Interim methods for development of inhalation reference concentrations. Draft report

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

Blackburn, K.; Dourson, M.; Erdreich, L.

1990-08-01

An inhalation reference concentration (RfC) is an estimate of continuous inhalation exposure over a human lifetime that is unlikely to pose significant risk of adverse noncancer health effects and serves as a benchmark value for assisting in risk management decisions. Derivation of an RfC involves dose-response assessment of animal data to determine the exposure levels at which no significant increase in the frequency or severity of adverse effects between the exposed population and its appropriate control exists. The assessment requires an interspecies dose extrapolation from a no-observed-adverse-effect level (NOAEL) exposure concentration of an animal to a human equivalent NOAEL (NOAEL(HBC)).more » The RfC is derived from the NOAEL(HBC) by the application of generally order-of-magnitude uncertainty factors. Intermittent exposure scenarios in animals are extrapolated to chronic continuous human exposures. Relationships between external exposures and internal doses depend upon complex simultaneous and consecutive processes of absorption, distribution, metabolism, storage, detoxification, and elimination. To estimate NOAEL(HBC)s when chemical-specific physiologically-based pharmacokinetic models are not available, a dosimetric extrapolation procedure based on anatomical and physiological parameters of the exposed human and animal and the physical parameters of the toxic chemical has been developed which gives equivalent or more conservative exposure concentrations values than those that would be obtained with a PB-PK model.« less

Impact of multiple-dose versus single-dose inhaler devices on COPD patients’ persistence with long-acting β2-agonists: a dispensing database analysis

PubMed Central

van Boven, Job FM; van Raaij, Joost J; van der Galiën, Ruben; Postma, Maarten J; van der Molen, Thys; Dekhuijzen, PN Richard; Vegter, Stefan

2014-01-01

Background: With a growing availability of different devices and types of medication, additional evidence is required to assist clinicians in prescribing the optimal medication in relation to chronic obstructive pulmonary disease (COPD) patients’ persistence with long-acting β2-agonists (LABAs). Aims: To assess the impact of the type of inhaler device (multiple-dose versus single-dose inhalers) on 1-year persistence and switching patterns with LABAs. Methods: A retrospective observational cohort study was performed comparing a cohort of patients initiating multiple-dose inhalers and a cohort initiating single-dose inhalers. The study population consisted of long-acting bronchodilator naive COPD patients, initiating inhalation therapy with mono-LABAs (formoterol, indacaterol or salmeterol). Analyses were performed using pharmacy dispensing data from 1994 to 2012, obtained from the IADB.nl database. Study outcomes were 1-year persistence and switching patterns. Results were adjusted for initial prescriber, initial medication, dosing regimen and relevant comorbidities. Results: In all, 575 patients initiating LABAs were included in the final study cohort. Among them, 475 (83%) initiated a multiple-dose inhaler and 100 (17%) a single-dose inhaler. Further, 269 (47%) initiated formoterol, 9 (2%) indacaterol and 297 (52%) salmeterol. There was no significant difference in persistence between users of multiple-dose or single-dose inhalers (hazard ratio: 0.98, 95% confidence interval: 0.76–1.26, P=0.99). Over 80% re-started or switched medication. Conclusions: There seems no impact of inhaler device (multiple-dose versus single-dose inhalers) on COPD patients’ persistence with LABAs. Over 80% of patients who initially seemed to discontinue LABAs, re-started their initial medication or switched inhalers or medication within 1 year. PMID:25274453

Risk assessment of manganese: A comparison of oral and inhalation derivations

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

Poirier, K.A.; Velazquez, S.F.

1991-03-11

An oral and inhalation human exposure-response risk assessment was calculated for manganese (Mn) using USEPA methodologies for both oral reference dose (RfD) and inhalation reference concentration (RfC) determination. When ingested, Mn is among the least toxic of the essential trace elements. The RfD for Mn is based on ingestion data from normal human diets, balance studies and neurotoxicity resulting from drinking contaminated well water. From these data, a NOAEL of 0.14 mg/kb/day was estimated. Since the NOAEL was thought to account for human sensitivity and Mn is an essential element required for normal human growth, an uncertainty factor (UF) ofmore » 1 was used resulting in a RfD of 1E-1 mg/kg/day. Although neurotoxic effects are rarely observed from oral exposures, they are more commonly associated with exposure to Mn by inhalation. Toxicity from inhaled Mn results in an increased prevalence of respiratory symptoms, reproductive dysfunction and psychomotor disturbances that can ultimately be expressed in a frank effect of manganism characterized by Parkinson disease-like symptoms. Using data from occupational exposure to in organic Mn, a dose duration adjusted LOAEL of 0.34 mg/m{sup 3} is identified. Application of an UF of 300 results in an RfC of 4E-4 mg/m{sup 3}. The RfD and RfC analyses demonstrate a dichotomous data set of toxicological effects dependent upon the route of exposure to Mn. Furthermore, these analyses demonstrate the unique issues of characterizing toxicological risk assessment for essential trace elements.« less

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.

Inhaled corticosteroid metered-dose inhalers: how do variations in technique for solutions versus suspensions affect drug distribution?

PubMed

Robinson, Christie A; Tsourounis, Candy

2013-03-01

To assess the literature that evaluates how variations in metered-dose inhaler (MDI) technique affect lung distribution for inhaled corticosteroids (ICSs) formulated as MDI suspensions and solutions. PubMed (up to November 2012) and Cochrane Library (up to November 2012) were searched using the terms metered-dose inhalers, HFA 134a, Asthma/*drug therapy, and inhaled corticosteroids. In addition, reference citations from publications identified were reviewed. All articles in English from the data sources that assessed MDI technique comparing total lung distribution (TLD) of MDI solutions or suspensions formulated with ICSs were included in the review. Five relevant studies were identified. Five controlled studies compared how variations in MDI technique affect TLD for ICS MDI solutions with suspensions. MDI solutions resulted in greater TLD compared with larger particle MDI suspensions. Delayed or early inspiration upon device actuation of MDI solutions resulted in less TLD than coordinated actuation, but with a 3- to 4-times greater TLD than MDI suspensions inhaled using a standard technique. A sixth study evaluated inspiratory flow rates (IFR) for small, medium, and large particles. Rapid and slow IFRs resulted in similar TLD for small particles, while far fewer particles reached the airways with medium and large particles at rapid, rather than slow, IFRs. Based on the literature evaluated, standard MDI technique should be used for ICS suspensions. ICS MDI solutions can provide a higher average TLD than larger-particle ICS suspensions using standard technique, discoordinated inspiration and medication actuation timing, or rapid and slow IFRs. ICS MDI solutions allow for a more forgiving technique, which makes them uniquely suitable options for patients with asthma who have difficultly with MDI technique.

COPD Medicine

MedlinePlus

... Rotahaler® Turbuhaler® Twisthaler® Metered-Dose Inhaler (MDI) HFA Propellant Metered-Dose Inhaler and Spacer AeroChamber® AeroChamber® with ... Rotahaler® Turbuhaler® Twisthaler® Metered-Dose Inhaler (MDI) HFA Propellant Metered-Dose Inhaler and Spacer AeroChamber® AeroChamber® with ...

Estimating human-equivalent no observed adverse-effect levels for VOCs (volatile organic compounds) based on minimal knowledge of physiological parameters. Technical paper

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

Overton, J.H.; Jarabek, A.M.

1989-01-01

The U.S. EPA advocates the assessment of health-effects data and calculation of inhaled reference doses as benchmark values for gauging systemic toxicity to inhaled gases. The assessment often requires an inter- or intra-species dose extrapolation from no observed adverse effect level (NOAEL) exposure concentrations in animals to human equivalent NOAEL exposure concentrations. To achieve this, a dosimetric extrapolation procedure was developed based on the form or type of equations that describe the uptake and disposition of inhaled volatile organic compounds (VOCs) in physiologically-based pharmacokinetic (PB-PK) models. The procedure assumes allometric scaling of most physiological parameters and that the value ofmore » the time-integrated human arterial-blood concentration must be limited to no more than to that of experimental animals. The scaling assumption replaces the need for most parameter values and allows the derivation of a simple formula for dose extrapolation of VOCs that gives equivalent or more-conservative exposure concentrations values than those that would be obtained using a PB-PK model in which scaling was assumed.« less

IRIS Toxicological Review of Dichloromethane (Methylene ...

EPA Pesticide Factsheets

EPA has finalized the Toxicological Review of Dichloromethane (Methylene Chloride): In support of the Integrated Risk Information System (IRIS). Now final, this assessment may be used by EPA’s program and regional offices to inform decisions to protect human health. This document presents background information and justification for the Intergrated Risk Information System (IRIS) Summary of the hazard and dose-response assessment of dichloromethane. IRIS Summaries may include oral reference dose (RfD) and inhalation reference concentration (RfC) values for chronic and other exposure durations, and a carcinogencity assessment. Internet/NCEA web site

Quick-Relief Medications for Lung Diseases

MedlinePlus

... Rotahaler® Turbuhaler® Twisthaler® Metered-Dose Inhaler (MDI) HFA Propellant Metered-Dose Inhaler and Spacer AeroChamber® AeroChamber® with ... Rotahaler® Turbuhaler® Twisthaler® Metered-Dose Inhaler (MDI) HFA Propellant Metered-Dose Inhaler and Spacer AeroChamber® AeroChamber® with ...

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.

Estimation of chloroform inhalation dose by other routes based on the relationship of area under the blood concentration-time curve (AUC)-inhalation dose to chloroform distribution in the blood of rats.

PubMed

Take, Makoto; Takeuchi, Tetsuya; Haresaku, Mitsuru; Matsumoto, Michiharu; Nagano, Kasuke; Yamamoto, Seigo; Takamura-Enya, Takeji; Fukushima, Shoji

2014-01-01

The present study investigated the time-course changes of concentration of chloroform (CHCl3) in the blood during and after exposure of male rats to CHCl3 by inhalation. Increasing the dose of CHCl3 in the inhalation exposed groups caused a commensurate increase in the concentration of CHCl3 in the blood and the area under the blood concentration-time curve (AUC). There was good correlation (r = 0.988) between the inhalation dose and the AUC/kg body weight. Based on the AUC/kg body weight-inhalation dose curve and the AUC/kg body weight after oral administration, inhalation equivalent doses of orally administered CHCl3 were calculated. Calculation of inhalation equivalent doses allows the body burden due to CHCl3 by inhalation exposure and oral exposure to be directly compared. This type of comparison facilitates risk assessment in humans exposed to CHCl3 by different routes. Our results indicate that when calculating inhalation equivalent doses of CHCl3, it is critical to include the AUC from the exposure period in addition to the AUC after the end of the exposure period. Thus, studies which measure the concentration of volatile organic compounds in the blood during the inhalation exposure period are crucial. The data reported here makes an important contribution to the physiologically based pharmacokinetic (PBPK) database of CHCl3 in rodents.

Pitfalls associated with the therapeutic reference pricing practice of asthma medication

PubMed Central

2012-01-01

Background Therapeutic reference pricing (TRP) based on the WHO daily defined dose (DDD) is a method frequently employed for the cost-containment of pharmaceuticals. Our objective was to compare average drug use in the real world with DDD and to evaluate whether TRP based on DDD could result in cost savings on maintenance medication and the total direct health expenditures for asthma patients treated with Symbicort Turbuhaler (SYT) and Seretide Diskus (SED) in Hungary. Methods Real-world data were derived from the Hungarian National Health Insurance Fund database. Average doses and costs were compared between the high-dose and medium-dose SYT and SED groups. Multiple linear regressions were employed to adjust the data for differences in the gender and age distribution of patients. Results 27,779 patients with asthma were included in the analysis. Average drug use was lower than DDD in all groups, 1.38-1.95 inhalations in both SED groups, 1.28-1.97 and 1.74-2.49 inhalations in the medium and high-dose SYT groups, respectively. Although the cost of SED based on the DDD would be much lower than the cost of SYT in the medium-dose groups, no difference was found in the actual cost of the maintenance therapy. No significant differences were found between the groups in terms of total medical costs. Conclusions Cost-containment initiatives by payers may influence clinical decisions. TRP for inhalation asthma drugs raises special concern, because of differences in the therapeutic profile of pharmaceuticals and the lack of proven financial benefits after exclusion of the effect of generic price erosion. Our findings indicate that the presented TRP approach of asthma medications based on the daily therapeutic costs according to the WHO DDD does not result in reduced public healthcare spending in Hungary. Further analysis is required to show whether TRP generates additional expenditures by inducing switching costs and reducing patient compliance. Potential confounding factors may limit the generalisability of our conclusions. PMID:22818402

Pitfalls associated with the therapeutic reference pricing practice of asthma medication.

PubMed

Kalo, Zoltan; Abonyi-Toth, Zsolt; Bartfai, Zoltan; Voko, Zoltan

2012-07-20

Therapeutic reference pricing (TRP) based on the WHO daily defined dose (DDD) is a method frequently employed for the cost-containment of pharmaceuticals. Our objective was to compare average drug use in the real world with DDD and to evaluate whether TRP based on DDD could result in cost savings on maintenance medication and the total direct health expenditures for asthma patients treated with Symbicort Turbuhaler (SYT) and Seretide Diskus (SED) in Hungary. Real-world data were derived from the Hungarian National Health Insurance Fund database. Average doses and costs were compared between the high-dose and medium-dose SYT and SED groups. Multiple linear regressions were employed to adjust the data for differences in the gender and age distribution of patients. 27,779 patients with asthma were included in the analysis. Average drug use was lower than DDD in all groups, 1.38-1.95 inhalations in both SED groups, 1.28-1.97 and 1.74-2.49 inhalations in the medium and high-dose SYT groups, respectively. Although the cost of SED based on the DDD would be much lower than the cost of SYT in the medium-dose groups, no difference was found in the actual cost of the maintenance therapy. No significant differences were found between the groups in terms of total medical costs. Cost-containment initiatives by payers may influence clinical decisions. TRP for inhalation asthma drugs raises special concern, because of differences in the therapeutic profile of pharmaceuticals and the lack of proven financial benefits after exclusion of the effect of generic price erosion. Our findings indicate that the presented TRP approach of asthma medications based on the daily therapeutic costs according to the WHO DDD does not result in reduced public healthcare spending in Hungary. Further analysis is required to show whether TRP generates additional expenditures by inducing switching costs and reducing patient compliance. Potential confounding factors may limit the generalisability of our conclusions.

Site-Specific Reference Person Parameters and Derived Concentration Standards for the Savannah River Site

DOE PAGES

Stone, Daniel K.; Higley, Kathryn A.; Jannik, G. Timothy

2014-05-01

The U.S. Department of Energy Order 458.1 states that the compliance with the 1 mSv annual dose constraint to a member of the public may be demonstrated by calculating dose to the maximally exposed individual (MEI) or to a representative person. Historically, the MEI concept was used for dose compliance at the Savannah River Site (SRS) using adult dose coefficients and adult male usage parameters. For future compliance, SRS plans to use the representative person concept for dose estimates to members of the public. The representative person dose will be based on the reference person dose coefficients from the U.S.more » DOE Derived Concentration Technical Standard and on usage parameters specific to SRS for the reference and typical person. Usage parameters and dose coefficients were determined for inhalation, ingestion and external exposure pathways. The parameters for the representative person were used to calculate and tabulate SRS-specific derived concentration standards (DCSs) for the pathways not included in DOE-STD-1196-2011.« less

Case study: three acute 241Am inhalation exposures with DTPA therapy.

PubMed

Carbaugh, Eugene H; Lynch, Timothy P; Cannon, Curt N; Lewis, Loren L

2010-10-01

Three workers incurred inhalation exposures to Am oxide as a result of waste sorting and compaction activities. The exposure magnitudes were not fully recognized until the following day when an in-vivo lung count identified a significant lung deposition of Am in a male worker, and DTPA chelation therapy was initiated. Two additional workers (one female and one male) were then identified as sufficiently exposed to also warrant therapy. In-vivo bioassay measurements were performed over the ensuing 6 mo to quantify the 241Am activity in the lungs, liver, and skeleton. Urine and fecal samples were collected and showed readily detectable 241Am. Clinical lab tests and medical evaluations all showed normal results. There were no significant adverse clinical health effects from the therapy. The estimated 241Am inhalation intakes for the three workers were 1,800 Bq, 630 Bq, and 150 Bq. Lung retention showed somewhat longer pulmonary clearance half-times than standard inhalation class W or absorption Type M assumptions. The three subjects underwent slightly different therapy regimens, with therapy effectiveness factors (defined as the ratio of the reference doses without therapy relative to the final assessed doses) of 4.5, 1.9, and 1.7, respectively.

SITE SPECIFIC REFERENCE PERSON PARAMETERS AND DERIVED CONCENTRATION STANDARDS FOR THE SAVANNAH RIVER SITE

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

Jannik, T.

2013-03-14

The purpose of this report is twofold. The first is to develop a set of behavioral parameters for a reference person specific for the Savannah River Site (SRS) such that the parameters can be used to determine dose to members of the public in compliance with Department of Energy (DOE) Order 458.1 “Radiation Protection of the Public and the Environment.” A reference person is a hypothetical, gender and age aggregation of human physical and physiological characteristics arrived at by international consensus for the purpose of standardizing radiation dose calculations. DOE O 458.1 states that compliance with the annual dose limitmore » of 100 mrem (1 mSv) to a member of the public may be demonstrated by calculating the dose to the maximally exposed individual (MEI) or to a representative person. Historically, for dose compliance, SRS has used the MEI concept, which uses adult dose coefficients and adult male usage parameters. Beginning with the 2012 annual site environmental report, SRS will be using the representative person concept for dose compliance. The dose to a representative person will be based on 1) the SRS-specific reference person usage parameters at the 95th percentile of appropriate national or regional data, which are documented in this report, 2) the reference person (gender and age averaged) ingestion and inhalation dose coefficients provided in DOE Derived Concentration Technical Standard (DOE-STD-1196-2011), and 3) the external dose coefficients provided in the DC_PAK3 toolbox. The second purpose of this report is to develop SRS-specific derived concentration standards (DCSs) for all applicable food ingestion pathways, ground shine, and water submersion. The DCS is the concentration of a particular radionuclide in water, in air, or on the ground that results in a member of the public receiving 100 mrem (1 mSv) effective dose following continuous exposure for one year. In DOE-STD-1196-2011, DCSs were developed for the ingestion of water, inhalation of air and submersion in air pathways, only. These DCSs are required by DOE O 458.1 to be used at all DOE sites in the design and conduct of radiological environmental protection programs. In this report, DCSs for the following additional pathways were considered and documented: ingestion of meat, dairy, grains, produce (fruits and vegetables), seafood, submersion in water and ground shine. These additional DCSs were developed using the same methods as in DOE-STD-1196-2011 and will be used at SRS, where appropriate, as screening and reference values.« less

Levels of ambient air pollution according to mode of transport: a systematic review.

