersen, Bo H.; Shoemaker, Christine; Sivko, Gloria S.; Tordoff, Kevin P.; Stark, Gregory V.; Zhang, Jianfeng; Feng, Tsungwei; Duchars, Matthew

2015-01-01

AdVAV is a replication-deficient adenovirus type 5-vectored vaccine expressing the 83-kDa protective antigen (PA83) from Bacillus anthracis that is being developed for the prevention of disease caused by inhalation of aerosolized B. anthracis spores. A noninferiority study comparing the efficacy of AdVAV to the currently licensed Anthrax Vaccine Absorbed (AVA; BioThrax) was performed in New Zealand White rabbits using postchallenge survival as the study endpoint (20% noninferiority margin for survival). Three groups of 32 rabbits were vaccinated with a single intranasal dose of AdVAV (7.5 × 107, 1.5 × 109, or 3.5 × 1010 viral particles). Three additional groups of 32 animals received two doses of either intranasal AdVAV (3.5 × 1010 viral particles) or intramuscular AVA (diluted 1:16 or 1:64) 28 days apart. The placebo group of 16 rabbits received a single intranasal dose of AdVAV formulation buffer. All animals were challenged via the inhalation route with a targeted dose of 200 times the 50% lethal dose (LD50) of aerosolized B. anthracis Ames spores 70 days after the initial vaccination and were followed for 3 weeks. PA83 immunogenicity was evaluated by validated toxin neutralizing antibody and serum anti-PA83 IgG enzyme-linked immunosorbent assays (ELISAs). All animals in the placebo cohort died from the challenge. Three of the four AdVAV dose cohorts tested, including two single-dose cohorts, achieved statistical noninferiority relative to the AVA comparator group, with survival rates between 97% and 100%. Vaccination with AdVAV also produced antibody titers with earlier onset and greater persistence than vaccination with AVA. PMID:25673303

Systemic inflammatory responses following welding inhalation challenge test.

PubMed

Kauppi, Paula; Järvelä, Merja; Tuomi, Timo; Luukkonen, Ritva; Lindholm, Tuula; Nieminen, Riina; Moilanen, Eeva; Hannu, Timo

2015-01-01

The aim of this study was to investigate inflammatory and respiratory responses to welding fume exposure in patients with suspected occupational asthma. Sixteen patients referred to the Finnish Institute of Occupational Health underwent mild steel (MS) and stainless steel (SS) welding challenge tests, due to suspicion of OA. Platelet count, leucocytes and their differential count, hemoglobin, sensitive CRP, lipids, glucose and fibrinogen were analyzed in addition to interleukin (IL)-1β, IL-6, IL-8, TNF-α, endothelin-1, and E-selectin in plasma samples. Peak expiratory flow (PEF), forced expiratory volume in 1 min (FEV 1 ) and exhaled nitric oxide (NO) measurements were performed before and after the challenge test. Personal particle exposure was assessed using IOM and a mini sampler. Particle size distribution was measured by an Electric Low Pressure Impactor (ELPI). The number of leukocytes, neutrophils, and platelets increased significantly, and the hemoglobin level and number of erythrocytes decreased significantly after both the MS and SS exposure tests. Five of the patients were diagnosed with OA, and their maximum fall in FEV 1 values was 0.70 l (±0.32) 4 h after SS exposure. MS welding generated an average inhalable particle mass concentration of 31.6, and SS welding of 40.2 mg/m 3 . The mean particle concentration measured inside the welding face shields by the mini sampler was 30.2 mg/m 3 and 41.7 mg/m 3 , respectively. Exposure to MS and SS welding fume resulted in a mild systemic inflammatory response. The particle concentration from the breathing zones correlated with the measurements inside the welding face shields.

Effect of mouse strain in a model of chemical-induced respiratory allergy.