PubMed

Cepeda, Magda; Schoufour, Josje; Freak-Poli, Rosanne; Koolhaas, Chantal M; Dhana, Klodian; Bramer, Wichor M; Franco, Oscar H

2017-01-01

Controversy exists about the differences in air pollution exposure and inhalation dose between mode of transport. We aimed to review air pollution exposure and inhaled dose according to mode of transport and pollutant and their effect in terms of years of life expectancy (YLE). In this systematic review, we searched ten online databases from inception to April 13, 2016, without language or temporal restrictions, for cohort, cross-sectional, and experimental studies that compared exposure to carbon monoxide, black carbon, nitrogen dioxide, and fine and coarse particles in active commuters (pedestrian or cyclist) and commuters using motorised transport (car, motorcycle, bus, or massive motorised transport [MMT-ie, train, subway, or metro]). We excluded studies that measured air pollution exposure exclusively with biomarkers or on the basis of simulated data, reviews, comments, consensuses, editorials, guidelines, in-vitro studies, meta-analyses, ecological studies, and protocols. We extracted average exposure and commuting time per mode of transport and pollutant to calculate inhaled doses. We calculated exposure and inhaled dose ratios using active commuters as the reference and summarised them with medians and IQRs. We also calculated differences in YLE due to fine particle inhaled dose and physical activity. We identified 4037 studies, of which 39 were included in the systematic review. Overall, car commuters had higher exposure to all pollutants than did active commuters in 30 (71%) of 42 comparisons (median ratio 1·22 [IQR 0·90-1·76]), followed by those who commuted by bus in 57 (52%) of 109 (1·0 [0·79-1·41]), by motorcycle in 16 (50%) of 32 (0·99 [0·86-1·38]), by a car with controlled ventilation settings in 39 (45%) of 86 (0·95 [0·66-1·54]), and by MMT in 21 (38%) of 55 (0·67 [0·49-1·13]). Overall, active commuters had higher inhalation doses than did commuters using motorised transport (median ratio car with controlled ventilation settings 0·16 [0·10-0·28]; car 0·22 [0·15-0·30]; motorcycle 0·38 [0·26-0·78]; MMT 0·49 [0·34-0·81]; bus 0·72 [IQR 0·50-0·99]). Commuters using motorised transport lost up to 1 year in YLE more than did cyclists. Proximity to traffic and high air interchange increased the exposure to air pollution of commuters using motorised transport. Larger inhalation rates and commuting time increased inhaled dose among active commuters. Benefits of active commuting from physical activity are larger than the risk from an increased inhaled dose of fine particles. Departamento Administrativo de Ciencia, Tecnología e Innovación (COLCIENCIAS), National Health and Medical Research Council, Nestlé Nutrition (Nestec), Metagenics, and AXA. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.

Selective cognitive deficits in adult rats after prenatal exposure to inhaled ethanol.

PubMed

Oshiro, W M; Beasley, T E; McDaniel, K L; Taylor, M M; Evansky, P; Moser, V C; Gilbert, M E; Bushnell, P J

2014-01-01

Increased use of ethanol blends in gasoline suggests a need to assess the potential public health risks of exposure to these fuels. Ethanol consumed during pregnancy is a teratogen. However, little is known about the potential developmental neurotoxicity of ethanol delivered by inhalation, the most likely route of exposure from gasoline-ethanol fuel blends. We evaluated the potential cognitive consequences of ethanol inhalation by exposing pregnant Long Evans rats to clean air or ethanol vapor from gestational days 9-20, a critical period of neuronal development. Concentrations of inhaled ethanol (5000, 10,000, or 21,000 ppm for 6.5h/day) produced modeled peak blood ethanol concentrations (BECs) in exposed dams of 2.3, 6.8, and 192 mg/dL, respectively. In offspring, no dose-related impairments were observed on spatial learning or working memory in the Morris water maze or in operant delayed match-to-position tests. Two measures showed significant effects in female offspring at all ethanol doses: 1) impaired cue learning after trace fear conditioning, and 2) an absence of bias for the correct quadrant after place training during a reference memory probe in the Morris water maze. In choice reaction time tests, male offspring (females were not tested) from the 5000 and 10,000 ppm groups showed a transient increase in decision times. Also, male offspring from the 21,000 ppm group made more anticipatory responses during a preparatory hold period, suggesting a deficit in response inhibition. The increase in anticipatory responding during the choice reaction time test shows that inhaled ethanol yielding a peak BEC of ~200mg/dL can produce lasting effects in the offspring. The lack of a dose-related decrement in the effects observed in females on cue learning and a reference memory probe may reflect confounding influences in the exposed offspring possibly related to maternal care or altered anxiety levels in females. The surprising lack of more pervasive cognitive deficits, as reported by others at BECs in the 200mg/dL range, may reflect route-dependent differences in the kinetics of ethanol. These data show that response inhibition was impaired in the offspring of pregnant rats that inhaled ethanol at concentrations at least 5 orders of magnitude higher than concentrations observed during normal automotive transport and fueling operations, which rarely exceed 100 ppb. Published by Elsevier Inc.

Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

PubMed

Jackson, Daniel J; Bacharier, Leonard B; Mauger, David T; Boehmer, Susan; Beigelman, Avraham; Chmiel, James F; Fitzpatrick, Anne M; Gaffin, Jonathan M; Morgan, Wayne J; Peters, Stephen P; Phipatanakul, Wanda; Sheehan, William J; Cabana, Michael D; Holguin, Fernando; Martinez, Fernando D; Pongracic, Jacqueline A; Baxi, Sachin N; Benson, Mindy; Blake, Kathryn; Covar, Ronina; Gentile, Deborah A; Israel, Elliot; Krishnan, Jerry A; Kumar, Harsha V; Lang, Jason E; Lazarus, Stephen C; Lima, John J; Long, Dayna; Ly, Ngoc; Marbin, Jyothi; Moy, James N; Myers, Ross E; Olin, J Tod; Raissy, Hengameh H; Robison, Rachel G; Ross, Kristie; Sorkness, Christine A; Lemanske, Robert F

2018-03-08

Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).

Pharmacokinetics and Bioavailability of Inhaled Esketamine in Healthy Volunteers.

PubMed

Jonkman, Kelly; Duma, Andreas; Olofsen, Erik; Henthorn, Thomas; van Velzen, Monique; Mooren, René; Siebers, Liesbeth; van den Beukel, Jojanneke; Aarts, Leon; Niesters, Marieke; Dahan, Albert

2017-10-01

Esketamine is traditionally administered via intravenous or intramuscular routes. In this study we developed a pharmacokinetic model of inhalation of nebulized esketamine with special emphasis on pulmonary absorption and bioavailability. Three increasing doses of inhaled esketamine (dose escalation from 25 to 100 mg) were applied followed by a single intravenous dose (20 mg) in 19 healthy volunteers using a nebulizer system and arterial concentrations of esketamine and esnorketamine were obtained. A multicompartmental pharmacokinetic model was developed using population nonlinear mixed-effects analyses. The pharmacokinetic model consisted of three esketamine, two esnorketamine disposition and three metabolism compartments. The inhalation data were best described by adding two absorption pathways, an immediate and a slower pathway, with rate constant 0.05 ± 0.01 min (median ± SE of the estimate). The amount of esketamine inhaled was reduced due to dose-independent and dose-dependent reduced bioavailability. The former was 70% ± 5%, and the latter was described by a sigmoid EMAX model characterized by the plasma concentration at which absorption was impaired by 50% (406 ± 46 ng/ml). Over the concentration range tested, up to 50% of inhaled esketamine is lost due to the reduced dose-independent and dose-dependent bioavailability. We successfully modeled the inhalation of nebulized esketamine in healthy volunteers. Nebulized esketamine is inhaled with a substantial reduction in bioavailability. Although the reduction in dose-independent bioavailability is best explained by retention of drug and particle exhalation, the reduction in dose-dependent bioavailability is probably due to sedation-related loss of drug into the air.

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.

Development of Room Temperature Stable Formulation of Formoterol Fumarate/Beclomethasone HFA pMDI

PubMed Central

Purohit, D.; Trehan, A.; Arora, V.

2009-01-01

The primary aim of present investigation was to develop and formulate room temperature stable formulation of formoterol fumarate and beclomethasone dipropionate with extra fine part size of hydrofluoroalkane pressurized metered dose inhalers. Particle size distribution of hydrofluoroalkane pressurized metered dose inhalers was evaluated using Twin Stage Glass Impinger and Anderson Cascade Impactor. A tetrafluoroethane and/or heptafluoropropane were evaluated for preparation of hydrofluoroalkane pressurized metered dose inhalers. The fine particle fractions delivered from hydrofluoroalkane propellant suspension pressurized metered dose inhalers can be predicted on the basis of formulation parameters and is dependent of metering chamber of valve and orifice size of actuators. The results presented in investigation showed the importance of formulation excipients with formulation of pressurized metered dose inhalers viz, canister, valve and actuators used in formulations.

Inhaled nitric oxide, oxygen, and alkalosis: dose-response interactions in a lamb model of pulmonary hypertension.

PubMed

Heidersbach, R S; Johengen, M J; Bekker, J M; Fineman, J R

1999-07-01

Inhaled nitric oxide (NO) is currently used as an adjuvant therapy for a variety of pulmonary hypertensive disorders. In both animal and human studies, inhaled NO induces selective, dose-dependent pulmonary vasodilation. However, its potential interactions with other simultaneously used pulmonary vasodilator therapies have not been studied. Therefore, the objective of this study was to determine the potential dose-response interactions of inhaled NO, oxygen, and alkalosis therapies. Fourteen newborn lambs (age 1-6 days) were instrumented to measure vascular pressures and left pulmonary artery blood flow. After recovery, the lambs were sedated and mechanically ventilated. During steady-state pulmonary hypertension induced by U46619 (a thromboxane A2 mimic), the lambs were exposed to the following conditions: Protocol A, inhaled NO (0, 5, 40, and 80 ppm) and inspired oxygen concentrations (FiO2) of 0.21, 0.50, and 1.00; and Protocol B, inhaled NO (0, 5, 40, and 80 ppm) and arterial pH levels of 7.30, 7.40, 7.50, and 7.60. Each condition (in randomly chosen order) was maintained for 10 min, and all variables were allowed to return to baseline between conditions. Inhaled NO, oxygen, and alkalosis produced dose-dependent decreases in mean pulmonary arterial pressures (P < 0.05). Systemic arterial pressure remained unchanged. At 5 ppm of inhaled NO, alkalosis and oxygen induced further dose-dependent decreases in mean pulmonary arterial pressures (P < 0.05). At inhaled NO doses > 5 ppm, alkalosis induced further dose-independent decreases in mean pulmonary arterial pressure, while oxygen did not. We conclude that in this animal model, oxygen, alkalosis, and inhaled NO induced selective, dose-dependent pulmonary vasodilation. However, when combined, a systemic arterial pH > 7.40 augmented inhaled NO-induced pulmonary vasodilation, while an FiO2 > 0.5 did not. Therefore, weaning high FiO2 during inhaled NO therapy should be considered, since it may not diminish the pulmonary vasodilating effects. Further studies are warranted to guide the clinical weaning strategies of these pulmonary vasodilator therapies.

Estimates of internal-dose equivalent from inhalation and ingestion of selected radionuclides

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

Dunning, D.E.

1982-01-01

This report presents internal radiation dose conversion factors for radionuclides of interest in environmental assessments of nuclear fuel cycles. This volume provides an updated summary of estimates of committed dose equivalent for radionuclides considered in three previous Oak Ridge National Laboratory (ORNL) reports. Intakes by inhalation and ingestion are considered. The International Commission on Radiological Protection (ICRP) Task Group Lung Model has been used to simulate the deposition and retention of particulate matter in the respiratory tract. Results corresponding to activity median aerodynamic diameters (AMAD) of 0.3, 1.0, and 5.0 ..mu..m are given. The gastorintestinal (GI) tract has been representedmore » by a four-segment catenary model with exponential transfer of radioactivity from one segment to the next. Retention of radionuclides in systemic organs is characterized by linear combinations of decaying exponential functions, recommended in ICRP Publication 30. The first-year annual dose rate, maximum annual dose rate, and fifty-year dose commitment per microcurie intake of each radionuclide is given for selected target organs and the effective dose equivalent. These estimates include contributions from specified source organs plus the systemic activity residing in the rest of the body; cross irradiation due to penetrating radiations has been incorporated into these estimates. 15 references.« less

Assessment of occupational exposure in a granite quarry and processing factory.

PubMed

Tejado, J J; Guillén, J; Baeza, A

2016-09-01

Workers in the granite industry face an occupational hazard: silicosis due to the crystalline silica present in inhalable dust. As granite can also present a variable, and occasionally significant, content of naturally occurring radionuclides, they may also face a radiological hazard. In order to assess the risk, a granite industry with a quarry and processing factory was selected to assess the occupational exposure. Three main potential pathways were observed: external irradiation, inhalation of granite dust, and radon exposure. The external dose rate was similar to that in a nearby farming area. A slight increment (0.016-0.076 mSv yr -1 ) was observed in the quarry and stockpile, due to quarry faces and granite blocks. The effective dose due to granite dust inhalation was 0.182  ±  0.009 mSv yr -1 in the worst case scenario (3 mg m -3 dust load in air and no use of filter masks). Thus, the mean value of the effective dose from these two pathways was 0.26 mSv yr -1 , lower than the reference level of 1 mSv yr -1 for the general population. The annual mean value of radon concentration in the indoor air was 33 Bq m -3 . However, during granite processing works the radon concentration can increase up to 216 Bq m -3 , due to mechanical operations (sawing, polishing, sanding, etc). This radon concentration was below the 600 Bq m -3 reference level for action in working places. Therefore, workers in this granite factory face no significant additional radiological exposure, and no-one needs to be designated as occupationally exposed and subject to individual dosimetry.

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.

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.

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

Spray dried amikacin powder for inhalation in cystic fibrosis patients: a quality by design approach for product construction.

PubMed

Belotti, Silvia; Rossi, Alessandra; Colombo, Paolo; Bettini, Ruggero; Rekkas, Dimitrios; Politis, Stavros; Colombo, Gaia; Balducci, Anna Giulia; Buttini, Francesca

2014-08-25

An amikacin product for convenient and compliant inhalation in cystic fibrosis patients was constructed by spray-drying in order to produce powders of pure drug having high respirability and flowability. An experimental design was applied as a statistical tool for the characterization of amikacin spray drying process, through the establishment of mathematical relationships between six Critical Quality Attributes (CQAs) of the finished product and five Critical Process Parameters (CPPs). The surface-active excipient, PEG-32 stearate, studied for particle engineering, in general did not benefit the CQAs of the spray dried powders for inhalation. The spray drying feed solution required the inclusion of 10% (v/v) ethanol in order to reach the desired aerodynamic performance of powders. All desirable function solutions indicated that the favourable concentration of amikacin in the feed solution had to be kept at 1% w/v level. It was found that when the feed rate of the sprayed solution was raised, an increase in the drying temperature to the maximum value (160 °C) was required to maintain good powder respirability. Finally, the increase in drying temperature always led to an evident increase in emitted dose (ED) without affecting the desirable fine particle dose (FPD) values. The application of the experimental design enabled us to obtain amikacin powders with both ED and FPD, well above the regulatory and scientific references. The finished product contained only the active ingredient, which keeps low the mass to inhale for dose requirement. Copyright © 2014 Elsevier B.V. All rights reserved.

Olfactory deposition of inhaled nanoparticles in humans

PubMed Central

Garcia, Guilherme J. M.; Schroeter, Jeffry D.; Kimbell, Julia S.

2016-01-01

Context Inhaled nanoparticles can migrate to the brain via the olfactory bulb, as demonstrated in experiments in several animal species. This route of exposure may be the mechanism behind the correlation between air pollution and human neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Objectives This manuscript aims to (1) estimate the dose of inhaled nanoparticles that deposit in the human olfactory epithelium during nasal breathing at rest and (2) compare the olfactory dose in humans with our earlier dose estimates for rats. Materials and methods An anatomically-accurate model of the human nasal cavity was developed based on computed tomography scans. The deposition of 1–100 nm particles in the whole nasal cavity and its olfactory region were estimated via computational fluid dynamics (CFD) simulations. Our CFD methods were validated by comparing our numerical predictions for whole-nose deposition with experimental data and previous CFD studies in the literature. Results In humans, olfactory dose of inhaled nanoparticles is highest for 1–2 nm particles with approximately 1% of inhaled particles depositing in the olfactory region. As particle size grows to 100 nm, olfactory deposition decreases to 0.01% of inhaled particles. Discussion and conclusion Our results suggest that the percentage of inhaled particles that deposit in the olfactory region is lower in humans than in rats. However, olfactory dose per unit surface area is estimated to be higher in humans due to their larger minute volume. These dose estimates are important for risk assessment and dose-response studies investigating the neurotoxicity of inhaled nanoparticles. PMID:26194036

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

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

Systemic Delivery of Atropine Sulfate by the MicroDose Dry-Powder Inhaler

PubMed Central

Venkataramanan, R.; Hoffman, R.M.; George, M.P.; Petrov, A.; Richards, T.; Zhang, S.; Choi, J.; Gao, Y.Y.; Oakum, C.D.; Cook, R.O.; Donahoe, M.

2013-01-01

Abstract Background Inhaled atropine is being developed as a systemic and pulmonary treatment for the extended recovery period after chemical weapons exposure. We performed a pharmacokinetics study comparing inhaled atropine delivery using the MicroDose Therapeutx Dry Powder Inhaler (DPIA) with intramuscular (IM) atropine delivery via auto-injector (AUTO). Methods The MicroDose DPIA utilizes a novel piezoelectric system to aerosolize drug and excipient from a foil dosing blister. Subjects inhaled a 1.95-mg atropine sulfate dose from the dry powder inhaler on one study day [5 doses×0.4 mg per dose (nominal) delivered over 12 min] and received a 2-mg IM injection via the AtroPen® auto-injector on another. Pharmacokinetics, pharmacodynamic response, and safety were studied for 12 hr. Results A total of 17 subjects were enrolled. All subjects completed IM dosing. One subject did not perform inhaled delivery due to a skin reaction from the IM dose. Pharmacokinetic results were as follows: area under the curve concentration, DPIA=20.1±5.8, AUTO=23.7±4.9 ng hr/mL (means±SD); maximum concentration reached, DPIA=7.7±3.5, AUTO=11.0±3.8 ng/mL; time to reach maximum concentration, DPIA=0.25±0.47, AUTO=0.19±0.23 hr. Pharmacodynamic results were as follows: maximum increase in heart rate, DPIA=18±12, AUTO=23±13 beats/min; average change in 1-sec forced expiratory volume at 30 min, DPIA=0.16±0.22 L, AUTO=0.11±0.29 L. The relative bioavailability for DPIA was 87% (based on output dose). Two subjects demonstrated allergic responses: one to the first dose (AUTO), which was mild and transient, and one to the second dose (DPIA), which was moderate in severity, required treatment with oral and intravenous (IV) diphenhydramine and IV steroids, and lasted more than 7 days. Conclusions Dry powder inhalation is a highly bioavailable route for attaining rapid and consistent systemic concentrations of atropine. PMID:22691110

Systemic delivery of atropine sulfate by the MicroDose Dry-Powder Inhaler.

PubMed

Corcoran, T E; Venkataramanan, R; Hoffman, R M; George, M P; Petrov, A; Richards, T; Zhang, S; Choi, J; Gao, Y Y; Oakum, C D; Cook, R O; Donahoe, M

2013-02-01

Inhaled atropine is being developed as a systemic and pulmonary treatment for the extended recovery period after chemical weapons exposure. We performed a pharmacokinetics study comparing inhaled atropine delivery using the MicroDose Therapeutx Dry Powder Inhaler (DPIA) with intramuscular (IM) atropine delivery via auto-injector (AUTO). The MicroDose DPIA utilizes a novel piezoelectric system to aerosolize drug and excipient from a foil dosing blister. Subjects inhaled a 1.95-mg atropine sulfate dose from the dry powder inhaler on one study day [5 doses × 0.4 mg per dose (nominal) delivered over 12 min] and received a 2-mg IM injection via the AtroPen® auto-injector on another. Pharmacokinetics, pharmacodynamic response, and safety were studied for 12 hr. A total of 17 subjects were enrolled. All subjects completed IM dosing. One subject did not perform inhaled delivery due to a skin reaction from the IM dose. Pharmacokinetic results were as follows: area under the curve concentration, DPIA=20.1±5.8, AUTO=23.7±4.9 ng hr/mL (means±SD); maximum concentration reached, DPIA=7.7±3.5, AUTO=11.0±3.8 ng/mL; time to reach maximum concentration, DPIA=0.25±0.47, AUTO=0.19±0.23 hr. Pharmacodynamic results were as follows: maximum increase in heart rate, DPIA=18±12, AUTO=23±13 beats/min; average change in 1-sec forced expiratory volume at 30 min, DPIA=0.16±0.22 L, AUTO=0.11±0.29 L. The relative bioavailability for DPIA was 87% (based on output dose). Two subjects demonstrated allergic responses: one to the first dose (AUTO), which was mild and transient, and one to the second dose (DPIA), which was moderate in severity, required treatment with oral and intravenous (IV) diphenhydramine and IV steroids, and lasted more than 7 days. Dry powder inhalation is a highly bioavailable route for attaining rapid and consistent systemic concentrations of atropine.

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

Carbaugh, Eugene H.; Lynch, Timothy P.; Cannon, Curt

Three workers incurred inhalation exposures to 241Am oxide as a result of waste sorting and compaction activities. The magnitudes of the exposures were not fully recognized until the following day when an in vivo chest count identified a significant lung deposition of 241Am in a male worker, and DTPA chelation therapy was initiated. Two additional workers (one female and one male) were then identified as sufficiently exposed to also warrant therapy. In vivo bioassay measurements were performed over the ensuing 6 months to quantify the 241Am activity in the lungs, liver, and skeleton. Urine and fecal samples were collected andmore » showed readily detectable 241Am. Clinical lab tests and medical evaluations all showed normal results. There were no significant adverse clinical health effects from the therapy. The estimated 241Am inhalation intakes for the three workers were 1800 Bq, 630 Bq, and 150 Bq. Lung retention showed somewhat longer pulmonary clearance half-times than standard inhalation class W or absorption Type M assumptions. The three underwent slightly different therapy regimes, with therapy effectiveness factors (defined as the ratio of the reference doses without therapy relative to the final assessed doses) of 4.65, 1.93, and 1.67, respectively.« less

Radiological Modeling for Determination of Derived Concentration Levels of an Area with Uranium Residual Material - 13533

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

Perez-Sanchez, Danyl

As a result of a pilot project developed at the old Spanish 'Junta de Energia Nuclear' to extract uranium from ores, tailings materials were generated. Most of these residual materials were sent back to different uranium mines, but a small amount of it was mixed with conventional building materials and deposited near the old plant until the surrounding ground was flattened. The affected land is included in an area under institutional control and used as recreational area. At the time of processing, uranium isotopes were separated but other radionuclides of the uranium decay series as Th-230, Ra-226 and daughters remainmore » in the residue. Recently, the analyses of samples taken at different ground's depths confirmed their presence. This paper presents the methodology used to calculate the derived concentration level to ensure that the reference dose level of 0.1 mSv y-1 used as radiological criteria. In this study, a radiological impact assessment was performed modeling the area as recreational scenario. The modelization study was carried out with the code RESRAD considering as exposure pathways, external irradiation, inadvertent ingestion of soil, inhalation of resuspended particles, and inhalation of radon (Rn-222). As result was concluded that, if the concentration of Ra-226 in the first 15 cm of soil is lower than, 0.34 Bq g{sup -1}, the dose would not exceed the reference dose. Applying this value as a derived concentration level and comparing with the results of measurements on the ground, some areas with a concentration of activity slightly higher than latter were found. In these zones the remediation proposal has been to cover with a layer of 15 cm of clean material. This action represents a reduction of 85% of the dose and ensures compliance with the reference dose. (authors)« less

Study of antioxidative effects and anti-inflammatory effects in mice due to low-dose X-irradiation or radon inhalation

PubMed Central

Kataoka, Takahiro

2013-01-01

Low-dose irradiation induces various stimulating effects, especially activation of the biological defense system including antioxidative and immune functions. Oxidative stress induced by reactive oxygen species (ROS) can cause cell damage and death and can induce many types of diseases. This paper reviews new insights into inhibition of ROS-related diseases with low-dose irradiation or radon inhalation. X-irradiation (0.5 Gy) before or after carbon tetrachloride (CCl4) treatment inhibits hepatopathy in mice. X-irradiation (0.5 Gy) before ischemia-reperfusion injury or cold-induced brain injury also inhibits edema. These findings suggest that low-dose X-irradiation has antioxidative effects due to blocking the damage induced by free radicals or ROS. Moreover, radon inhalation increases superoxide dismutase activity in many organs and inhibits CCl4-induced hepatic and renal damage and streptozotocin-induced type I diabetes. These findings suggest that radon inhalation also has antioxidative effects. This antioxidative effect against CCl4-induced hepatopathy is comparable to treatment with ascorbic acid (vitamin C) at a dose of 500 mg/kg weight, or α-tocopherol (vitamin E) treatment at a dose of 300 mg/kg weight, and is due to activation of antioxidative functions. In addition, radon inhalation inhibits carrageenan-induced inflammatory paw edema, suggesting that radon inhalation has anti-inflammatory effects. Furthermore, radon inhalation inhibits formalin-induced inflammatory pain and chronic constriction injury-induced neuropathic pain, suggesting that radon inhalation relieves pain. Thus, low-dose irradiation very likely activates the defense systems in the body, and therefore, contributes to preventing or reducing ROS-related injuries, which are thought to involve peroxidation. PMID:23420683

Study of antioxidative effects and anti-inflammatory effects in mice due to low-dose X-irradiation or radon inhalation.

PubMed

Kataoka, Takahiro

2013-07-01

Low-dose irradiation induces various stimulating effects, especially activation of the biological defense system including antioxidative and immune functions. Oxidative stress induced by reactive oxygen species (ROS) can cause cell damage and death and can induce many types of diseases. This paper reviews new insights into inhibition of ROS-related diseases with low-dose irradiation or radon inhalation. X-irradiation (0.5 Gy) before or after carbon tetrachloride (CCl4) treatment inhibits hepatopathy in mice. X-irradiation (0.5 Gy) before ischemia-reperfusion injury or cold-induced brain injury also inhibits edema. These findings suggest that low-dose X-irradiation has antioxidative effects due to blocking the damage induced by free radicals or ROS. Moreover, radon inhalation increases superoxide dismutase activity in many organs and inhibits CCl4-induced hepatic and renal damage and streptozotocin-induced type I diabetes. These findings suggest that radon inhalation also has antioxidative effects. This antioxidative effect against CCl4-induced hepatopathy is comparable to treatment with ascorbic acid (vitamin C) at a dose of 500 mg/kg weight, or α-tocopherol (vitamin E) treatment at a dose of 300 mg/kg weight, and is due to activation of antioxidative functions. In addition, radon inhalation inhibits carrageenan-induced inflammatory paw edema, suggesting that radon inhalation has anti-inflammatory effects. Furthermore, radon inhalation inhibits formalin-induced inflammatory pain and chronic constriction injury-induced neuropathic pain, suggesting that radon inhalation relieves pain. Thus, low-dose irradiation very likely activates the defense systems in the body, and therefore, contributes to preventing or reducing ROS-related injuries, which are thought to involve peroxidation.

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. ...

Studies on possibility for alleviation of lifestyle diseases by low-dose irradiation or radon inhalation.

PubMed

Kataoka, Takahiro; Sakoda, Akihiro; Yoshimoto, Masaaki; Nakagawa, Shinya; Toyota, Teruaki; Nishiyama, Yuichi; Yamato, Keiko; Ishimori, Yuu; Kawabe, Atsushi; Hanamoto, Katsumi; Taguchi, Takehito; Yamaoka, Kiyonori

2011-07-01

Our previous studies showed the possibility that activation of the antioxidative function alleviates various oxidative damages, which are related to lifestyle diseases. Results showed that, low-dose X-ray irradiation activated superoxide dismutase and inhibits oedema following ischaemia-reperfusion. To alleviate ischaemia-reperfusion injury with transplantation, the changes of the antioxidative function in liver graft using low-dose X-ray irradiation immediately after exenteration were examined. Results showed that liver grafts activate the antioxidative function as a result of irradiation. In addition, radon inhalation enhances the antioxidative function in some organs, and alleviates alcohol-induced oxidative damage of mouse liver. Moreover, in order to determine the most effective condition of radon inhalation, mice inhaled radon before or after carbon tetrachloride (CCl(4)) administration. Results showed that radon inhalation alleviates CCl(4)-induced hepatopathy, especially prior inhalation. It is highly possible that adequate activation of antioxidative functions induced by low-dose irradiation can contribute to preventing or reducing oxidative damages, which are related to lifestyle diseases.

In vitro dose comparison of Respimat® inhaler with dry powder inhalers for COPD maintenance therapy.

PubMed

Ciciliani, Anna-Maria; Langguth, Peter; Wachtel, Herbert

2017-01-01

Combining in vitro mouth-throat deposition measurements, cascade impactor data and computational fluid dynamics (CFD) simulations, four different inhalers were compared which are indicated for chronic obstructive pulmonary disease (COPD) treatment. The Respimat inhaler, the Breezhaler, the Genuair, and the Ellipta were coupled to the idealized Alberta throat model. The modeled dose to the lung (mDTL) was collected downstream of the Alberta throat model using either a filter or a next generation impactor (NGI). Idealized breathing patterns from COPD patient groups - moderate and very severe COPD - were applied. Theoretical lung deposition patterns were assessed by an individual path model. For the Respimat the mDTL was found to be 59% (SD 5%) for the moderate COPD breathing pattern and 67% (SD 5%) for very severe COPD breathing pattern. The percentages refer to nominal dose (ND) in vitro. This is in the range of 44%-63% in vivo in COPD patients who display large individual variability. Breezhaler showed a mDTL of 43% (SD 2%) for moderate disease simulation and 51% (SD 2%) for very severe simulation. The corresponding results for Genuair are mDTL of 32% (SD 2%) for moderate and 42% (SD 1%) for very severe disease. Ellipta vilanterol particles showed a mDTL of 49% (SD 3%) for moderate and 55% (SD 2%) for very severe disease simulation, and Ellipta fluticasone particles showed a mDTL of 33% (SD 3%) and 41% (SD 2%), respectively for the two breathing patterns. Based on the throat output and average flows of the different inhalers, CFD simulations were performed. Laminar and turbulent steady flow calculations indicated that deposition occurs mainly in the small airways. In summary, Respimat showed the lowest amount of particles depositing in the mouth-throat model and the highest amount reaching all regions of the simulation lung model.

In vitro dose comparison of Respimat® inhaler with dry powder inhalers for COPD maintenance therapy

PubMed Central

Ciciliani, Anna-Maria; Langguth, Peter; Wachtel, Herbert

2017-01-01

Background Combining in vitro mouth–throat deposition measurements, cascade impactor data and computational fluid dynamics (CFD) simulations, four different inhalers were compared which are indicated for chronic obstructive pulmonary disease (COPD) treatment. Methods The Respimat inhaler, the Breezhaler, the Genuair, and the Ellipta were coupled to the idealized Alberta throat model. The modeled dose to the lung (mDTL) was collected downstream of the Alberta throat model using either a filter or a next generation impactor (NGI). Idealized breathing patterns from COPD patient groups – moderate and very severe COPD – were applied. Theoretical lung deposition patterns were assessed by an individual path model. Results and conclusion For the Respimat the mDTL was found to be 59% (SD 5%) for the moderate COPD breathing pattern and 67% (SD 5%) for very severe COPD breathing pattern. The percentages refer to nominal dose (ND) in vitro. This is in the range of 44%–63% in vivo in COPD patients who display large individual variability. Breezhaler showed a mDTL of 43% (SD 2%) for moderate disease simulation and 51% (SD 2%) for very severe simulation. The corresponding results for Genuair are mDTL of 32% (SD 2%) for moderate and 42% (SD 1%) for very severe disease. Ellipta vilanterol particles showed a mDTL of 49% (SD 3%) for moderate and 55% (SD 2%) for very severe disease simulation, and Ellipta fluticasone particles showed a mDTL of 33% (SD 3%) and 41% (SD 2%), respectively for the two breathing patterns. Based on the throat output and average flows of the different inhalers, CFD simulations were performed. Laminar and turbulent steady flow calculations indicated that deposition occurs mainly in the small airways. In summary, Respimat showed the lowest amount of particles depositing in the mouth–throat model and the highest amount reaching all regions of the simulation lung model. PMID:28603412

Analysis of Exposure-Dose Variation of Inhaled Particles in Adult Subjects.

EPA Science Inventory

Although internal dose is a key factor for determining the health risk of inhaled pollutant particles, available dose information is largely limited to young healthy adults under a few typical exposure conditions. Extrapolation of the limited dose information to different populat...

Effect of Study Design on Sample Size in Studies Intended to Evaluate Bioequivalence of Inhaled Short‐Acting β‐Agonist Formulations

PubMed Central

Zeng, Yaohui; Singh, Sachinkumar; Wang, Kai

2017-01-01

Abstract Pharmacodynamic studies that use methacholine challenge to assess bioequivalence of generic and innovator albuterol formulations are generally designed per published Food and Drug Administration guidance, with 3 reference doses and 1 test dose (3‐by‐1 design). These studies are challenging and expensive to conduct, typically requiring large sample sizes. We proposed 14 modified study designs as alternatives to the Food and Drug Administration–recommended 3‐by‐1 design, hypothesizing that adding reference and/or test doses would reduce sample size and cost. We used Monte Carlo simulation to estimate sample size. Simulation inputs were selected based on published studies and our own experience with this type of trial. We also estimated effects of these modified study designs on study cost. Most of these altered designs reduced sample size and cost relative to the 3‐by‐1 design, some decreasing cost by more than 40%. The most effective single study dose to add was 180 μg of test formulation, which resulted in an estimated 30% relative cost reduction. Adding a single test dose of 90 μg was less effective, producing only a 13% cost reduction. Adding a lone reference dose of either 180, 270, or 360 μg yielded little benefit (less than 10% cost reduction), whereas adding 720 μg resulted in a 19% cost reduction. Of the 14 study design modifications we evaluated, the most effective was addition of both a 90‐μg test dose and a 720‐μg reference dose (42% cost reduction). Combining a 180‐μg test dose and a 720‐μg reference dose produced an estimated 36% cost reduction. PMID:29281130

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.

Effect of aerosol fenoterol on the severity of bronchial hyperreactivity in patients with asthma.

PubMed Central

Salome, C M; Schoeffel, R E; Yan, K; Woolcock, A J

1983-01-01

Beta adrenergic agents given by aerosol decrease the responsiveness of the airways to histamine and methacholine in subjects with asthma, causing a shift of the dose response curve to the right. To find out whether the shift is related to the dose of beta adrenergic agent given and to determine the duration of the reduced responsiveness, eight subjects with asthma were given histamine inhalation tests after inhaled saline and after increasing doses of inhaled fenoterol on different days. The histamine inhalation tests were repeated at hourly intervals for five hours after a selected dose of fenoterol. Fenoterol caused a dose related shift to the right of the histamine dose response curve in each subject and in some the dose response relationship reached the "non-symptomatic range." The shift in the dose response curve was short lived and had returned towards the control position within three hours in all subjects. There was no change in shape of the curves at the time of maximal shift. The results show that inhaled fenoterol greatly reduces the airway responsiveness to histamine, but up to 400 micrograms of fenoterol every four to five hours may be needed to keep the responsiveness of the airways in the non-symptomatic range. PMID:6648868

Incidence of polybrominated diphenyl ethers in central air conditioner filter dust from a new office building.

PubMed

Ni, Hong-Gang; Cao, Shan-Ping; Chang, Wen-Jing; Zeng, Hui

2011-07-01

This study examined polybrominated diphenyl ethers (PBDEs) in central air conditioner filter (CACF) dust from a new office building in Shenzhen, China. Human exposure to PBDE via dust inhalation and ingestion were also estimated. PBDEs level in CACF dust was lower than those in the other countries and regions. Approximately 0.671 pg/kg bw/day PM(2.5) (Particulate Matter up to 2.5 μm in size) bounded Σ(15)PBDEs can be inhaled deep into the lungs and 4.123 pg/kg bw/day PM(10) (Particulate Matter up to 10 μm in size) bounded Σ(15)PBDEs tend to be deposited in the upper parts of the respiratory system. The average total intake of Σ(15)PBDEs via dust inhalation and ingestion for adults reached ∼ 141 pg/kg bw/day in this building. This value was far below the reference dose (RfD) recommended by United States Environmental Protection Agency. Human exposure to PBDEs via dust inhalation and ingestion in the new building is less than the old ones. Copyright © 2010 Elsevier Ltd. All rights reserved.

Safety of inhaled corticosteroids in the treatment of persistent asthma.

PubMed Central

Peters, Stephen P.