PubMed

Nishino, Risako; Fukuyama, Tomoki; Watanabe, Yuko; Kurosawa, Yoshimi; Ueda, Hideo; Kosaka, Tadashi

2014-01-01

The inhalation of many types of chemicals is a leading cause of allergic respiratory diseases, and effective protocols are needed for the detection of environmental chemical-related respiratory allergies. In our previous studies, we developed a method for detecting environmental chemical-related respiratory allergens by using a long-term sensitization-challenge protocol involving BALB/c mice. In the current study, we sought to improve our model by characterizing strain-associated differences in respiratory allergic reactions to the well-known chemical respiratory allergen glutaraldehyde (GA). According to our protocol, BALB/c, NC/Nga, C3H/HeN, C57BL/6N, and CBA/J mice were sensitized dermally with GA for 3 weeks and then challenged with intratracheal or inhaled GA at 2 weeks after the last sensitization. The day after the final challenge, all mice were euthanized, and total serum IgE levels were assayed. In addition, immunocyte counts, cytokine production, and chemokine levels in the hilar lymph nodes (LNs) and bronchoalveolar lavage fluids (BALF) were also assessed. In conclusion, BALB/c and NC/Nga mice demonstrated markedly increased IgE reactions. Inflammatory cell counts in BALF were increased in the treated groups of all strains, especially BALB/c, NC/Nga, and CBA/J strains. Cytokine levels in LNs were increased in all treated groups except for C3H/HeN and were particularly high in BALB/c and NC/Nga mice. According to our results, we suggest that BALB/c and NC/Nga are highly susceptible to respiratory allergic responses and therefore are good candidates for use in our model for detecting environmental chemical respiratory allergens.

Diesel exhaust augments allergen-induced lower airway inflammation in allergic individuals: a controlled human exposure study.

PubMed

Carlsten, Chris; Blomberg, Anders; Pui, Mandy; Sandstrom, Thomas; Wong, Sze Wing; Alexis, Neil; Hirota, Jeremy

2016-01-01

Traffic-related air pollution has been shown to augment allergy and airway disease. However, the enhancement of allergenic effects by diesel exhaust in particular is unproven in vivo in the human lung, and underlying details of this apparent synergy are poorly understood. To test the hypothesis that a 2 h inhalation of diesel exhaust augments lower airway inflammation and immune cell activation following segmental allergen challenge in atopic subjects. 18 blinded atopic volunteers were exposed to filtered air or 300 µg PM(2.5)/m(3) of diesel exhaust in random fashion. 1 h post-exposure, diluent-controlled segmental allergen challenge was performed; 2 days later, samples from the challenged segments were obtained by bronchoscopic lavage. Samples were analysed for markers and modifiers of allergic inflammation (eosinophils, Th2 cytokines) and adaptive immune cell activation. Mixed effects models with ordinal contrasts compared effects of single and combined exposures on these end points. Diesel exhaust augmented the allergen-induced increase in airway eosinophils, interleukin 5 (IL-5) and eosinophil cationic protein (ECP) and the GSTT1 null genotype was significantly associated with the augmented IL-5 response. Diesel exhaust alone also augmented markers of non-allergic inflammation and monocyte chemotactic protein (MCP)-1 and suppressed activity of macrophages and myeloid dendritic cells. Inhalation of diesel exhaust at environmentally relevant concentrations augments allergen-induced allergic inflammation in the lower airways of atopic individuals and the GSTT1 genotype enhances this response. Allergic individuals are a susceptible population to the deleterious airway effects of diesel exhaust. NCT01792232. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A Tablet-Based Multimedia Education Tool Improves Provider and Subject Knowledge of Inhaler Use Techniques.

PubMed

Mulhall, Aaron M; Zafar, Muhammad A; Record, Samantha; Channell, Herman; Panos, Ralph J

2017-02-01

Although inhaled medications are effective therapies for COPD, many patients and providers use them incorrectly. We recruited providers who prescribe inhalers or teach inhaler technique and assessed their use of metered-dose inhalers (MDIs), various dry powder inhalers (DPIs), and Respimat using predefined checklists. Then they watched tablet-based multimedia educational videos that demonstrated correct inhaler technique by a clinical pharmacist with teach-back from a patient and were re-evaluated. We also recruited patients with COPD and assessed their use of their prescribed inhalers and then retested them after 3-6 months. Baseline and follow-up respiratory symptoms were measured by the COPD Assessment Test. Fifty-eight providers and 50 subjects participated. For all providers, correct inhaler technique (reported as percentage correct steps) increased after the videos: MDI without a spacer (72% vs 97%) MDI with a spacer (72% vs 96%), formoterol DPI (50% vs 94%), mometasone DPI (43% vs 95%), tiotropium DPI (73% vs 99%), and Respimat (32% vs 93%) (before vs after, P < .001 for all comparisons). Subjects also improved their inhaler use technique after viewing the educational videos: MDI without a spacer (69% vs 92%), MDI with a spacer (73% vs 95%), and tiotropium DPI (83% vs 96%) (before vs after, P < .001 for all comparisons). The beneficial effect of this educational intervention declined slightly for subjects but was durably improved after several months. COPD Assessment Test scores did not demonstrate any change in respiratory symptoms. A tablet-based inhaler education tool improved inhaler technique for both providers and subjects. Although this intervention did show durable efficacy for improving inhaler use by patients, it did not reduce their respiratory symptoms. Copyright © 2017 by Daedalus Enterprises.