2006-01-01

OBJECTIVE: Inhaled corticosteroids (ICSs) are the most effective medications available for patients with persistent asthma of all severities and currently are recommended as the preferred asthma controller therapy by the National Heart, Lung and Blood Institute. Nevertheless, lingering concerns about potential adverse systemic effects of ICSs contribute to their underuse. This review discusses the safety of ICSs with respect to potential systemic effects of most concern to physicians and patients. METHODS: Articles reporting on the safety of ICSs in children and adults with persistent asthma were identified from the Medline database from January 1966 through December 2003, reference lists of review articles and international respiratory meetings. RESULTS: Ocular effects of ICSs and ICS effects on bone mineral density and adrenal function are minimal in patients maintained on recommended ICS doses. One-year growth studies in children have shown decreased growth velocity with ICSs, but long-term studies with inhaled budesonide and beclomethasone show no effect on final adult height, suggesting that these effects are transient. In addition, extensive data from the Swedish Medical Birth Registry show no increased risk of adverse perinatal outcomes when inhaled budesonide is administered to pregnant women with asthma. CONCLUSIONS: ICSs have minimal systemic effects in most patients when taken at recommended doses. The benefits of ICS therapy clearly outweigh the risks of uncontrolled asthma, and ICSs should be prescribed routinely as first-line therapy for children and adults with persistent disease. PMID:16775906

Anticonvulsant and antipunishment effects of toluene

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

Wood, R.W.; Coleman, J.B.; Schuler, R.

1984-01-01

Toluene can have striking acute behavioral effects and is subject to abuse by inhalation. To determine if its actions resemble those of drugs used in the treatment of anxiety (anxiolytics), two sets of experiments were undertaken. Inasmuch as prevention of pentylenetetrazol-induced convulsions is an identifying property of this class of agents, the authors first demonstrated that pretreatment of mice with injections of toluene delayed the onset of convulsive signs and prevented the tonic extension phase of the convulsant activity in a dose-related manner. Injections of another alkyl benzene, m-xylene, were of comparable potency to toluene. Inhalation of toluene delayed themore » time of death after pentylenetetrazol injection in a manner related to the duration and concentration of exposure; at lower convulsant doses, inhalation of moderate concentrations (EC/sub 58/, 1300 ppm) prevented death. Treatment with a benzodiazepine receptor antagonist (Ro 15-1788) failed to reduce the anticonvulsant activity of inhaled toluene. Anxiolytics also attenuate the reduction in response rate produced by punishment with electric shock. Toluene increased rates of responding suppressed by punishment when responding was maintained under a multiple fixed-interval fixed-interval punishment schedule of reinforcement. Distinct antipunishment effects were observed in rats after 2 hr of exposure to 1780 and 3000 ppm of toluene; the rate-increasing effects of toluene were related to concentration and to time after the termination of exposure. Thus, toluene and m-xylene resemble in several respects clinically useful drugs such as the benzodiazepines. 51 references, 3 figures, 2 tables.« less

Cardiovascular and hypokalaemic effects of inhaled salbutamol, fenoterol, and isoprenaline.

PubMed Central

Crane, J; Burgess, C; Beasley, R

1989-01-01

The cardiovascular and hypokalaemic effects of equal doses of inhaled fenoterol, isoprenaline and salbutamol were compared in eight healthy male volunteers, in a double blind, placebo controlled study. Increasing doses of 400, 600, and 800 micrograms were given from a metered dose inhaler at 15 minute intervals, followed by measurements of heart rate, blood pressure, total electromechanical systole (as a measure of inotropic response), QTc interval, and plasma potassium concentration. After repeated inhalation, fenoterol resulted in significantly greater chronotropic, electrocardiographic, and hypokalaemic effects than either isoprenaline or salbutamol. The maximum inotropic effect of fenoterol was similar to that of isoprenaline. PMID:2928998

Delivery of propellant soluble drug from a metered dose inhaler.

PubMed Central

Ashworth, H L; Wilson, C G; Sims, E E; Wotton, P K; Hardy, J G

1991-01-01

The deposition of particulate suspensions delivered from a metered dose inhaler has been investigated extensively. The distribution of propellant, delivered from a metered dose inhaler, was studied by radiolabelling it with technetium-99m hexamethylpropyleneamine oxime. Andersen sampler measurements indicated that half of the dose was associated with particles in the size range 0.5-5 microns diameter. The preparation was administered to healthy subjects by inhalation and deposition was monitored with a gamma camera. Each lung image was divided into an inner, mid, and peripheral zone. The effects on deposition of varying the size of the delivery orifice (0.46, 0.61, and 0.76 mm internal diameters) and the effect of attaching a spacer were assessed. Lung deposition was independent of the orifice size within the actuator. Without the spacer the average dose deposited in the lungs was 39%, with 15% penetrating into the peripheral part of the lungs. Attachment of the spacer to the mouth-piece increased the mean lung deposition to 57% and reduced oropharyngeal deposition. The study has shown that propellant soluble drugs can be delivered efficiently to the lungs from a metered dose inhaler. Images PMID:2038731

Study of the Emitted Dose After Two Separate Inhalations at Different Inhalation Flow Rates and Volumes and an Assessment of Aerodynamic Characteristics of Indacaterol Onbrez Breezhaler® 150 and 300 μg.

PubMed

Abadelah, Mohamad; Chrystyn, Henry; Bagherisadeghi, Golshan; Abdalla, Gaballa; Larhrib, Hassan

2018-01-01

Onbrez Breezhaler® is a low-resistance capsule-based device that was developed to deliver indacaterol maleate. The study was designed to investigate the effects of both maximum flow rate (MIF) and inhalation volume (Vin) on the dose emission of indacaterol 150 and 300 μg dose strengths after one and two inhalations using dose unit sampling apparatus (DUSA) as well as to study the aerodynamic characteristics of indacaterol Breezhaler® using the Andersen cascade impactor (ACI) at a different set of MIF and Vin. Indacaterol 150 and 300 μg contain equal amounts of lactose per carrier. However, 150 μg has the smallest carrier size. The particle size distribution (PSD) of indacaterol DPI formulations 150 and 300 μg showed that the density of fine particles increased with the increase of the primary pressure. For both strengths (150 μg and 300 μg), ED1 increased and ED2 decreased when the inhalation flow rate and inhaled volume increased. The reduction in ED1 and subsequent increase in ED2 was such that when the Vin is greater than 1 L, then 60 L/min could be regarded as the minimum MIF. The Breezhaler was effective in producing respirable particles with an MMAD ≤5 μm irrespective of the inhalation flow rate, but the mass fraction of particles with an aerodynamic diameter <3 μm is more pronounced between 60 and 90 L/min. The dose emission of indacaterol was comparable for both dose strengths 150 and 300 μg. These in vitro results suggest that a minimum MIF of 60 L/min is required during routine use of Onbrez Breezhaler®, and confirm the good practice to make two separate inhalations from the same dose.

Add-on LABA in a separate inhaler as asthma step-up therapy versus increased dose of ICS or ICS/LABA combination inhaler.

PubMed

Price, David B; Colice, Gene; Israel, Elliot; Roche, Nicolas; Postma, Dirkje S; Guilbert, Theresa W; van Aalderen, Willem M C; Grigg, Jonathan; Hillyer, Elizabeth V; Thomas, Victoria; Martin, Richard J

2016-04-01

Asthma management guidelines recommend adding a long-acting β 2 -agonist (LABA) or increasing the dose of inhaled corticosteroid (ICS) as step-up therapy for patients with uncontrolled asthma on ICS monotherapy. However, it is uncertain which option works best, which ICS particle size is most effective, and whether LABA should be administered by separate or combination inhalers. This historical, matched cohort study compared asthma-related outcomes for patients (aged 12-80 years) prescribed step-up therapy as a ≥50% extrafine ICS dose increase or add-on LABA, via either a separate inhaler or a fine-particle ICS/LABA fixed-dose combination (FDC) inhaler. Risk-domain asthma control was the primary end-point in comparisons of cohorts matched for asthma severity and control during the baseline year. After 1:2 cohort matching, the increased extrafine ICS versus separate ICS+LABA cohorts included 3232 and 6464 patients, respectively, and the fine-particle ICS/LABA FDC versus separate ICS+LABA cohorts included 7529 and 15 058 patients, respectively (overall mean age 42 years; 61-62% females). Over one outcome year, adjusted OR (95% CI) for achieving asthma control were 1.25 (1.13-1.38) for increased ICS versus separate ICS+LABA and 1.06 (1.05-1.09) for ICS/LABA FDC versus separate ICS+LABA. For patients with asthma, increased dose of extrafine-particle ICS, or add-on LABA via ICS/LABA combination inhaler, is associated with significantly better outcomes than ICS+LABA via separate inhalers.

Natural radionuclides in cigarette tobacco from Serbian market and effective dose estimate from smoke inhalation.

PubMed

Janković Mandić, Ljiljana; Đolić, Maja; Marković, Dragana; Todorović, Dragana; Onjia, Antonije; Dragović, Snežana

2016-01-01

The activity concentrations of natural radionuclides ((40)K, (210)Pb, (210)Po, (226)Ra and (228)Ra) in 17 most frequently used cigarette brands in Serbia and corresponding effective doses due to smoke inhalation are presented. The mean annual effective doses for (210)Pb and (210)Po were estimated to be 47.3 and 724 µSv y(-1) for (210)Pb and (210)Po, respectively. Serbia currently has the highest smoking rate in the world. The results of this study indicate the high contribution of the annual effective dose due to smoke inhalation to the total inhalation dose from natural radionuclides. The more effective implementation of actions for reducing smoking prevalence in Serbia is highly needed. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Anticoagulant effects of inhaled unfractionated heparin in the dog as determined by partial thromboplastin time and factor Xa activity.

PubMed

Manion, Jill S; Thomason, John M; Langston, Vernon C; Claude, Andrew K; Brooks, Marjory B; Mackin, Andrew J; Lunsford, Kari V

2016-01-01

To evaluate the anticoagulant effects of inhaled heparin in dogs. This study was conducted in 3 phases. In phase 1, bronchoalveolar lavage fluid (BALf) was collected to generate an in vitro calibration curve to relate heparin concentration to the activated partial thromboplastin time (aPTT). In phase 2, heparin was administered via nebulization to determine the threshold dose needed to prolong systemic aPTT. In phase 3, the local anticoagulant activity of inhaled heparin was determined by measurement of BALf anti-Xa activity and aPTT. University teaching hospital. Six healthy intact female Walker Hounds were used in this study. Two dogs were used for each phase. Inhaled unfractionated sodium heparin was administered in doses ranging from 50,000 to 200,000 IU. In vitro addition of heparin to BALf caused a prolongation in aPTT. Inhaled heparin at doses as high as 200,000 IU failed to prolong systemic aPTT, and a threshold dose could not be determined. No significant local anticoagulant effects were detected. Even at doses higher than those known to be effective in people, inhaled heparin appears to have no detectable local or systemic anticoagulant effects in dogs with the current delivery method. © Veterinary Emergency and Critical Care Society 2015.

The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study.

PubMed

Eisenberg, Elon; Ogintz, Miri; Almog, Shlomo

2014-09-01

Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a "main stream" pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ(9)-tetrahydrocannabinol (THC) and 11-hydroxy-Δ(9)-THC were taken at baseline and up to 120 minutes. Pain intensity (0-10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ(9)-THC plasma Cmax ± SD was 38 ± 10 ng/mL, Tmax ± SD was 3 ± 1 minutes, AUC₀→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma Cmax increase per mg Δ(9)-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of Cmax (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15-30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ(9)-THC pharmacokinetic profile with low interindividual variation of Cmax, achieving pharmaceutical standards for inhaled drugs.

ANALYSIS OF RESPIRATORY DEPOSITION OF INHALED PARTICLES FOR DIFFERENT DOSE METRICS: COMPARISON OF NUMBER, SURFACE AREA AND MASS DOSE OF TYPICAL AMBIENT BI-MODAL AEROSOLS

EPA Science Inventory

ANALYSIS OF RESPIRATORY DEPOSITION OF INHALED PARTICLES FOR DIFFERENT DOSE METRICS: COMPARISON OF NUMBER, SURFACE AREA AND MASS DOSE OF TYPICAL AMBIENT BI-MODAL AEROSOLS.
Chong S. Kim, SC. Hu*, PA Jaques*, US EPA, National Health and Environmental Effects Research Laboratory, ...

The Ellipta® in asthma and chronic obstructive pulmonary disease: device characteristics and patient acceptability.

PubMed

Jones, Thomas L; Neville, Daniel M; Chauhan, Anoop J

2018-02-01

Asthma and chronic obstructive pulmonary disease are primarily treated with inhaled medication, but delivery of that medication to its site of action is problematic; patients' ability to use inhalers will affect therapeutic response. Multiple inhaler devices are available but they are variably easy to use with consequent effects on compliance, intentional or otherwise. The Ellipta ® device is a novel blister strip dry powder inhaler with medium resistance and a consistent delivered dose across a range of inspiratory flow rates. The Ellipta has proven easy to use and is preferred by patients across several evaluations and compared with other inhaler devices. The Ellipta is used to administer multiple inhaled medications, all in single daily-dose regimens, making it ideal for patients who struggle with complex inhaled therapy regimens.

Cumulative high doses of inhaled formoterol have less systemic effects in asthmatic children 6–11 years-old than cumulative high doses of inhaled terbutaline

PubMed Central

Kaae, Rikke; Agertoft, Lone; Pedersen, Sören; Nordvall, S Lennart; Pedroletti, Christophe; Bengtsson, Thomas; Johannes-Hellberg, Ingegerd; Rosenborg, Johan

2004-01-01

Objectives To evaluate high dose tolerability and relative systemic dose potency between inhaled clinically equipotent dose increments of formoterol and terbutaline in children. Methods Twenty boys and girls (6–11 years-old) with asthma and normal ECGs were studied. Ten doses of formoterol (Oxis®) 4.5 µg (F4.5) or terbutaline (Bricanyl®) 500 µg (T500) were inhaled cumulatively via a dry powder inhaler (Turbuhaler®) over 1 h (three patients) or 2.5 h (17 patients) and compared to a day of no treatment, in a randomised, double-blind (active treatments only), crossover trial. Blood pressure (BP), ECG, plasma potassium, glucose, lactate, and adverse events were monitored up to 10 h to assess tolerability and relative systemic dose potency. Results Formoterol and terbutaline had significant β2-adrenergic effects on most outcomes. Apart from the effect on systolic BP, QRS duration and PR interval, the systemic effects were significantly more pronounced with terbutaline than with formoterol. Thus, mean minimum plasma potassium, was suppressed from 3.56 (95% confidence interval, CI: 3.48–3.65) mmol l−1 on the day of no treatment to 2.98 (CI: 2.90–3.08) after 10 × F4.5 and 2.70 (CI: 2.61–2.78) mmol l−1 after 10 × T500, and maximum Q-Tc (heart rate corrected Q-T interval [Bazett's formula]) was prolonged from 429 (CI: 422–435) ms on the day of no treatment, to 455 (CI: 448–462) ms after 10 × F4.5 and 470 (CI: 463–476) ms after 10 × T500. Estimates of relative dose potency indicated that F4.5 µg had the same systemic activity as the clinically less effective dose of 250 µg terbutaline. The duration of systemic effects differed marginally between treatments. Spontaneously reported adverse events (most frequently tremor) were fewer with formoterol (78% of the children) than with terbutaline (95%). A serious adverse event occurred after inhalation of 45 µg formoterol over the 1 h dosing time, that prompted the extension of dosing time to 2.5 h. Conclusions Multiple inhalations over 2.5 h of formoterol (4.5 µg) via Turbuhaler® are at least as safe as and associated with less systemic effects than multiple inhalations of the clinically equipotent dose of terbutaline (500 µg) in children with asthma. PMID:15373934

Cumulative high doses of inhaled formoterol have less systemic effects in asthmatic children 6-11 years-old than cumulative high doses of inhaled terbutaline.

PubMed

Kaae, Rikke; Agertoft, Lone; Pedersen, Sören; Nordvall, S Lennart; Pedroletti, Christophe; Bengtsson, Thomas; Johannes-Hellberg, Ingegerd; Rosenborg, Johan

2004-10-01

To evaluate high dose tolerability and relative systemic dose potency between inhaled clinically equipotent dose increments of formoterol and terbutaline in children. Twenty boys and girls (6-11 years-old) with asthma and normal ECGs were studied. Ten doses of formoterol (Oxis) 4.5 microg (F4.5) or terbutaline (Bricanyl) 500 microg (T500) were inhaled cumulatively via a dry powder inhaler (Turbuhaler) over 1 h (three patients) or 2.5 h (17 patients) and compared to a day of no treatment, in a randomised, double-blind (active treatments only), crossover trial. Blood pressure (BP), ECG, plasma potassium, glucose, lactate, and adverse events were monitored up to 10 h to assess tolerability and relative systemic dose potency. Formoterol and terbutaline had significant beta2-adrenergic effects on most outcomes. Apart from the effect on systolic BP, QRS duration and PR interval, the systemic effects were significantly more pronounced with terbutaline than with formoterol. Thus, mean minimum plasma potassium, was suppressed from 3.56 (95% confidence interval, CI: 3.48-3.65) mmol l(-1) on the day of no treatment to 2.98 (CI: 2.90-3.08) after 10 x F4.5 and 2.70 (CI: 2.61-2.78) mmol l(-1) after 10 x T500, and maximum Q-Tc (heart rate corrected Q-T interval [Bazett's formula]) was prolonged from 429 (CI: 422-435) ms on the day of no treatment, to 455 (CI: 448-462) ms after 10 x F4.5 and 470 (CI: 463-476) ms after 10 x T500. Estimates of relative dose potency indicated that F4.5 microg had the same systemic activity as the clinically less effective dose of 250 microg terbutaline. The duration of systemic effects differed marginally between treatments. Spontaneously reported adverse events (most frequently tremor) were fewer with formoterol (78% of the children) than with terbutaline (95%). A serious adverse event occurred after inhalation of 45 microg formoterol over the 1 h dosing time, that prompted the extension of dosing time to 2.5 h. Multiple inhalations over 2.5 h of formoterol (4.5 microg) via Turbuhaler) are at least as safe as and associated with less systemic effects than multiple inhalations of the clinically equipotent dose of terbutaline (500 microg) in children with asthma. Copyright 2004 Blackwell Publishing Ltd

Modeling low-dose mortality and disease incubation period of inhalational anthrax in the rabbit.