Child-Specific Exposure Factors Handbook (2000, External Review Draft)

EPA Science Inventory

Children are often more heavily exposed to environmental toxicants than adults. They consume more food and water and have higher inhalation rates per pound of body weight than adults. Young children play close to the ground and come into contact with contaminated soil outdoors an...

Comparative inhalation toxicity of multi-wall carbon nanotubes, graphene, graphite nanoplatelets and low surface carbon black

PubMed Central

2013-01-01

Background Carbon nanotubes, graphene, graphite nanoplatelets and carbon black are seemingly chemically identical carbon-based nano-materials with broad technological applications. Carbon nanotubes and carbon black possess different inhalation toxicities, whereas little is known about graphene and graphite nanoplatelets. Methods In order to compare the inhalation toxicity of the mentioned carbon-based nanomaterials, male Wistar rats were exposed head-nose to atmospheres of the respective materials for 6 hours per day on 5 consecutive days. Target concentrations were 0.1, 0.5, or 2.5 mg/m3 for multi-wall carbon nanotubes and 0.5, 2.5, or 10 mg/m3 for graphene, graphite nanoplatelets and low-surface carbon black. Toxicity was determined after end of exposure and after three-week recovery using broncho-alveolar lavage fluid and microscopic examinations of the entire respiratory tract. Results No adverse effects were observed after inhalation exposure to 10 mg/m3 graphite nanoplatelets or relatively low specific surface area carbon black. Increases of lavage markers indicative for inflammatory processes started at exposure concentration of 0.5 mg/m3 for multi-wall carbon nanotubes and 10 mg/m3 for graphene. Consistent with the changes in lavage fluid, microgranulomas were observed at 2.5 mg/m3 multi-wall carbon nanotubes and 10 mg/m3 graphene. In order to evaluate volumetric loading of the lung as the key parameter driving the toxicity, deposited particle volume was calculated, taking into account different methods to determine the agglomerate density. However, the calculated volumetric load did not correlate to the toxicity, nor did the particle surface burden of the lung. Conclusions The inhalation toxicity of the investigated carbon-based materials is likely to be a complex interaction of several parameters. Until the properties which govern the toxicity are identified, testing by short-term inhalation is the best option to identify hazardous properties in order to avoid unsafe applications or select safer alternatives for a given application. PMID:23773277

Investigation into pedestrian exposure to near-vehicle exhaust emissions

PubMed Central

2009-01-01

Background Inhalation of diesel particulate matter (DPM) is known to have a negative impact on human health. Consequently, there are regulations and standards that limit the maximum concentrations to which persons may be exposed and the maximum concentrations allowed in the ambient air. However, these standards consider steady exposure over large spatial and time scales. Due to the nature of many vehicle exhaust systems, pedestrians in close proximity to a vehicle's tailpipe may experience events where diesel particulate matter concentrations are high enough to cause acute health effects for brief periods of time. Methods In order to quantify these exposure events, instruments which measure specific exhaust constituent concentrations were placed near a roadway and connected to the mouth of a mannequin used as a pedestrian surrogate. By measuring concentrations at the mannequin's mouth during drive-by events with a late model diesel truck, a representative estimate of the exhaust constituent concentrations to which a pedestrian may be exposed was obtained. Typical breathing rates were then multiplied by the measured concentrations to determine the mass of pollutant inhaled. Results The average concentration of diesel particulate matter measured over the duration of a single drive-by test often exceeded the low concentrations used in human clinical studies which are known to cause acute health effects. It was also observed that higher concentrations of diesel particulate matter were measured at the height of a stroller than were measured at the mouth of a mannequin. Conclusion Diesel particulate matter concentrations during drive-by incidents easily reach or exceed the low concentrations that can cause acute health effects for brief periods of time. For the case of a particularly well-tuned late-model year vehicle, the mass of particulate matter inhaled during a drive-by incident is small compared to the mass inhaled daily at ambient conditions. On a per breath basis, however, the mass of particulate matter inhaled is large compared to the mass inhaled at ambient conditions. Finally, it was determined that children, infants, or people breathing at heights similar to that of a passing vehicle's tailpipe may be exposed to higher concentrations of particulate matter than those breathing at higher locations, such as adults standing up. PMID:19331669

Risk assessment of inhalation exposure to Particulate Polycyclic Aromatic Hydrocarbons in school children

NASA Astrophysics Data System (ADS)

Jyethi, D. S.; Khillare, P. S.; Sarkar, S.

2013-12-01

Polycyclic aromatic hydrocarbons (PAHs) associated with the inhalable fraction of particulate matter were determined for one year (2009-10) at an urban site located in proximity of industrial and heavy traffic roads in Delhi, India. PM10 (aerodynamic diameter ≤10 μm) levels were ~11.6 times the World Health Organization standard. Vehicular (59.5%) and coal combustion (40.5%) sources accounted for the high levels of PAHs (range 38.1 ng m-3 - 217.3 ng m-3) with four and five ring PAHs having ~80 % contribution. Atmospheric distribution of total PAHs were heavily influenced (~75%) by the carcinogenic species and the B[a]P equivalent concentrations, through both TEF and MEF approach, exhibited highest exposure risks during winter. Extremely high daily inhalation exposure of PAHs was observed during winter (439.43 ng day-1) followed by monsoon (232.59 ng day-1) and summer (171.08 ng day-1). Daily inhalation exposure of PAHs to school children during a day exhibited the trend: school hours>commuting to school>resting period, in all the seasons. Vehicular source contributions to daily PAH levels were significantly correlated (r=0.94, p<0.001) with the daily inhalation exposure level of school children. It is important to note that health hazards posed by vehicular pollution are born disproportionately by children attending certain schools based on the location of the school. Interestingly, since India is a tropical country, most of the buildings are naturally ventilated and their air exchange rates are higher than heating, ventilation, and air conditioning (HVAC)-equipped buildings, resulting into a significant impact of outdoor air on indoor air quality. In the apparent absence of any indoor PAH sources, outdoor concentrations and in turn air exchange rates (that are specific for infiltration and natural ventilation pathways) play a key role in assessing PAH exposure. A conservative estimate of ~11 excess cancer cases in children during childhood and ~ 652 cases for a lifetime inhalation exposure of PAHs at the observed concentration have been calculated in Delhi.

How to use an inhaler - with spacer

MedlinePlus

... MDIs) usually have 3 parts: A mouthpiece A cap that goes over the mouthpiece A canister full ... Take the cap off the inhaler and spacer. Shake the inhaler hard. Attach the spacer to the inhaler. If you have ...

Modeling Deposition of Inhaled Particles

EPA Science Inventory

The mathematical modeling of the deposition and distribution of inhaled aerosols within human lungs is an invaluable tool in predicting both the health risks associated with inhaled environmental aerosols and the therapeutic dose delivered by inhaled pharmacological drugs. Howeve...

MODELING DEPOSITION OF INHALED PARTICLES

EPA Science Inventory

Modeling Deposition of Inhaled Particles: ABSTRACT

The mathematical modeling of the deposition and distribution of inhaled aerosols within human lungs is an invaluable tool in predicting both the health risks associated with inhaled environmental aerosols and the therapeut...

Age of Inhalant First Time Use and Its Association to the Use of Other Drugs

ERIC Educational Resources Information Center

Ding, Kele; Chang, G. Andy; Southerland, Ron

2009-01-01

Inhalants are the 4th most commonly abused drugs after alcohol, tobacco, and marijuana. Although inhalants are often referred as Gateway Drugs this hypothesis is less examined. Using the 2003 National Survey on Drug Use and Health data, age of first time inhalant use was compared with the age of onset of other drugs among 6466 inhalant users who…

Characterisation of dry powder inhaler formulations using atomic force microscopy.