PubMed

Gutting, Bradford W; Marchette, David; Sherwood, Robert; Andrews, George A; Director-Myska, Alison; Channel, Stephen R; Wolfe, Daniel; Berger, Alan E; Mackie, Ryan S; Watson, Brent J; Rukhin, Andrey

2013-07-21

There is a need to advance our ability to conduct credible human risk assessments for inhalational anthrax associated with exposure to a low number of bacteria. Combining animal data with computational models of disease will be central in the low-dose and cross-species extrapolations required in achieving this goal. The objective of the current work was to apply and advance the competing risks (CR) computational model of inhalational anthrax where data was collected from NZW rabbits exposed to aerosols of Ames strain Bacillus anthracis. An initial aim was to parameterize the CR model using high-dose rabbit data and then conduct a low-dose extrapolation. The CR low-dose attack rate was then compared against known low-dose rabbit data as well as the low-dose curve obtained when the entire rabbit dose-response data set was fitted to an exponential dose-response (EDR) model. The CR model predictions demonstrated excellent agreement with actual low-dose rabbit data. We next used a modified CR model (MCR) to examine disease incubation period (the time to reach a fever >40 °C). The MCR model predicted a germination period of 14.5h following exposure to a low spore dose, which was confirmed by monitoring spore germination in the rabbit lung using PCR, and predicted a low-dose disease incubation period in the rabbit between 14.7 and 16.8 days. Overall, the CR and MCR model appeared to describe rabbit inhalational anthrax well. These results are discussed in the context of conducting laboratory studies in other relevant animal models, combining the CR/MCR model with other computation models of inhalational anthrax, and using the resulting information towards extrapolating a low-dose response prediction for man. Published by Elsevier Ltd.

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.

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...

Dispersing the Mists: An Experimental History of Medicine Study into the Quality of Volatile Inhalations.

PubMed

Murnane, Barry; Gallagher, Cathal T; Snell, Noel; Sanders, Mark; Moshksar, Ramin; Murnane, Darragh

2017-06-01

Dr. Nelson's Improved Inhaler was first marketed with an advertisement in The Lancet in 1865. Revolutionary at the time for its ease of use and patient-friendliness, the inhaler is still in use for self-treatment by many all over the world. On the occasion of its 150th anniversary, this study reports an experimental historical medicine approach to identify evidence for the quality of vapor inhalers. Through accessing reviews of the device's use by the contemporary medical establishment, it was established that Dr. Nelson's Inhaler enjoyed a reputation of quality and efficacy among reputable physicians generating empirical evidence of clinical performance. There was a general absence of product performance tests during this period. Therefore, modern inhalation performance testing was applied to test the aerosol delivery performance for Friars' Balsam, and its key chemical constituent, benzoic acid (BA). A respirable dose of 59.9 ± 9.0 μg of BA was aerosolized in a 10 minutes period from a dose of 3.3 mL Friars' Balsam (equivalent to 35.1 ± 0.2 mg of BA) in 375 mL of steaming water using the glass twin stage impinger at a flow rate of 60 L·min -1 . The respirable dose from a standardized aqueous BA inhalation formulation increased from 115.9 ± 10.6 to 200.2 ± 19.9 μg by increasing the simulated inhalation period from 5 to 10 minutes. When tested with a simulated inhalation maneuver (500 mL tidal volume, 13 minutes -1 respiration rate, 1:2 inspiratory:expiratory ratio) a respirable dose of 112.8 ± 40.3 μg was produced. This work has highlighted the potential for aerosol drug delivery using steam inhalers that are popular with patients. Physicians should therefore be aware of the potential for lung dosing with irritants when patients self-medicate using the Nelson Inhaler with vaporizing formulations such as Friars' Balsam.

In vivo effects of synthetic cannabinoids JWH-018 and JWH-073 and phytocannabinoid Δ9-THC in mice: inhalation versus intraperitoneal injection.

PubMed

Marshell, R; Kearney-Ramos, T; Brents, L K; Hyatt, W S; Tai, S; Prather, P L; Fantegrossi, W E

2014-09-01

Human users of synthetic cannabinoids (SCBs) JWH-018 and JWH-073 typically smoke these drugs, but preclinical studies usually rely on injection for drug delivery. We used the cannabinoid tetrad and drug discrimination to compare in vivo effects of inhaled drugs with injected doses of these two SCBs, as well as with the phytocannabinoid Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Mice inhaled various doses of Δ(9)-THC, JWH-018 or JWH-073, or were injected intraperitoneally (IP) with these same compounds. Rectal temperature, tail flick latency in response to radiant heat, horizontal bar catalepsy, and suppression of locomotor activity were assessed in each animal. In separate studies, mice were trained to discriminate Δ(9)-THC (IP) from saline, and tests were performed with inhaled or injected doses of the SCBs. Both SCBs elicited Δ(9)-THC-like effects across both routes of administration, and effects following inhalation were attenuated by pretreatment with the CB1 antagonist/inverse agonist rimonabant. No cataleptic effects were observed following inhalation, but all compounds induced catalepsy following injection. Injected JWH-018 and JWH-073 fully substituted for Δ(9)-THC, but substitution was partial (JWH-073) or required relatively higher doses (JWH-018) when drugs were inhaled. These studies demonstrate that the SCBs JWH-018 and JWH-073 elicit dose-dependent, CB1 receptor-mediated Δ(9)-THC-like effects in mice when delivered via inhalation or via injection. Across these routes of administration, differences in cataleptic effects and, perhaps, discriminative stimulus effects, may implicate the involvement of active metabolites of these compounds. Copyright © 2014 Elsevier Inc. All rights reserved.

Particle exposure and inhaled dose during commuting in Singapore

NASA Astrophysics Data System (ADS)

Tan, Sok Huang; Roth, Matthias; Velasco, Erik

2017-12-01

Exposure concentration and inhaled dose of particles during door-to-door trips walking and using motorized transport modes (subway, bus, taxi) are evaluated along a selected route in a commercial district of Singapore. Concentrations of particles smaller than 2.5 μm in size (PM2.5), black carbon, particle-bound polycyclic aromatic hydrocarbons, number of particles, active surface area and carbon monoxide have been measured in-situ using portable instruments. Simultaneous measurements were conducted at a nearby park to capture the background concentrations. The heart rate of the participants was monitored during the measurements as a proxy of the inhalation rate used to calculate the inhaled dose of particles. All measured metrics were highest and well above background levels during walking. No significant difference was observed in the exposure concentration of PM2.5 for the three motorized transport modes, unlike for the metrics associated with ultrafine particles (UFP). The concentration of these freshly emitted particles was significantly lower on subway trips. The absence of combustion sources, use of air conditioning and screen doors at station platforms are effective measures to protect passengers' health. For other transport modes, sections of trips close to accelerating and idling vehicles, such as bus stops, traffic junctions and taxi stands, represent hotspots of particles. Reducing the waiting time at such locations will lower pollutants exposure and inhaled dose during a commute. After taking into account the effect of inhalation and travel duration when calculating dose, the health benefit of commuting by subway for this particular district of Singapore became even more evident. For example, pedestrians breathe in 2.6 and 3.2 times more PM2.5 and UFP, respectively than subway commuters. Public buses were the second best alternative. Walking emerged as the worst commuting mode in terms of particle exposure and inhaled dose.

Delivery of fenoterol via Respimat, a novel 'soft mist' inhaler. a randomised, double-blind (within device), placebo-controlled, cross-over, dose-ranging study in asthmatic patients.

PubMed

van Noord, J A; Smeets, J J; Creemers, J P; Greefhorst, L P; Dewberry, H; Cornelissen, P J

2000-01-01

The phase-out of chlorofluorocarbons (CFCs) for metered dose inhalers (MDIs) has prompted the development of alternative propellants and the design of propellant-free devices for inhalation therapy. This study was carried out to determine the dose of fenoterol inhaled from Respimat (RMT), a new propellant-free soft mist inhaler, which is equivalent in terms of efficacy and safety to 1 puff of either 100 or 200 microg fenoterol inhaled from a conventional CFC-MDI (Berotec). Sixty-two asthmatic patients (35 male, 27 female) with a mean baseline FEV(1) of 1.7 liters, corresponding to 55% of the predicted normal value, were randomized at two study centers to 4 of a total of 8 possible treatments: placebo; 12.5, 25, 50, 100, or 200 microg fenoterol via RMT, and 100 or 200 microg fenoterol delivered via the MDI. Fifty-nine patients completed the study as planned. Results of the therapeutic equivalence test for the primary endpoint, average FEV(1) (AUC(0-6))/6 and for the secondary endpoint, peak FEV(1), showed that the 12.5- and 25-microg fenoterol doses administered via RMT were equivalent to the 100 microg fenoterol dose from the MDI. The 50-, 100- and 200-microg fenoterol doses delivered by RMT did not meet the criterion for therapeutic equivalence with the 100-microg dose from the MDI, and if tested for a difference would have been significantly different in favor of RMT. All 5 RMT fenoterol doses were therapeutically equivalent to the MDI 200-microg fenoterol dose. Headache, reported by 4 patients on test days and 2 patients between test days in those randomized to RMT, was the most common adverse event, but the active treatments were generally well tolerated with no dose-dependent increases in incidence or severity of adverse events observed. The results from the study suggest that safe and efficacious bronchodilation can be obtained from single-dose fenoterol administered via RMT. Use of lower absolute doses to obtain a clinically significant improvement in pulmonary function may be possible because of the increased lung deposition achievable with the novel soft mist inhaler. Copyright 2000 S. Karger AG, Basel

Improved delivery of fenoterol plus ipratropium bromide using Respimat compared with a conventional metered dose inhaler.

PubMed

Goldberg, J; Freund, E; Beckers, B; Hinzmann, R

2001-02-01

Asthma can be effectively treated by the use of bronchodilator therapies administered by inhalation. The objective of this study was to describe the dose-response relationship of combined doses of fenoterol hydrobromide (F) and ipratropium bromide (I) (F/I) delivered via Respimat, a soft mist inhaler, and to establish the Respimat dose which is as efficacious and as safe as the standard marketed dose of F/I (100/40 microg) which is delivered via a conventional metered dose inhaler (MDI). In a double-blind (within device) cross-over study with a balanced incomplete block design, 62 patients with stable bronchial asthma (mean forced expiratory volume in one second (FEV1) 63% predicted) were randomized at five study centres to receive five out of eight possible treatments: placebo, F/I 12.5/5, 25/10, 50/20, 100/40 or 200/80 microg delivered via Respimat; F/I 50/20 or 100/40 microg delivered via MDI. Pulmonary function results were based on the per-protocol dataset, comprising 47 patients. All F/I doses produced greater increases in FEV1 than placebo. A log-linear dose-response was obtained for the average increase in FEV1 up to 6 h (AUC0-6 h) and peak FEV1 across the dose range administered by Respimat. Statistically, therapeutic equivalence was not demonstrated between any F/I dose administered by Respimat compared with the MDI. However 12.5/5 and 25/10 microg F/I administered via Respimat were closest (slightly superior) to the F/I dose of 100/40 microg delivered via MDI. Pharmacokinetic data from 34 patients indicated a two-fold greater systemic availability of both drugs following inhalation by Respimat compared to MDI. In general, the active treatments were well tolerated and safe with regard to vital signs, electrocardiography, laboratory parameters and adverse events. In conclusion, combined administration of fenoterol hydrobromide and ipratropium bromide via Respimat, is as effective and as safe as higher doses given via a metered dose inhaler.

MICRO DOSE ASESSMENT OF INHALED PARTICLES IN HUMAN LUNGS: A STEP CLOSER TOWARDS THE TARGET TISSUE DOSE

EPA Science Inventory

Rationale: Inhaled particles deposit inhomogeneously in the lung and this may result in excessive deposition dose at local regions of the lung, particularly at the anatomic sites of bifurcations and junctions of the airways, which in turn leads to injuries to the tissues and adve...

Effect of Study Design on Sample Size in Studies Intended to Evaluate Bioequivalence of Inhaled Short-Acting β-Agonist Formulations.

PubMed

Zeng, Yaohui; Singh, Sachinkumar; Wang, Kai; Ahrens, Richard C

2018-04-01

Pharmacodynamic studies that use methacholine challenge to assess bioequivalence of generic and innovator albuterol formulations are generally designed per published Food and Drug Administration guidance, with 3 reference doses and 1 test dose (3-by-1 design). These studies are challenging and expensive to conduct, typically requiring large sample sizes. We proposed 14 modified study designs as alternatives to the Food and Drug Administration-recommended 3-by-1 design, hypothesizing that adding reference and/or test doses would reduce sample size and cost. We used Monte Carlo simulation to estimate sample size. Simulation inputs were selected based on published studies and our own experience with this type of trial. We also estimated effects of these modified study designs on study cost. Most of these altered designs reduced sample size and cost relative to the 3-by-1 design, some decreasing cost by more than 40%. The most effective single study dose to add was 180 μg of test formulation, which resulted in an estimated 30% relative cost reduction. Adding a single test dose of 90 μg was less effective, producing only a 13% cost reduction. Adding a lone reference dose of either 180, 270, or 360 μg yielded little benefit (less than 10% cost reduction), whereas adding 720 μg resulted in a 19% cost reduction. Of the 14 study design modifications we evaluated, the most effective was addition of both a 90-μg test dose and a 720-μg reference dose (42% cost reduction). Combining a 180-μg test dose and a 720-μg reference dose produced an estimated 36% cost reduction. © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Achieving Consistent Multiple Daily Low-Dose Bacillus anthracis Spore Inhalation Exposures in the Rabbit Model

PubMed Central

Barnewall, Roy E.; Comer, Jason E.; Miller, Brian D.; Gutting, Bradford W.; Wolfe, Daniel N.; Director-Myska, Alison E.; Nichols, Tonya L.; Taft, Sarah C.

2012-01-01

Repeated low-level exposures to biological agents could occur before or after the remediation of an environmental release. This is especially true for persistent agents such as B. anthracis spores, the causative agent of anthrax. Studies were conducted to examine aerosol methods needed for consistent daily low aerosol concentrations to deliver a low-dose (less than 106 colony forming units (CFU) of B. anthracis spores) and included a pilot feasibility characterization study, acute exposure study, and a multiple 15 day exposure study. This manuscript focuses on the state-of-the-science aerosol methodologies used to generate and aerosolize consistent daily low aerosol concentrations and resultant low inhalation doses to rabbits. The pilot feasibility characterization study determined that the aerosol system was consistent and capable of producing very low aerosol concentrations. In the acute, single day exposure experiment, targeted inhaled doses of 1 × 102, 1 × 103, 1 × 104, and 1 × 105 CFU were used. In the multiple daily exposure experiment, rabbits were exposed multiple days to targeted inhaled doses of 1 × 102, 1 × 103, and 1 × 104 CFU. In all studies, targeted inhaled doses remained consistent from rabbit-to-rabbit and day-to-day. The aerosol system produced aerosolized spores within the optimal mass median aerodynamic diameter particle size range to reach deep lung alveoli. Consistency of the inhaled dose was aided by monitoring and recording respiratory parameters during the exposure with real-time plethysmography. Overall, the presented results show that the animal aerosol system was stable and highly reproducible between different studies and over multiple exposure days. PMID:22919662

A comparison between a combination of ipratropium bromide plus fenoterol in a single metered dose inhaler (Duovent) and salbutamol in asthma.

PubMed Central

Flint, K. C.; Hockley, B.; Johnson, N. M.

1983-01-01

The efficacy of a single metered dose inhaler containing a combination of fenoterol (100 micrograms/puff) and ipratropium bromide (40 micrograms/puff) has been assessed in 12 asthmatics. We conclude that the bronchodilator effect of 2 puffs of the combination inhaler was significantly greater than that achieved by 2 puffs of salbutamol (100 micrograms/puff). PMID:6227877

Inhaled vs. oral alprazolam: subjective, behavioral and cognitive effects, and modestly increased abuse potential

PubMed Central

Reissig, Chad J.; Harrison, Joseph A.; Carter, Lawrence P.; Griffiths, Roland R.

2014-01-01

Rationale Infrahuman and human studies suggest that a determinant of the abuse potential of a drug is rate of onset of subjective effects. Objectives This study sought to determine if the rate of onset of subjective effects and abuse potential of alprazolam would be increased when administered via inhalation vs. the oral route. Methods Placebo, inhaled alprazolam (0.5, 1, 2 mg), and oral alprazolam (1, 2, 4 mg) were administered under double-blind, double-dummy conditions using a cross-over design in 14 healthy participants with histories of drug abuse. Participant and observer ratings, and behavioral and cognitive performance measures were assessed repeatedly during 9 hour sessions. Results Both routes of administration produced orderly dose and time-related effects, with higher doses producing greater and longer lasting effects. Onset of subjective effects following inhaled alprazolam was very rapid (e.g., 2 vs. 49 minutes after 2 mg inhaled vs. oral). On measures of abuse potential (e.g., liking and good effects), inhaled alprazolam was more potent, as evidenced by a leftward shift in the dose response curve. Despite the potency difference, at the highest doses, peak ratings of subjective effects related to abuse potential (e.g., “drug liking”) were similar across the two routes. On other measures (e.g., sedation and performance) the routes were equipotent. Conclusions The inhaled route of administration modestly increased the abuse potential of alprazolam despite significantly increasing its rate of onset. If marketed, the reduced availability and increased cost of inhaled alprazolam may render the societal risk of increased abuse to be low. PMID:25199955

Inhaled vs. oral alprazolam: subjective, behavioral and cognitive effects, and modestly increased abuse potential.

PubMed

Reissig, Chad J; Harrison, Joseph A; Carter, Lawrence P; Griffiths, Roland R

2015-03-01

Infrahuman and human studies suggest that a determinant of the abuse potential of a drug is rate of onset of subjective effects. This study sought to determine if the rate of onset of subjective effects and abuse potential of alprazolam would be increased when administered via inhalation vs. the oral route. Placebo, inhaled alprazolam (0.5, 1, and 2 mg), and oral alprazolam (1, 2, and 4 mg) were administered under double-blind, double-dummy conditions using a crossover design in 14 healthy participants with histories of drug abuse. Participant and observer ratings and behavioral and cognitive performance measures were assessed repeatedly during 9-h sessions. Both routes of administration produced orderly dose and time-related effects, with higher doses producing greater and longer-lasting effects. Onset of subjective effects following inhaled alprazolam was very rapid (e.g., 2 vs. 49 min after 2 mg inhaled vs. oral). On measures of abuse potential (e.g., liking and good effects), inhaled alprazolam was more potent, as evidenced by a leftward shift in the dose-response curve. Despite the potency difference, at the highest doses, peak ratings of subjective effects related to abuse potential (e.g., "drug liking") were similar across the two routes. On other measures (e.g., sedation and performance), the routes were equipotent. The inhaled route of administration modestly increased the abuse potential of alprazolam despite significantly increasing its rate of onset. If marketed, the reduced availability and increased cost of inhaled alprazolam may render the societal risk of increased abuse to be low.

Use of epidemiologic data in Integrated Risk Information System (IRIS) assessments

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

Persad, Amanda S.; Cooper, Glinda S.