PubMed

Weiss, Cordula; McLoughlin, Peter; Cathcart, Helen

2015-10-15

Inhalation formulations are a popular way of treating the symptoms of respiratory diseases. The active pharmaceutical ingredient (API) is delivered directly to the site of action within the deep lung using an inhalation device such as the dry powder inhaler (DPI). The performance of the formulation and the efficiency of the treatment depend on a number of factors including the forces acting between the components. In DPI formulations these forces are dominated by interparticulate interactions. Research has shown that adhesive and cohesive forces depend on a number of particulate properties such as size, surface roughness, crystallinity, surface energetics and combinations of these. With traditional methods the impact of particulate properties on interparticulate forces could be evaluated by examining the bulk properties. Atomic force microscopy (AFM), however, enables the determination of local surface characteristics and the direct measurement of interparticulate forces using the colloidal probe technique. AFM is considered extremely useful for evaluating the surface topography of a substrate (an API or carrier particle) and even allows the identification of crystal faces, defects and polymorphs from high-resolution images. Additionally, information is given about local mechanical properties of the particles and changes in surface composition and energetics. The assessment of attractive forces between two bodies is possible by using colloidal probe AFM. This review article summarises the application of AFM in DPI formulations while specifically focussing on the colloidal probe technique and the evaluation of interparticulate forces. Copyright © 2015 Elsevier B.V. All rights reserved.

Differential effects of phosphoramidon on neurokinin A- and substance P-induced airflow obstruction and airway microvascular leakage in guinea-pig.

PubMed Central

Lötvall, J. O.; Elwood, W.; Tokuyama, K.; Barnes, P. J.; Chung, K. F.

1991-01-01

1. The effects of the inhaled neuropeptides, neurokinin A (NKA) and substance P (SP) on lung resistance (RL) and airway microvascular permeability were studied in anaesthetized guinea-pigs. 2. Single doses of inhaled NKA (3 x 10(-5), 1 x 10(-4), 3 x 10(-4) M; 45 breaths) and SP (1 x 10(-4), 3 x 10(-4), 1 x 10(-3); 45 breaths) caused a dose-dependent increase in both RL and airway microvascular leakage, assessed as extravasation of the albumin marker, Evans blue dye. 3. NKA at 1 x 10(-4) and 3 x 10(-4) M resulted in a significantly higher increase in RL than SP at the same doses. 4. Inhaled SP (3 x 10(-4) M; 45 breaths) caused significantly higher Evans blue dye extravasation in main bronchi and proximal intrapulmonary airways compared to the same dose of NKA. 5. Pretreatment with the specific inhibitor of neural endopeptidase (NEP24.11), phosphoramidon, caused an approximately 100 fold leftward shift of the RL responses to inhaled NKA and SP. 6. Phosphoramidon significantly potentiated both NKA- and SP-induced airway microvascular leakage at proximal intrapulmonary airways, but not at any other airway level. 7. Inhibition of NEP24.11 potentiate both the SP- or NKA-induced airflow obstruction to a larger extent than the induced airway microvascular leakage, suggesting that NEP24.11 is more important in the modulation of the airflow obstruction observed after these mediators. PMID:1725766

Differential effects of phosphoramidon on neurokinin A- and substance P-induced airflow obstruction and airway microvascular leakage in guinea-pig.

PubMed

Lötvall, J O; Elwood, W; Tokuyama, K; Barnes, P J; Chung, K F

1991-12-01

1. The effects of the inhaled neuropeptides, neurokinin A (NKA) and substance P (SP) on lung resistance (RL) and airway microvascular permeability were studied in anaesthetized guinea-pigs. 2. Single doses of inhaled NKA (3 x 10(-5), 1 x 10(-4), 3 x 10(-4) M; 45 breaths) and SP (1 x 10(-4), 3 x 10(-4), 1 x 10(-3); 45 breaths) caused a dose-dependent increase in both RL and airway microvascular leakage, assessed as extravasation of the albumin marker, Evans blue dye. 3. NKA at 1 x 10(-4) and 3 x 10(-4) M resulted in a significantly higher increase in RL than SP at the same doses. 4. Inhaled SP (3 x 10(-4) M; 45 breaths) caused significantly higher Evans blue dye extravasation in main bronchi and proximal intrapulmonary airways compared to the same dose of NKA. 5. Pretreatment with the specific inhibitor of neural endopeptidase (NEP24.11), phosphoramidon, caused an approximately 100 fold leftward shift of the RL responses to inhaled NKA and SP. 6. Phosphoramidon significantly potentiated both NKA- and SP-induced airway microvascular leakage at proximal intrapulmonary airways, but not at any other airway level. 7. Inhibition of NEP24.11 potentiate both the SP- or NKA-induced airflow obstruction to a larger extent than the induced airway microvascular leakage, suggesting that NEP24.11 is more important in the modulation of the airflow obstruction observed after these mediators.