2008-11-15

In human health risk assessment, information from epidemiologic studies is typically utilized in the hazard identification step of the risk assessment paradigm. However, in the assessment of many chemicals by the Integrated Risk Information System (IRIS), epidemiologic data, both observational and experimental, have also been used in the derivation of toxicological risk estimates (i.e., reference doses [RfD], reference concentrations [RfC], oral cancer slope factors [CSF] and inhalation unit risks [IUR]). Of the 545 health assessments posted on the IRIS database as of June 2007, 44 assessments derived non-cancer or cancer risk estimates based on human data. RfD and RfC calculationsmore » were based on a spectrum of endpoints from changes in enzyme activity to specific neurological or dermal effects. There are 12 assessments with IURs based on human data, two assessments that extrapolated human inhalation data to derive CSFs and one that used human data to directly derive a CSF. Lung or respiratory cancer is the most common endpoint for cancer assessments based on human data. To date, only one chemical, benzene, has utilized human data for derivation of all three quantitative risk estimates (i.e., RfC, RfD, and dose-response modeling for cancer assessment). Through examples from the IRIS database, this paper will demonstrate how epidemiologic data have been used in IRIS assessments for both adding to the body of evidence in the hazard identification process and in the quantification of risk estimates in the dose-response component of the risk assessment paradigm.« less

Mometasone Oral Inhalation

MedlinePlus

... or she watches.The dose counter on the base of your mometasone inhaler tells you how many ... Hold the inhaler straight up with the colored base on the bottom. Twist the white cap counterclockwise ...

Suppression of streptozotocin-induced type-1 diabetes in mice by radon inhalation.

PubMed

Nishiyama, Y; Kataoka, T; Teraoka, J; Sakoda, A; Tanaka, H; Ishimori, Y; Mitsunobu, F; Taguchi, T; Yamaoka, K

2013-01-01

We examined the protective effect of radon inhalation on streptozotocin (STZ)-induced type-1 diabetes in mice. Mice inhaled radon at concentrations of 1000, 2500, and 5500 Bq/m3 for 24 hours before STZ administration. STZ administration induced characteristics of type-1 diabetes such as hyperglycemia and hypoinsulinemia; however, radon inhalation at doses of 1000 and 5500 Bq/m3 significantly suppressed the elevation of blood glucose in diabetic mice. Serum insulin was significantly higher in mice pre-treated with radon at a dose of 1000 Bq/m3 than in mice treated with a sham. In addition, superoxide dismutase activities and total glutathione contents were significantly higher and lipid peroxide was significantly lower in mice pre-treated with radon at doses of 1000 and 5500 Bq/m3 than in mice treated with a sham. These results were consistent with the result that radon inhalation at 1000 and 5500 Bq/m3 suppressed hyperglycemia. These findings suggested that radon inhalation suppressed STZ-induced type-1 diabetes through the enhancement of antioxidative functions in the pancreas.

Cycling to work in London and inhaled dose of black carbon.

PubMed

Nwokoro, Chinedu; Ewin, Clare; Harrison, Clare; Ibrahim, Mubin; Dundas, Isobel; Dickson, Iain; Mushtaq, Naseem; Grigg, Jonathan

2012-11-01

Modelling studies suggest that urban cycling is associated with an increased inhaled dose of fossil fuel-derived black carbon (BC). Using the amount of black material in airway macrophages as a marker of long-term inhaled BC, we sought to compare inhaled BC dose in London (UK) cyclists and non-cyclists. Airway macrophage carbon was assessed in 28 (58%) out of 48 healthy adults (14 cyclists and 14 non-cyclists) who attended for induced sputum. Short-term (24 h) exposure to BC was assessed on a representative working day in 27 out of 28 subjects. Serum interleukin (IL)-1β, IL-2, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor and tumour necrosis factor (TNF)-α were assessed in 26 out of the 28 subjects. Cyclists were found to have increased airway macrophage carbon when compared with non-cyclists (mean ± se 1.81 ± 0.21 versus 1.11 ± 0.07 μm(2); p<0.01). Short-term monitoring showed no difference in 24 h BC exposure between the two groups. However, cyclists were exposed to higher concentrations of BC during commuting (p<0.01). Airway macrophage carbon was associated with monitored commute BC (n=28; r=0.47, p<0.05). TNF-α was found to be increased in cyclists (p<0.05), but no other cytokines were increased. Commuting to work by bicycle in London is associated with increased long-term inhaled dose of BC. Whether cycling per se increases inhaled BC dose remains unclear.

Commentary on Inhaled 239PuO 2 in Dogs — A Prophylaxis against Lung Cancer?

DOE PAGES

Cuttler, Jerry M.; Feinendegen, Ludwig E.

2015-01-01

Several studies on the effect of inhaled plutonium-dioxide particulates and the incidence of lung tumors in dogs reveal beneficial effects when the cumulative alpha-radiation dose is low. There is a threshold at an exposure level of about 100 cGy for excess tumor incidence and reduced lifespan. The observations conform to the expectations of the radiation hormesis dose-response model and contradict the predictions of the LNT hypothesis. These studies suggest investigating the possibility of employing low-dose alpha-radiation, such as from 239PuO 2 inhalation, as a prophylaxis against lung cancer.

Commentary on Inhaled 239PuO 2 in Dogs — A Prophylaxis against Lung Cancer?

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

Cuttler, Jerry M.; Feinendegen, Ludwig E.

Several studies on the effect of inhaled plutonium-dioxide particulates and the incidence of lung tumors in dogs reveal beneficial effects when the cumulative alpha-radiation dose is low. There is a threshold at an exposure level of about 100 cGy for excess tumor incidence and reduced lifespan. The observations conform to the expectations of the radiation hormesis dose-response model and contradict the predictions of the LNT hypothesis. These studies suggest investigating the possibility of employing low-dose alpha-radiation, such as from 239PuO 2 inhalation, as a prophylaxis against lung cancer.

A Proposed In Vitro Method to Assess Effects of Inhaled Particles on Lung Surfactant Function.

PubMed

Sørli, Jorid B; Da Silva, Emilie; Bäckman, Per; Levin, Marcus; Thomsen, Birthe L; Koponen, Ismo K; Larsen, Søren T

2016-03-01

The lung surfactant (LS) lining is a thin liquid film covering the air-liquid interface of the respiratory tract. LS reduces surface tension, enabling lung surface expansion and contraction with minimal work during respiration. Disruption of surface tension is believed to play a key role in severe lung conditions. Inhalation of aerosols that interfere with the LS may induce a toxic response and, as a part of the safety assessment of chemicals and inhaled medicines, it may be relevant to study their impact on LS function. Here, we present a novel in vitro method, based on the constrained drop surfactometer, to study LS functionality after aerosol exposure. The applicability of the method was investigated using three inhaled asthma medicines, micronized lactose, a pharmaceutical excipient used in inhaled medication, and micronized albumin, a known inhibitor of surfactant function. The surfactometer was modified to allow particles mixed in air to flow through the chamber holding the surfactant drop. The deposited dose was measured with a custom-built quartz crystal microbalance. The alterations allowed the study of continuously increasing quantified doses of particles, allowing determination of the dose of particles that affects the LS function. The tested pharmaceuticals did not inhibit the function of a model LS even at extreme doses--neither did lactose. Micronized albumin, however, impaired surfactant function. The method can discriminate between safe inhaled aerosols--as exemplified by the approved inhaled medicines and the pharmaceutical excipient lactose--and albumin known to impair lung functionality by inhibiting LS function.

Asthma Inhalers: Which One's Right for You?

MedlinePlus

... medication in these inhalers by breathing in a deep, fast breath. There are multiple-dose devices, which ... and convenient to carry. Doesn't require a deep, fast, inhaled breath. Doesn't require a deep, ...

Small difference in carcinogenic potency between GBP nanomaterials and GBP micromaterials.

PubMed

Gebel, Thomas

2012-07-01

Materials that can be described as respirable granular biodurable particles without known significant specific toxicity (GBP) show a common mode of toxicological action that is characterized by inflammation and carcinogenicity in chronic inhalation studies in the rat. This study was carried out to compare the carcinogenic potency of GBP nanomaterials (primary particle diameter 1-100 nm) to GBP micromaterials (primary particle diameter >100 nm) in a pooled approach. For this purpose, the positive GBP rat inhalation carcinogenicity studies have been evaluated. Inhalation studies on diesel engine emissions have also been included due to the fact that the mode of carcinogenic action is assumed to be the same. As it is currently not clear which dose metrics may best explain carcinogenic potency, different metrics have been considered. Cumulative exposure concentrations related to mass, surface area, and primary particle volume have been included as well as cumulative lung burden metrics related to mass, surface area, and primary particle volume. In total, 36 comparisons have been conducted. Including all dose metrics, GBP nanomaterials were 1.33- to 1.69-fold (mean values) and 1.88- to 3.54-fold (median values) more potent with respect to carcinogenicity than GBP micromaterials, respectively. Nine of these 36 comparisons showed statistical significance (p < 0.05, U test), all of which related to dose metrics based on particle mass. The maximum comparative potency factor obtained for one of these 9 dose metric comparisons based on particle mass was 4.71. The studies with diesel engine emissions did not have a major impact on the potency comparison. The average duration of the carcinogenicity studies with GBP nanomaterials was 4 months longer (median values 30 vs. 26 months) than the studies with GBP micromaterials, respectively. Tumor rates increase with age and lung tumors in the rat induced by GBP materials are known to appear late, that is, mainly after study durations longer than 24 months. Taking the different study durations into account, the real potency differences were estimated to be twofold lower than the relative potency factors identified. In conclusion, the chronic rat inhalation studies with GBP materials indicate that the difference in carcinogenic potency between GBP nanomaterials and GBP micromaterials is low can be described by a factor of 2-2.5 referring to the dose metrics mass concentration.

76 FR 59144 - Novartis Pharmaceuticals Corp. et al.; Withdrawal of Approval of 27 New Drug Applications and 58...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-23

... oral pressurized metered-dose inhaler that contained chlorofluorocarbons (CFCs) as a propellant. CFCs may no longer be used as a propellant for any albuterol metered-dose inhalers. (See 70 FR 17168, April...

78 FR 43210 - Bracco Diagnostics et al.; Withdrawal of Approval of 52 New Drug Applications and 77 Abbreviated...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-19

... pressurized metered-dose inhaler that contained chlorofluorocarbons (CFCs) as a propellant. CFCs may no longer be used as a propellant for any albuterol metered-dose inhalers (see 70 FR 17168, April 4, 2005...

Technical Note: A proposal of air ventilation system design criteria for a clinical room in a heavy-ion medical facility.

PubMed

Kum, Oyeon

2018-06-01

An optimized air ventilation system design for a treatment room in Heavy-ion Medical Facility is an important issue in the aspects of nuclear safety because the activated air produced in a treatment room can directly affect the medical staff and the general public in the radiation-free area. Optimized design criteria of air ventilation system for a clinical room in 430 MeV/u carbon ion beam medical accelerator facility was performed by using a combination of MCNPX2.7.0 and CINDER'90 codes. Effective dose rate and its accumulated effective dose by inhalation and residual gamma were calculated for a normal treatment scenario (2 min irradiation for one fraction) as a function of decay time. Natural doses around the site were measured before construction and used as reference data. With no air ventilation system, the maximum effective dose rate was about 3 μSv/h (total dose of 90 mSv/y) and minimum 0.2 μSv/h (total dose of 6 mSv/y), which are over the legal limits for medical staff and for the general public. Although inhalation dose contribution was relatively small, it was considered seriously because of its long-lasting effects in the body. The integrated dose per year was 1.8 mSv/y in the radiation-free area with the 20-min rate of air ventilation system. An optimal air ventilation rate of 20 min is proposed for a clinical room, which also agrees with the best mechanical design value. © 2018 American Association of Physicists in Medicine.

Drug delivery.

PubMed

Le Souëf, Peter N

2002-09-16

What we know: In preschool children, small-volume spacers perform better than large-volume spacers. Detergent is the best antistatic agent for spacers, increasing lung delivery two- to threefold, but it must not be rinsed off. A mouthpiece should be used in children aged 2-3 years or older, as lung delivery is two- to threefold higher for oral inhalation than nasal inhalation (ie, by mask). Inhaled drug doses do not generally need to be reduced in infants and young children owing to inefficiencies of delivery in younger patients. Nebulisers are "dinosaurs" and not needed for most children with asthma. What we need to know: What is the best inhalation technique for spacers? How long should children breathe, how many breaths should they take, and at what age should they breath-hold? How should children, parents and doctors be instructed to achieve optimal levels of electrostatic charge reduction for spacers? How much should inhaled steroid dose be reduced when a spacer is used optimally? What dosing instructions should be given for beta(2)-agonists delivered by spacer?

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

INDOS: conversational computer codes to implement ICRP-10-10A models for estimation of internal radiation dose to man

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

Killough, G.G.; Rohwer, P.S.

1974-03-01

INDOS1, INDOS2, and INDOS3 (the INDOS codes) are conversational FORTRAN IV programs, implemented for use in time-sharing mode on the ORNL PDP-10 System. These codes use ICRP10-10A models to estimate the radiation dose to an organ of the body of Reference Man resulting from the ingestion or inhalation of any one of various radionuclides. Two patterns of intake are simulated: intakes at discrete times and continuous intake at a constant rate. The IND0S codes provide tabular output of dose rate and dose vs time, graphical output of dose vs time, and punched-card output of organ burden and dose vs time.more » The models of internal dose calculation are discussed and instructions for the use of the INDOS codes are provided. The INDOS codes are available from the Radiation Shielding Information Center, Oak Ridge National Laboratory, P. O. Box X, Oak Ridge, Tennessee 37830. (auth)« less

Inhalational and dermal exposures during spray application of biocides.

PubMed

Berger-Preiss, Edith; Boehncke, Andrea; Könnecker, Gustav; Mangelsdorf, Inge; Holthenrich, Dagmar; Koch, Wolfgang

2005-01-01

Data on inhalational and potential dermal exposures during spray application of liquid biocidal products were generated. On the one hand, model experiments with different spraying devices using fluorescent tracers were carried out to investigate the influence of parameters relevant to the exposure (e.g. spraying equipment, nozzle size, direction of application). On the other hand, measurements were performed at selected workplaces (during disinfection operations in food and feed areas; pest control operations for private, public and veterinary hygiene; wood protection and antifouling applications) after application of biocidal products such as Empire 20, Responsar SC, Omexan-forte, Actellic, Perma-forte; Fendona SC, Pyrethrum mist; CBM 8, Aldekol Des 03, TAD CID, Basileum, Basilit. The measurements taken in the model rooms demonstrated dependence of the inhalation exposure on the type of spraying device used, in the following order: "spraying with low pressure" < "airless spraying" < "fogging" indicating that the particle diameter of the released spray droplets is the most important parameter. In addition inhalation exposure was lowest when the spraying direction was downward. Also for the potential dermal exposure, the spraying direction was of particular importance: overhead spraying caused the highest contamination of body surfaces. The data of inhalational and potential dermal exposures gained through workplace measurements showed considerable variation. During spraying procedures with low-pressure equipments, dose rates of active substances inhaled by the operators ranged from 7 to 230 microg active substance (a.s.)/h. An increase in inhaled dose rates (6-33 mg a.s./h) was observed after use of high application volumes/time unit during wood protection applications indoors. Spraying in the veterinary sector using medium-pressure sprayers led to inhaled dose rates between 2 and 24mga.s./h. The highest inhaled dose rates were measured during fogging (114 mg a.s./h) and after-high-pressure applications in the antifouling sector (110-300 mg a.s./h). The potential dermal exposure of spray operators was lowest (dose rates from 0.2 to 7 mg a.s./h) in the areas of food and feed disinfection and private and public hygiene during spraying with low-pressure devices. During fogging, wood protection and antifouling applications, high-potential dermal exposures of the operators were determined. Dermal dose rates varied between 100 and 34,000 mg a.s./h.

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.

Competence in metered dose inhaler technique among community pharmacy professionals in Gondar town, Northwest Ethiopia: Knowledge and skill gap analysis.

PubMed

Belachew, Sewunet Admasu; Tilahun, Fasil; Ketsela, Tirsit; Achaw Ayele, Asnakew; Kassie Netere, Adeladlew; Getnet Mersha, Amanual; Befekadu Abebe, Tamrat; Melaku Gebresillassie, Begashaw; Getachew Tegegn, Henok; Asfaw Erku, Daniel

2017-01-01

When compared to systemic administration, if used correctly inhalers deliver a smaller enough percent of the drug right to the site of action in the lungs, with a faster onset of effect and with reduced systemic availability that minimizes adverse effects. However, the health professionals' and patients' use of metered dose inhaler is poor. This study was aimed to explore community pharmacy professionals' (pharmacists' and druggists') competency on metered dose inhaler (MDI) technique. A cross sectional study was employed on pharmacy professionals working in community drug retail outlets in Gondar town, northwest Ethiopia from March to May 2017. Evaluation tool was originally taken and adapted from the National Asthma Education and Prevention Programmes of America (NAEPP) step criteria for the demonstration of a metered dose inhaler to score the knowledge/proficiency of using the inhaler. Among 70 community pharmacy professionals approached, 62 (32 pharmacists and 30 druggists/Pharmacy technicians) completed the survey with a response rate of 85.6%. Only three (4.8%) respondents were competent by demonstrating the vital steps correctly. Overall, only 13 participants got score seven or above, but most of them had missed the essential steps which included steps 1, 2, 5, 6, 7 or 8. There was a significant difference (P = 0.015) in competency of demonstrating adequate inhalational technique among respondents who took training on basic inhalational techniques and who did not. This study shown that, community pharmacy professionals' competency of MDI technique was very poor. So as to better incorporate community pharmacies into future asthma illness management and optimize the contribution of pharmacists, interventions would emphasis to improve the total competence of community pharmacy professionals through establishing and providing regular educational programs.

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.

Mercury study report to Congress. Volume 5. Health effects of mercury and mercury compounds

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

Hassett-Sipple, B.; Swartout, J.; Schoeny, R.

1997-12-01

This volume summarizes the available information on human health effects and animal data for hazard identification and dose-response assessment for three forms of mercury: elemental mercury, mercury chloride (inorganic mercury), and methylmercury (organic mercury). Effects are summarized by endpoint. The risk assessment evaluates carcinogenicity, mutagenicity, developmental toxicity and general systemic toxicity of these chemical species of mercury. Toxicokinetics (absorption, distribution, metabolism and excretion) are described for each of the three mercury species. Reference doses are calculated for inorganic and methylmercury; a reference concentrations for inhaled elemental mercury is provided. A quantitative analysis of factors contributing to variability and uncertainty inmore » the methylmercury RfD is provided in an appendix. Interactions and sensitive populations are described. the draft volume assesses ongoing research and research needs to reduce uncertainty surrounding adverse human health consequences of methylmercury exposure.« less

ANALYSIS OF RESPIRATORY DESPOSITION DOSE OF INHALED AMBIENT AEROSOLS FOR DIFFERENT SIZE FRACTIONS

EPA Science Inventory

ANALYSIS OF RESPIRATORY DEPOSITION DOSE OF INHALED AMBIENT AEROSOLS FOR DIFFERENT SIZE FRACTIONS. Chong S. Kim, SC. Hu**, PA Jaques*, US EPA, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711; **IIT Research Institute, Chicago, IL; *S...

ANALYSIS OF RESPIRATORY DEPOSITION OF INHALED AMBIENT AEROSOLS FOR DIFFERENT DOSE METRICS

EPA Science Inventory

ANALYSIS OF RESPIRATORY DEPOSITION OF INHALED AMBIENT AEROSOLS FOR DIFFERENT DOSE METRICS.
Chong S. Kim, SC. Hu**, PA Jaques*, US EPA, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711; **IIT Research Institute, Chicago, IL; *South...

Decision Support Model to Optimize Site Characterization Activities Taken in Compliance with the Comprehensive Environmental Response Compensation and Liability Act

DTIC Science & Technology

1995-12-01

Contingency Plan ............................... 10 Table 2: Summary of Inhalation Emission Factors (K) for Equation ( 1 ...surveys for exposure factors commonly used in risk assessment (EPA, 1989a: 1 - 1 ). Exposure can take place via three possible routes, the inhalation ...Equation ( 1 ) calculates the dose for the inhalation route (USEPA, 1991 a:51-52; USEPA, 1989b:6-44). Dose - (C)(IRXETXEFXED) (K)(BWXAT) where C

IRIS Toxicological Review of Vanadium Pentoxide ...

EPA Pesticide Factsheets

On September 30, 2011, the draft Toxicological Review of Vanadium Pentoxide and the charge to external peer reviewers were released for external peer review and public comment. The Toxicological Review and charge were reviewed internally by EPA and by other federal agencies and White House Offices before public release. In the new IRIS process (May 2009), introduced by the EPA Administrator, all written comments on IRIS assessments submitted by other federal agencies and White House Offices will be made publicly available. Accordingly, interagency comments and the interagency science consultation draft of the IRIS Toxicological Review of Vanadium Pentoxide and the charge to external peer reviewers are posted on this site. EPA is reassessing its IRIS toxicological review of vanadium pentoxide (CASRN 1314-62-1). This vanadium pentoxide reassessment consists of an oral reference dose (RfD), an inhalation reference concentration (RfC), an inhalation unit risk (IUR) and a cancer weight of evidence descriptor. This is the first assessment developing an RfC or IUR for this compound. This assessment is intended to provide human health data to support agency regulatory decisions.

Fenoterol delivery by Respimat soft mist inhaler versus CFC metered dose inhaler: cumulative dose-response study in asthma patients.

PubMed

Vincken, Walter; Dewberry, Helen; Moonen, Diane

2003-09-01

Respimat (RMT) soft mist inhaler (SMI) is a novel, propellant-free alternative to chlorofluorocarbon metered-dose inhalers (CFC-MDIs). The aim of this study was to evaluate the safety and establish the equipotent dose of fenoterol delivered by RMT SMI vs. a conventional MDI. Double-blind, randomized, crossover, comparative study between fenoterol inhaled via RMT (either 50 microg/actuation, RMT50; or 100 microg/actuation. RMT100) and MDI (100 microg/actuation; MDI100). A total of 41 asthma patients received cumulative doses of fenoterol 600 microg (RMT50) or 1200 microg (RMT100 and MDI100) on 3 test days. The bronchodilator response (forced expiratory volume in 1 second [FEV1]) was considered therapeutically equivalent (i.e., noninferior) if the 95% confidence intervals for the difference in their mean changes from baseline were within limits of +/- 0.15L. Systemic exposure was evaluated from plasma fenoterol levels. Adverse events (AEs) were recorded. RMT50 and RMT100 produced noninferior bronchodilatation to MDI100 from 30minutes after the first dose. RMT50 showed equivalent safety and tolerability to MDI100, whereas RMT100 produced a higher incidence of AEs, a significantly greater plasma potassium reduction and a significant increase in pulse rate. Fenoterol plasma levels were twice as high with RMT100 as with RMT50 or MDI100. CONCLUSIONS; The nominal dose of fenoterol administered via RMT SMI can be at least halved to achieve equivalent efficacy, safety, and tolerability to a MDI.

Systemic and bronchodilator effects of inhaled rac-formoterol in subjects with chronic obstructive pulmonary disease: a dose–response study

PubMed Central

Whale, Christopher I; Sovani, Milind P; Mortimer, Kevin J; Harrison, Timothy W; Tattersfield, Anne E

2008-01-01

AIMS Rac-formoterol is effective as maintenance treatment for both asthma and chronic obstructive pulmonary disease (COPD) and is now used as relief therapy in asthma. Using rac-formoterol for relief and maintenance treatment could involve inhalation of high doses, and whether this is of benefit in COPD is uncertain. Our aim was to determine whether higher doses of inhaled rac-formoterol produce systemic adverse effects that outweigh the limited bronchodilator benefit seen in subjects with COPD. METHODS We examined airway and systemic effects of 6, 12, 24 and 48 μg rac-formoterol and placebo on separate days in 20 subjects with symptomatic COPD [forced expiratory volume in 1 s (FEV1) 47% predicted]. FEV1, oxygen saturation, dyspnoea, 6-min walk distance, patient satisfaction and systemic effects were measured and treatment was assessed against placebo and for dose–response effects. RESULTS FEV1[area under the time–response curve (AUC)] and satisfaction scores increased with all formoterol doses compared with placebo, as did AUC tremor with the 24- and 48-μg doses and AUC heart rate with the 48-μg dose. A dose–response relationship was seen with FEV1 and tremor, but not with satisfaction scores. There was no difference between placebo and rac-formoterol for other variables. CONCLUSIONS Our results show that in patients with COPD rac-formoterol improves FEV1 and patient satisfaction without a corresponding reduction in dyspnoea. Since the systemic effects from a relatively high dose were minimal, its use as relief medication in COPD merits further evaluation. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The long-acting inhaled β2-agonist formoterol has systemic effects when taken in high doses. It can be used as relief medication in asthma and there is interest in this approach in chronic obstructive pulmonary disease (COPD). Relief medication can involve high doses, and in subjects with COPD who have limited ability to bronchodilate the adverse effects can outweigh the benefits. There are concerns with the overall safety of high-dose β2-agonists in subjects with COPD, and this study looks at the balance of beneficial and adverse effects of a range of doses of inhaled formoterol. WHAT THIS STUDY ADDS Among subjects with COPD, high-dose inhaled formoterol produced a dose-related increase in forced expiratory volume in 1 s without a corresponding reduction in dyspnoea or increase in walk distance.Systemic effects were modest, however, and high doses did not appear to reduce patient satisfaction.Although further safety data are needed, inhaled formoterol may have a role as relief medication in COPD. PMID:18394012

Is the ‘blue’ colour convention for inhaled reliever medications important? A UK-based survey of healthcare professionals and patients with airways disease

PubMed Central

Fletcher, Monica; Scullion, Jane; White, John; Thompson, Bronwen; Capstick, Toby

2016-01-01

In many countries, short-acting β2-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. PMID:27808097

The combination of fluticasone furoate and vilanterol trifenatate in the management of asthma: clinical trial evidence and experience

PubMed Central

Albertson, Timothy E.; Richards, John R.; Zeki, Amir A.

2015-01-01

The treatment of persistent asthma has been aided by the recent approval of new medications. The combined inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) powder inhaler fluticasone furoate (FF)/vilanterol trifenatate (VI) is one of these new agents, which was recently approved as a maintenance therapy for persistent asthma. This once-daily ICS/LABA inhaler has previously been approved and used in chronic obstructive pulmonary disease as a maintenance therapy. Both FF and VI individually have been shown to have efficacy in the treatment of persistent asthma; the combination of FF/VI at the dose of 100/25 μg daily improves trough peak expiratory flows and forced expiratory volume in 1 s. It also reduces the frequency of asthma exacerbations in patients with persistent asthma. The once-daily dosing is well tolerated, with limited clinically significant adverse events; the once-daily inhaled dosing regimen should also improve medication adherence. The data supporting the use of the FF/VI inhaler in persistent asthma are reviewed. The dry powder inhaler of FF/VI (100/25 μg) is an effective and well tolerated once-daily maintenance treatment for patients with persistent asthma. PMID:26668137

Pressurised metered dose inhaler-spacer technique in young children improves with video instruction.

PubMed

Shaw, Nicole; Le Souëf, Peter; Turkovic, Lidija; McCahon, Lucy; Kicic, Anthony; Sly, Peter D; Devadason, Sunalene; Schultz, André

2016-07-01

The importance of good device technique to maximise delivery of aerosolised medications is widely recognised. Pressurised metered dose inhaler (pMDI)-spacer technique was investigated in 122 children, aged 2-7 years, with asthma. Eight individual steps of device technique were evaluated before and after viewing an instructional video for correct device technique. Video measurements were repeated every three months for nine months. Device technique improved directly after video instruction at the baseline study visit (p < 0.001) but had no immediate effect at subsequent visits. Additionally, pMDI-spacer technique improved with successive visits over one year for the group overall as evidenced by increases in the proportion of children scoring maximal (p = 0.02) and near-maximal (p = 0.04) scores. Repeated video instruction over time improves inhaler technique in young children. • Correct device technique is considered essential for sufficient delivery of inhaled medication. • Poor inhaler use is common in young asthmatic children using pressurised metered dose inhalers and spacers. What is New: • Video instruction could be used as a strategy to improve device technique in young children.

Radon-222 in groundwater and effective dose due to ingestion and inhalation in the city of Ibadan, Nigeria.

PubMed

Ademola, Janet Ayobami; Oyeleke, Oyebode Akanni

2017-03-20

Radon concentration in groundwater collected from the eleven Local Government Areas (LGAs) of Ibadan, Nigeria, was analyzed. Annual effective doses due to ingestion and inhalation of radon from the consumption of the water were determined. The arithmetic means (AMs) of radon concentration for the 11 LGAs varied from 2.18 to 76.75 Bq l -1 with a standard deviation of 1.57 and 70.64 Bq l -1 , respectively. The geometric means (GMs) varied from 1.67 to 49.47 Bq l -1 with geometric standard deviation of 2.22 and 3.04, respectively. About 58% of the 84 water samples examined had a higher concentration of radon than the 11.1 Bq l -1 recommended by United States Environmental Protection Agency (USEPA); the AMs of six LGAs and GMs of three LGAs were higher than the recommended value. However the AMs and GMs of all the LGAs with about 93% of the water sampled were lower than the 100 Bq l -1 recommended by the World Health Organization and EURATOM drinking water directive. The concentration of radon varied with the geological formation of the area. The AMs of the annual effective dose due to ingestion of radon in water ranged from 0.036 to 1.261 mSv y -1 , 0.071 to 2.521 mSv y -1 and 0.042 to 1.471 mSv y -1 for adult, child and infant, respectively and the GMs in the range of 0.026 to 0.813, 0.055 to 1.625 and 0.032 to 0.948 mSv y -1 , respectively. The AMs of 10 LGAs and GMs of 7 LGAs were higher than the recommended reference dose level of 0.1 mSv y -1 from the consumption of water for the duration of one year for all the three categories of people. The AMs and GMs of the annual effective dose due to inhalation of radon in drinking water ranged from 0.533 to 18.82 μSv y -1 and 0.411 to 12.13 μSv y -1 , respectively, contributing less to the overall dose.

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...

Immunoglobulin G particles manufacturing by spray drying process for pressurised metered dose inhaler formulations.

PubMed

Carli, V; Menu-Bouaouiche, L; Cardinael, P; Benissan, L; Coquerel, G

2018-07-01

The objective of this work is to show the feasibility of manufacturing from a spray drying process particles containing immunoglobulin G capable of being administered by inhalation via a pressurized metered dose inhaler. Spray drying were made from aqueous solutions containing IgG and two types of excipients, mannitol and trehalose, with two ratios: 25% w/w and 75%w/w. The physicochemical and aerodynamic properties of the powders obtained were characterized just after manufacturing and after 1 month of storage at 40°C/75% RH according to criteria defined as needed to satisfy an inhaled formulation with a pressurized metered dose inhaler. Maintain of the biological activity and the structure of IgG after atomization was also tested by slot blot and circular dichroism. All spray-dried powders presented a median diameter lower than 5μm. The powders atomized with trehalose showed a solid state more stable than those atomized with mannitol. All atomized powders were in the form of wrinkled particles regardless the nature and the ratios of excipients. The results showed that the aerosolisation properties were compliant with the target, independently of the excipient used at a ratio of 25% w/w IgG-excipient. Moreover, the addition of excipient during the atomization process the denaturation of IgG was limited. This study showed that the use of trehalose as excipient could satisfy the requirements of an inhaled formulation with a pressurized metered dose inhaler. Copyright © 2018 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

Modulation of Distinct Asthmatic Phenotypes in Mice by Dose-Dependent Inhalation of Microbial Products

PubMed Central

Whitehead, Gregory S.; Thomas, Seddon Y.

2013-01-01

Background: Humans with asthma display considerable heterogeneity with regard to T helper (Th) 2–associated eosinophilic and Th17-associated neutrophilic inflammation, but the impact of the environment on these different forms of asthma is poorly understood. Objective: We studied the nature and longevity of asthma-like responses triggered by inhalation of allergen together with environmentally relevant doses of inhaled lipopolysaccharide (LPS). Methods: Ovalbumin (OVA) was instilled into the airways of mice together with a wide range of LPS doses. Following a single OVA challenge, or multiple challenges, animals were assessed for pulmonary cytokine production, airway inflammation, and airway hyperresponsiveness (AHR). Results: Mice instilled with OVA together with very low doses (≤ 10–3 μg) of LPS displayed modest amounts of Th2 cytokines, with associated airway eosinophilia and AHR after a single challenge, and these responses were sustained after multiple OVA challenges. When the higher but still environmentally relevant dose of 10–1 μg LPS was used, mice initially displayed similar Th2 responses, as well as Th17-associated neutrophilia. After multiple OVA challenges, however, the 10–1 μg LPS animals also accumulated large numbers of allergen-specific T regulatory (Treg) cells with high levels of inducible co-stimulatory molecule (ICOS). As a result, asthma-like features in these mice were shorter-lived than in mice sensitized using lower doses of LPS. Conclusions: The nature and longevity of Th2, Th17, and Treg immune responses to inhaled allergen are dependent on the quantity of LPS inhaled at the time of allergic sensitization. These findings might account in part for the heterogeneity of inflammatory infiltrates seen in lungs of asthmatics. Citation: Whitehead GS, Thomas SY, Cook DN. 2014. Modulation of distinct asthmatic phenotypes in mice by dose-dependent inhalation of microbial products. Environ Health Perspect 122:34–42; http://dx.doi.org/10.1289/ehp.1307280 PMID:24168764

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.

A hand-held apparatus for "nose-only" exposure of mice to inhalable microparticles as a dry powder inhalation targeting lung and airway macrophages.

PubMed

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

2008-05-10

Microparticles containing isoniazid and rifabutin were aerosolised using a simple apparatus fabricated from a 15-ml centrifuge tube. The dose available for inhalation by rodents was determined by collecting microparticles emitted at the delivery port. The dose available for inhalation was proportional to durations of exposure ranging from 10 to 90 s (10.5-13.5 CV%) and the weight of powder taken for fluidization (10-50 mg, r2=0.982). The apparatus was then used to administer inhalations of microparticles to mice. Other groups of mice received free rifabutin orally, or by i.v. injection. Rifabutin was estimated in serum and tissues of dosed mice by HPLC. When approximately 20 mg of microparticles were loaded in the apparatus, approximately 2.5 mg were collected at the delivery port in 30 s of operation. Mice inhaled approximately 300 microg of the 2.5 mg emitted at the delivery port. Airway and lung macrophages of mice receiving inhalations for 30 s accumulated 0.38 microg of rifabutin, while the amount in blood serum of these mice was 0.62 microg. In mice receiving 83 microg rifabutin i.v. or orally, the intracellular amounts were 0.06 and 0.07 microg respectively, while the amounts in serum were 1.02 and 0.80 microg. These observations confirmed that inhalation of microparticles targeted airway and lung macrophages.

Dose and effect of inhaled ozone in resting versus exercising human subjects: comparison with resting rats

EPA Science Inventory

Dose and effect of inhaled ozone in resting versus exercising human subjects: comparison with resting rats Authors: Gary E. Hatch, John McKee, James Brown, Bill McDonnell, Elston Seal, Joleen Soukup, Ralph Slade, Kay Crissman and Robert Devlin, National Health and Environmental...

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.

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.

HADOC: a computer code for calculation of external and inhalation doses from acute radionuclide releases

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

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

The computer code HADOC (Hanford Acute Dose Calculations) is described and instructions for its use are presented. The code calculates external dose from air submersion and inhalation doses following acute radionuclide releases. Atmospheric dispersion is calculated using the Hanford model with options to determine maximum conditions. Building wake effects and terrain variation may also be considered. Doses are calculated using dose conversion factor supplied in a data library. Doses are reported for one and fifty year dose commitment periods for the maximum individual and the regional population (within 50 miles). The fractional contribution to dose by radionuclide and exposure modemore » are also printed if requested.« less

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.

Basis for the ICRP’s updated biokinetic model for carbon inhaled as CO 2

DOE PAGES

Leggett, Richard W.

2017-03-02

Here, the International Commission on Radiological Protection (ICRP) is updating its biokinetic and dosimetric models for occupational intake of radionuclides (OIR) in a series of reports called the OIR series. This paper describes the basis for the ICRP's updated biokinetic model for inhalation of radiocarbon as carbon dioxide (CO 2) gas. The updated model is based on biokinetic data for carbon isotopes inhaled as carbon dioxide or injected or ingested as bicarbonatemore » $$({{{\\rm{HCO}}}_{3}}^{-}).$$ The data from these studies are expected to apply equally to internally deposited (or internally produced) carbon dioxide and bicarbonate based on comparison of excretion rates for the two administered forms and the fact that carbon dioxide and bicarbonate are largely carried in a common form (CO 2–H$${{{\\rm{CO}}}_{3}}^{-})$$ in blood. Compared with dose estimates based on current ICRP biokinetic models for inhaled carbon dioxide or ingested carbon, the updated model will result in a somewhat higher dose estimate for 14C inhaled as CO 2 and a much lower dose estimate for 14C ingested as bicarbonate.« less

Basis for the ICRP’s updated biokinetic model for carbon inhaled as CO 2

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

Leggett, Richard W.