Inhalant abuse among adolescents: neurobiological considerations

PubMed Central

Lubman, D I; Yücel, M; Lawrence, A J

2008-01-01

Experimentation with volatile substances (inhalants) is common during early adolescence, yet limited work has been conducted examining the neurobiological impact of regular binge use during this key stage of development. Human studies consistently demonstrate that chronic use is associated with significant toxic effects, including neurological and neuropsychological impairment, as well as diffuse and subtle changes in white matter. However, most preclinical research has tended to focus on acute exposure, with limited work examining the neuropharmacological or toxicological mechanisms underpinning these changes or their potential reversibility with abstinence. Nevertheless, there is growing evidence that commonly abused inhalants share common cellular mechanisms, and have similar actions to other drugs of abuse. Indeed, the majority of acute behavioural effects appear to be underpinned by changes in receptor and/or ion channel activity (for example, GABAA, glycine and 5HT3 receptor activation, NMDA receptor inhibition), although nonspecific interactions can also arise at high concentrations. Recent studies examining the effects of toluene exposure during the early postnatal period are suggestive of long-term alterations in the function of NMDA and GABAA receptors, although limited work has been conducted investigating exposure during adolescence. Given the critical role of neurotransmitter systems in cognitive, emotional and brain development, future studies will need to take account of the substantial neuromaturational changes that are known to occur in the brain during childhood and adolescence, and to specifically investigate the neuropharmacological and toxicological profile of inhalant exposure during this period of development. PMID:18332858

Anti-stress and neuronal cell differentiation induction effects of Rosmarinus officinalis L. essential oil.

PubMed

Villareal, Myra O; Ikeya, Ayumi; Sasaki, Kazunori; Arfa, Abdelkarim Ben; Neffati, Mohamed; Isoda, Hiroko

2017-12-22

Mood disorder accounts for 13 % of global disease burden. And while therapeutic agents are available, usually orally administered, most have unwanted side effects, and thus making the inhalation of essential oils (EOs) an attractive alternative therapy. Rosmarinus officinalis EO (ROEO), Mediterranean ROEO reported to improve cognition, mood, and memory, the effect on stress of which has not yet been determined. Here, the anti-stress effect of ROEO on stress was evaluated in vivo and in vitro. Six-week-old male ICR mice were made to inhale ROEO and subjected to tail suspension test (TST). To determine the neuronal differentiation effect of ROEO in vitro, induction of ROEO-treated PC12 cells differentiation was observed. Intracellular acetylcholine and choline, as well as the Gap43 gene expression levels were also determined. Inhalation of ROEO significantly decreased the immobility time of ICR mice and serum corticosterone level, accompanied by increased brain dopamine level. Determination of the underlying mechanism in vitro revealed a PC12 differentiation-induction effect through the modulation of intracellular acetylcholine, choline, and Gap43 gene expression levels. ROEO activates the stress response system through the NGF pathway and the hypothalamus-pituitary-adrenal axis, promoting dopamine production and secretion. The effect of ROEO may be attributed to its bioactive components, specifically to α-pinene, one of its major compounds that has anxiolytic property. The results of this study suggest that ROEO inhalation has therapeutic potential against stress-related psychiatric disorders.

Sibship size and self-reported inhalant allergy among adult women. ALSPAC Study Team.

PubMed

Strachan, D P; Harkins, L S; Golding, J

1997-02-01

An association of allergic sensitization with small families and low birth order has been described and attributed to a protective effect of early infection. The influence of like-sex and unlike-sex siblings has not been investigated, although the severity of viral infections may be greater if acquired from unlike-sex siblings. To investigate the association of self-reported inhalant allergy with family composition. Reports of allergy to grass, dust or cats by 11042 pregnant women recruited to a longitudinal study of pregnancy and childhood in Avon, UK, were analysed in relation to respondent's age, maternal age and sibship composition (older and younger brothers and sisters) by multiple logistic regression. The prevalence of self-reported inhalant allergy decreased with increasing numbers of brothers (test for trend: P < 0.0001), but was unrelated to the number of sisters. The unadjusted prevalences for subjects with none, one, two and three or more brothers were 26%, 23%, 20% and 17%, respectively. The corresponding prevalences for numbers of sisters were 23%, 24%, 22% and 23%. After adjustment for total sibship size, offspring of older mothers were more likely to report allergy (test for trend: P < 0.001), but there was no association with position in the sibship. Although it is not possible to determine whether brothers specifically, or unlike-sex siblings in general, are inversely associated with inhalant allergy, these findings are consistent with the hypothesis that patterns of sibling interaction within young families influence the risk of future aeroallergen sensitization.

Skills in Handling Turbuhaler, Diskus, and Pressurized Metered-Dose Inhaler in Korean Asthmatic Patients

PubMed Central

Lee, Sang Min; Chang, Yoon-Seok; Kim, Cheol-Woo; Kim, Tae-Bum; Kim, Sang-Heon; Kwon, Yong-Eun; Lee, Jong-Myung; Lee, Soo-Keol; Jeong, Jae-Won; Park, Jung-Won; Cho, Sang-Heon; Moon, Hee-Bom

2011-01-01

Purpose The objective of this study was to evaluate skills in handling inhalers and factors associated with these skills among patients with asthma who had undergone treatment at special asthma and allergy clinics in Korea. Methods We enrolled 78 subjects who used Turbuhaler and 145 who used Diskus for asthma control at special clinics in 10 university hospitals and visually assessed their skills in handling these inhalers. We also evaluated skills in 137 subjects who had used pressurized metered-dose inhalers (pMDIs) for symptom relief. Age, sex, duration of asthma and inhaler use, smoking status, monthly income, highest grade completed in school and previous instruction for handling inhalers were also measured to evaluate their association with overall inhaler skills. Results Performance grade was inadequate for 12.8% of participants using Turbuhaler, 6.2% for Diskus, and 23.4% for pMDIs. The success rates for each step in handling the inhalers were relatively high except for the "exhale slowly to residual volume" step, in which success rates ranged from 24.2% to 28.5%. Older age, male sex, lower educational grade, and absence of previous instruction for handling inhalers were associated with inadequate inhaler technique in univariate analysis; however, only older age and absence of previous instruction remained significant independent risk factors in multivariate analysis. Conclusions Among Korean asthmatic patients in special asthma and allergy clinics, skills in handling their inhalers were mostly excellent; meanwhile, older age and absence of previous instruction for handling inhalers were associated with inadequate techniques. PMID:21217925

Exploring the role of quantitative feedback in inhaler technique education: a cluster-randomised, two-arm, parallel-group, repeated-measures study.

PubMed

Toumas-Shehata, Mariam; Price, David; Basheti, Iman Amin; Bosnic-Anticevich, Sinthia

2014-11-13

Feedback is a critical component of any educational intervention. When it comes to feedback associated with inhaler technique education, there is a lack of knowledge on its role or its potential to solve the major issue of poor inhaler technique. This study aims to explore the role of feedback in inhaler technique education and its impact on the inhaler technique of patients over time. A parallel-group, repeated-measures study was conducted in the community pharmacy in which the effectiveness of current best practice inhaler technique education utilising qualitative visual feedback (Group 1) was compared with a combination of qualitative and quantitative visual feedback (Group 2). The impact of these two interventions on inhaler technique maintenance was evaluated. Community pharmacists were randomly allocated to recruit people with asthma who were using a dry powder inhaler. At Visit 1 their inhaler technique was evaluated and education delivered and they were followed up at Visit 2 (1 month later). Both educational interventions resulted in an increase in the proportion of patients with correct inhaler technique: from 4% to 51% in Group 1 and from 6% to 83% in Group 2 (Pearson's Chi-Squared, P=0.03, n=49, and Pearson's Chi-Squared, P=0.01, n=48, respectively). The magnitude of improvement was statistically significantly higher for Group 2 compared with Group 1 (n=97, P=0.02, Pearson's Chi-Square test). The nature of feedback has an impact on the effectiveness of inhaler technique education with regard to correct inhaler technique maintenance over time.

Nurses' knowledge of inhaler technique in the inpatient hospital setting.

PubMed

De Tratto, Katie; Gomez, Christy; Ryan, Catherine J; Bracken, Nina; Steffen, Alana; Corbridge, Susan J

2014-01-01

High rates of inhaler misuse in patients with chronic obstructive pulmonary disease and asthma contribute to hospital readmissions and increased healthcare cost. The purpose of this study was to examine inpatient staff nurses' self-perception of their knowledge of proper inhaler technique compared with demonstrated technique and frequency of providing patients with inhaler technique teaching during hospitalization and at discharge. A prospective, descriptive study. A 495-bed urban academic medical center in the Midwest United States. A convenience sample of 100 nurses working on inpatient medical units. Participants completed a 5-item, 4-point Likert-scale survey evaluating self-perception of inhaler technique knowledge, frequency of providing patient education, and responsibility for providing education. Participants demonstrated inhaler technique to the investigators using both a metered dose inhaler (MDI) and Diskus device inhaler, and performance was measured via a validated checklist. Overall misuse rates were high for both MDI and Diskus devices. There was poor correlation between perceived ability and investigator-measured performance of inhaler technique. Frequency of education during hospitalization and at discharge was related to measured level of performance for the Diskus device but not for the MDI. Nurses are a key component of patient education in the hospital; however, nursing staff lack adequate knowledge of inhaler technique. Identifying gaps in nursing knowledge regarding proper inhaler technique and patient education about proper inhaler technique is important to design interventions that may positively impact patient outcomes. Interventions could include one-on-one education, Web-based education, unit-based education, or hospital-wide competency-based education. All should include return demonstration of appropriate technique.

Bronchodilator responses after methacholine and adenosine 5'-monophosphate (AMP) challenges in children with asthma: their relationships with eosinophil markers.

PubMed

Yoo, Young; Seo, Sung Chul; Kim, Young Il; Chung, Bo Hyun; Song, Dae Jin; Choung, Ji Tae

2012-09-01

Bronchodilator responsiveness (BDR) and eosinophilic inflammation are characteristic features of asthma. Objective. The aim of this study was to compare the relationships of BDR after methacholine challenge or adenosine 5'-monophosphate (AMP) challenge to blood eosinophil markers in children with asthma. Methacholine and AMP challenges were performed on 69 children with mild intermittent to moderate persistent asthma. BDR was calculated as the change in forced expiratory volume in 1 second, expressed as percentage change of the value immediately after the each challenge and the value after inhalation of salbutamol. Serum total IgE levels, blood eosinophil counts, and serum eosinophil cationic protein (ECP) levels were determined for each subject. A positive relationship between serum total IgE levels and BDR was found only after the AMP challenge (R(2) = 0.345, p = .001) rather than after the methacholine challenge (R(2) = 0.007, p = .495). Peripheral blood eosinophil counts correlated more significantly with BDR after AMP challenge (R(2) = 0.212, p = .001) than BDR after methacholine challenge (R(2) = 0.002, p = .724). Both BDR after methacholine challenge (R(2) = 0.063, p = .038) and BDR after AMP challenge (R(2) = 0.192, p = .001) were significantly correlated with serum ECP levels. BDR after AMP challenge may be more closely related to eosinophilic inflammation, compared with that after methacholine challenge.

3-D SIMULATIONS OF AIRWAYS WITHIN HUMAN LUNGS

EPA Science Inventory

Information regarding the deposition patterns of inhaled particles has important application to the fields of toxicology and medicine. The former concerns the risk assessment of inhaled air pollutants (inhalation toxicology); the latter concerns the targeted delivery of inhaled ...

Cyanide Antidotes for Mass Casualties: Comparison of Intramuscular Injector by Autoinjector, Intraosseous Injection, and Inhalational Delivery

DTIC Science & Technology

2015-12-01

oxygen consump- tion,46,47 we studied the effects of cyanide on cellular oxygen consumption using an XF extracellular flux analyzer (Seahorse...baseline values during whole blood resuscitation (−0.24 0.14 μM at the end of resuscita- tion). Figure 2 also shows the effect of inspired oxygen concen...during respiratory challenges. This composite effect demonstrates uncoupling of the hemo- globin oxygen signal changes from CcO redox state signals