Here, the International Commission on Radiological Protection (ICRP) is updating its biokinetic and dosimetric models for occupational intake of radionuclides (OIR) in a series of reports called the OIR series. This paper describes the basis for the ICRP's updated biokinetic model for inhalation of radiocarbon as carbon dioxide (CO 2) gas. The updated model is based on biokinetic data for carbon isotopes inhaled as carbon dioxide or injected or ingested as bicarbonatemore » $$({{{\\rm{HCO}}}_{3}}^{-}).$$ The data from these studies are expected to apply equally to internally deposited (or internally produced) carbon dioxide and bicarbonate based on comparison of excretion rates for the two administered forms and the fact that carbon dioxide and bicarbonate are largely carried in a common form (CO 2–H$${{{\\rm{CO}}}_{3}}^{-})$$ in blood. Compared with dose estimates based on current ICRP biokinetic models for inhaled carbon dioxide or ingested carbon, the updated model will result in a somewhat higher dose estimate for 14C inhaled as CO 2 and a much lower dose estimate for 14C ingested as bicarbonate.« less

Optimization and Dose Estimation of Aerosol Delivery to Non-Human Primates.

PubMed

MacLoughlin, Ronan J; van Amerongen, Geert; Fink, James B; Janssens, Hettie M; Duprex, W Paul; de Swart, Rik L

2016-06-01

In pre-clinical animal studies, the uniformity of dosing across subjects and routes of administration is a crucial requirement. In preparation for a study in which aerosolized live-attenuated measles virus vaccine was administered to cynomolgus monkeys (Macaca fascicularis) by inhalation, we assessed the percentage of a nebulized dose inhaled under varying conditions. Drug delivery varies with breathing parameters. Therefore we determined macaque breathing patterns (tidal volume, breathing frequency, and inspiratory to expiratory (I:E) ratio) across a range of 3.3-6.5 kg body weight, using a pediatric pneumotachometer interfaced either with an endotracheal tube or a facemask. Subsequently, these breathing patterns were reproduced using a breathing simulator attached to a filter to collect the inhaled dose. Albuterol was nebulized using a vibrating mesh nebulizer and the percentage inhaled dose was determined by extraction of drug from the filter and subsequent quantification. Tidal volumes ranged from 24 to 46 mL, breathing frequencies from 19 to 31 breaths per minute and I:E ratios from 0.7 to 1.6. A small pediatric resuscitation mask was identified as the best fitting interface between animal and pneumotachometer. The average efficiency of inhaled dose delivery was 32.1% (standard deviation 7.5, range 24%-48%), with variation in tidal volumes as the most important determinant. Studies in non-human primates aimed at comparing aerosol delivery with other routes of administration should take both the inter-subject variation and relatively low efficiency of delivery to these low body weight mammals into account.

Effect of delayed pMDI actuation on the lung deposition of a fixed-dose combination aerosol drug.

PubMed

Farkas, Árpád; Horváth, Alpár; Kerekes, Attila; Nagy, Attila; Kugler, Szilvia; Tamási, Lilla; Tomisa, Gábor

2018-06-07

Lack of coordination between the beginning of the inhalation and device triggering is one of the most frequent errors reported in connection with the use of pMDI devices. Earlier results suggested a significant loss in lung deposition as a consequence of late actuation. However, most of our knowledge on the effect of poor synchronization is based on earlier works on CFC devices emitting large particles with high initial velocities. The aim of this study was to apply numerical techniques to analyse the effect of late device actuation on the lung dose of a HFA pMDI drug emitting high fraction of extrafine particles used in current asthma and COPD therapy. A computational fluid and particle dynamics model was combined with stochastic whole lung model to quantify the amount of drug depositing in the extrathoracic airways and in the lungs. High speed camera measurements were also performed to characterize the emitted spray plume. Our results have shown that for the studied pMDI drug late actuation leads to reasonable loss in terms of lung dose, unless it happens in the second half of the inhalation period. Device actuation at the middle of the inhalation caused less than 25% lung dose reduction relative to the value characterizing perfect coordination, if the inhalation time was between 2-5 s and inhalation flow rate between 30-150 L/min. This dose loss is lower than the previously known values of CFC devices and further support the practice of triggering the device shortly after the beginning of the inhalation instead of forcing a perfect synchronization and risking mishandling and poor drug deposition. Copyright © 2018. Published by Elsevier B.V.

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 Central

Komase, Yuko; Asako, Akimoto; Kobayashi, Akihiro; Sharma, Raj

2014-01-01

Background 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. Methods 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. Results 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. Conclusion 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. PMID:25525354

Oral candidiasis associated with inhaled corticosteroid use: comparison of fluticasone and beclomethasone.

PubMed

Fukushima, Chizu; Matsuse, Hiroto; Tomari, Shinya; Obase, Yasushi; Miyazaki, Yoshitsugu; Shimoda, Terufumi; Kohno, Shigeru

2003-06-01

Inhaled steroids such as fluticasone propionate and beclomethasone dipropionate play a central role in the treatment of bronchial asthma. Fluticasone exhibits excellent clinical effectiveness; however, oral adverse effects can occur. To compare the frequency of oral candidiasis in asthmatic patients treated with fluticasone and beclomethasone, to evaluate the effect of gargling with amphotericin B, and to measure the inhalation flow rate on candidiasis. The study consisted of 143 asthmatic patients who were treated with inhaled steroids, 11 asthmatic patients not treated with inhaled steroids, and 86 healthy volunteers. Quantitative fungal culture was performed by aseptically obtaining a retropharyngeal wall swab from these patients. Patients with positive results were treated with gargling using a 1:50 dilution amphotericin B solution. In asthmatic patients treated with fluticasone, the inhalation flow rate was measured using an inspiratory flow meter. The amount of Candida spp. was significantly greater in asthmatic patients taking inhaled steroids compared with those who were not. It was also significantly greater in patients with oral symptoms than asymptomatic patients and significantly greater in asthmatic patients treated with fluticasone than in those treated with beclomethasone. Although the presence of Candida did not correlate with the inhaled dose of beclomethasone, it did increase with the dose of fluticasone. Gargling with amphotericin B was effective in most asthmatic patients with candidiasis. Candidiasis was not due to inappropriate flow rates during inhalation of steroids. Fungal culture of a retropharyngeal wall swab may be useful for predicting the risk of developing oral candidiasis in asthmatic patients treated with inhaled steroids. The amount of isolated Candida was significantly greater in asthmatic patients treated with fluticasone than in those treated with beclomethasone. Attention to dosage is required as the amount of Candida increased with dose of fluticasone. Gargling with a 1:50 dilution of amphotericin B is effective in treating oral candidiasis of asthmatic patients treated with inhaled steroids.

Incorporating a Capability for Estimating Inhalation Doses in ...

EPA Pesticide Factsheets

Report and Data Files This report presents the approach to be used to incorporate in the U.S. Environmental Protection Agency’s TEVA-SPOT software (U.S.EPA 2014) a capability for estimating inhalation doses that result from the most important sources of contaminated aerosols and volatile contaminants during a contamination event.

Safety of an alkalinizing buffer designed for inhaled medications in humans.

PubMed

Davis, Michael D; Walsh, Brian K; Dwyer, Scott T; Combs, Casey; Vehse, Nico; Paget-Brown, Alix; Pajewski, Thomas; Hunt, John F

2013-07-01

Airway acidification plays a role in disorders of the pulmonary tract. We hypothesized that the inhalation of alkalinized glycine buffer would measurably alkalinize the airways without compromising lung function or causing adverse events. We evaluated the safety of an inhaled alkaline glycine buffer in both healthy subjects and in subjects with stable obstructive airway disease. This work includes 2 open-label safety studies. The healthy controls were part of a phase 1 safety study of multiple inhalations of low-dose alkaline glycine buffer; nebulized saline was used as a comparator in 8 of the healthy controls. Subsequently, a phase 2 study in subjects with stable obstructive airway disease was completed using a single nebulized higher-dose strategy of the alkaline inhalation. We studied 20 non-smoking adults (10 healthy controls and 10 subjects with obstructive airway disease), both at baseline and after inhalation of alkaline buffer. We used spirometry and vital signs as markers of clinical safety. We used changes in fraction of exhaled nitric oxide (NO) and exhaled breath condensate (EBC) pH as surrogate markers of airway pH modification. Alkaline glycine inhalation was tolerated by all subjects in both studies, with no adverse effects on spirometric parameters or vital signs. Airway alkalinization was confirmed by a median increase in EBC pH of 0.235 pH units (IQR 0.56-0.03, P = .03) in subjects after inhalation of the higher-dose alkaline buffer (2.5 mL of 100 mmol/L glycine). Alkalinization of airway lining fluid is accomplished with inhalation of alkaline glycine buffer and causes no adverse effects on pulmonary function or vital signs.

Validation of a metered dose inhaler electronic monitoring device: implications for asthma clinical trial use.

PubMed

Pilcher, Janine; Holliday, Mark; Ebmeier, Stefan; McKinstry, Steve; Messaoudi, Fatiha; Weatherall, Mark; Beasley, Richard

2016-01-01

The SmartTouch Ventolin monitor (Adherium, Auckland, New Zealand) is an electronic monitor for use with a Ventolin metered dose inhaler, which records the date and time of inhaler actuations. This technology has the potential to allow in-depth analysis of patterns of inhaler use in clinical trial settings. The aim of this study was to determine the accuracy of the SmartTouch Ventolin monitor in recording Ventolin actuations. 20 SmartTouch Ventolin monitors were attached to Ventolin metered dose inhalers. Bench testing was performed over a 10-week period, to reflect the potential time frame between visits in a clinical trial. Inhaler actuations were recorded in a paper diary, which was compared with data uploaded from the monitors. 2560 actuations were performed during the 10-week study period. Monitor sensitivity for diary-recorded actuations was 99.9% with a lower 97.5% confidence bound of 99.7%. The positive predictive value for diary-recorded actuations was 100% with a 97.5% lower confidence bound of 99.9%. The SmartTouch Ventolin monitor is highly accurate in recording and retaining electronic data. It can be recommended for use in clinical trial settings in which training and quality control systems are incorporated into study protocols to ensure accurate data acquisition.

Validation of a metered dose inhaler electronic monitoring device: implications for asthma clinical trial use

PubMed Central

Pilcher, Janine; Holliday, Mark; Ebmeier, Stefan; McKinstry, Steve; Messaoudi, Fatiha; Weatherall, Mark; Beasley, Richard

2016-01-01

Background The SmartTouch Ventolin monitor (Adherium, Auckland, New Zealand) is an electronic monitor for use with a Ventolin metered dose inhaler, which records the date and time of inhaler actuations. This technology has the potential to allow in-depth analysis of patterns of inhaler use in clinical trial settings. The aim of this study was to determine the accuracy of the SmartTouch Ventolin monitor in recording Ventolin actuations. Methods 20 SmartTouch Ventolin monitors were attached to Ventolin metered dose inhalers. Bench testing was performed over a 10-week period, to reflect the potential time frame between visits in a clinical trial. Inhaler actuations were recorded in a paper diary, which was compared with data uploaded from the monitors. Results 2560 actuations were performed during the 10-week study period. Monitor sensitivity for diary-recorded actuations was 99.9% with a lower 97.5% confidence bound of 99.7%. The positive predictive value for diary-recorded actuations was 100% with a 97.5% lower confidence bound of 99.9%. Conclusions The SmartTouch Ventolin monitor is highly accurate in recording and retaining electronic data. It can be recommended for use in clinical trial settings in which training and quality control systems are incorporated into study protocols to ensure accurate data acquisition. PMID:27026805

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

The Evolution of Pressurized Metered-Dose Inhalers from Early to Modern Devices.

PubMed

Roche, Nicolas; Dekhuijzen, P N Richard

2016-08-01

Pressurized metered-dose inhalers (pMDIs) are sometimes viewed as old-fashioned and as having been superseded by dry powder inhalers (DPIs). Here, we review the technological advances that characterize modern pMDIs, and consider how they can influence the effectiveness of drug delivery for patients with asthma and chronic obstructive pulmonary disease. Compared with old chlorofluorocarbon (CFC)-based inhalers, many hydrofluoroalkane (HFA)-driven pMDIs have more favorable plume characteristics such as a reduced velocity and a higher fine particle fraction; together, these advances have resulted in the development of pMDIs with reduced oropharyngeal deposition and increased lung deposition. In addition, the plume from many HFA-pMDIs is warmer, which may facilitate their use by patients; moreover, devices are equipped with dose counters, which improves their reliability. As well as reviewing the technological advances of pMDIs, we also discuss the importance of individualizing inhaler therapies to each patient by accounting for their personal preferences and natural breathing patterns. Because pMDIs and DPIs differ considerably in their handling characteristics, matching the right inhaler to the right patient is key to ensuring effective therapy and good compliance. Finally, the majority of patients can be trained successfully in the correct use of their pMDI; training and regular monitoring of inhalation technique are essential prerequisites for effective therapy. While the 'ideal inhaler' may not exist, pMDIs are an effective device option suitable for many patients. pMDIs, together with other types of devices, offer opportunities for the effective individualization of treatments.

Cherry-flavoured electronic cigarettes expose users to the inhalation irritant, benzaldehyde.

PubMed

Kosmider, Leon; Sobczak, Andrzej; Prokopowicz, Adam; Kurek, Jolanta; Zaciera, Marzena; Knysak, Jakub; Smith, Danielle; Goniewicz, Maciej L

2016-04-01

Many non-cigarette tobacco products, including e-cigarettes, contain various flavourings, such as fruit flavours. Although many flavourings used in e-cigarettes are generally recognised as safe when used in food products, concerns have been raised about the potential inhalation toxicity of these chemicals. Benzaldehyde, which is a key ingredient in natural fruit flavours, has been shown to cause irritation of respiratory airways in animal and occupational exposure studies. Given the potential inhalation toxicity of this compound, we measured benzaldehyde in aerosol generated in a laboratory setting from flavoured e-cigarettes purchased online and detected benzaldehyde in 108 out of 145 products. The highest levels of benzaldehyde were detected in cherry-flavoured products. The benzaldehyde doses inhaled with 30 puffs from flavoured e-cigarettes were often higher than doses inhaled from a conventional cigarette. Levels in cherry-flavoured products were >1000 times lower than doses inhaled in the workplace. While e-cigarettes seem to be a promising harm reduction tool for smokers, findings indicate that using these products could result in repeated inhalation of benzaldehyde, with long-term users risking regular exposure to the substance. Given the uncertainty surrounding adverse health effects stemming from long-term inhalation of flavouring ingredients such as benzaldehyde, clinicians need to be aware of this emerging risk and ask their patients about use of flavoured e-cigarettes. 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/

IRIS TOXICOLOGICAL REVIEW AND SUMMARY ...

EPA Pesticide Factsheets

The Draft Toxicological Review was developed to evaluate both the cancer and non cancer human health risks from environmental exposure to vinyl chloride. A reference concentration (RfC), and a reference dose (RfD) were developed based upon induction of liver cell polymorphism in a chronic dietary study utilizing Wistar rats. An RfC of 1E-1 mg/m3 and an RfD of 5E-3 mg/kg-d are recommended. On the basis of sufficient evidence for carcinogenicity in human epidemiology studies vinyl chloride is reaffirmed to be a known human carcinogen. Cancer potencies were derived for oral and inhalation exposure. An oral slope factor of 1.3 per (mg/kg-day) for continuous exposure during adulthood and 2.5 per (mg/kg-day) for continuous lifetime exposure from birth, based upon a chronic dietary study in female Wistar rats is recommended; an inhalation unit risk of 4.3 E-6 per (55g/m3) for continuous exposure during adulthood and 8.7 E-6 per (55g/m3) for continuous lifetime exposure from birth is also recommended, based upon exposure of male and female Sprague Dawley rats and Swiss mice, via inhalation, for a lifetime. A PBPK model was used in the derivation of the RfC, RfD, and cancer potency estimates. Its use is based on the assumption that equal tissue concentrations of reactive metabolite, chlorethylene oxide or chloracetaldehyde, at the critical target site will result in equivalent toxicity between species.

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.

PREDICTING THE ACUTE BEHAVIORAL EFFECTS OF TOLUENE INHALED FOR 24 HRS IN RATS: DOSE METRICS, METABOLISM AND BEHAVIORAL TOLERANCE

EPA Science Inventory

Purpose: Recent research on the acute effects of volatile organic compounds (VOCs) suggests that extrapolation from short (~ 1 h) to long durations (up to 4 h) is improved by using estimates of brain toluene concentration ( Br[ToI)] instead of cumulative inhaled dose (C x t) as a...

Risk analysis for worker exposure to benzene

NASA Astrophysics Data System (ADS)

Hallenbeck, William H.; Flowers, Roxanne E.

1992-05-01

Cancer risk factors (characterized by route, dose, dose rate per kilogram, fraction of lifetime exposed, species, and sex) were derived for workers exposed to benzene via inhalation or ingestion. Exposure at the current Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) and at leaking underground storage tank (LUST) sites were evaluated. At the current PEL of 1 ppm, the theoretical lifetime excess risk of cancer from benzene inhalation is ten per 1000. The theoretical lifetime excess risk for worker inhalation exposure at LUST sites ranged from 10 to 40 per 1000. These results indicate that personal protection should be required. The theoretical lifetime excess risk due to soil ingestion is five to seven orders of magnitude less than the inhalation risks.

Oral and inhaled glucocorticoid use and risk of Achilles or biceps tendon rupture: a population-based case-control study.

PubMed

Spoendlin, Julia; Meier, Christian; Jick, Susan S; Meier, Christoph R

2015-01-01

Tendinotoxicity of glucocorticoids (GC) has been shown, but evidence on how this translates into clinical practice remains scarce. To explore the association between oral or inhaled GC use and the risk of Achilles or biceps tendon rupture (ATR/BTR). We identified patients aged 18 to 89 years with incident ATR or BTR (1995-2013) for a matched (1:4) case-control analysis using the UK-based Clinical Practice Research Datalink. We stratified oral GC use by indication, timing and duration of use, continuous versus intermittent use, cumulative dose, and average daily dose. We stratified inhaled GC use by timing and number of prescriptions. Among 8,202 cases, we observed increased odds ratios (ORs) around 3.0 for continuous oral GC use, which declined shortly after therapy cessation (similarly across indications). Odds ratios increased with average daily dose (≥ 10 mg/day, OR 4.05, 95% CI 2.32-7.08) and were elevated after one cycle of high-dose oral GC (≥ 20 mg/day). There was no effect of inhaled GC at any level of exposure. Our results provide evidence that oral GC therapy increases the risk of tendon rupture in a dose-response relationship. A single short-term high-dose GC treatment course may be sufficient transiently to increase the risk of tendon rupture.

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.

A planning study investigating dual-gated volumetric arc stereotactic treatment of primary renal cell carcinoma

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

Devereux, Thomas, E-mail: thomas.devereux@petermac.org; Pham, Daniel; Kron, Tomas

2015-04-01

This is a planning study investigating the dosimetric advantages of gated volumetric-modulated arc therapy (VMAT) to the end-exhale and end-inhale breathing phases for patients undergoing stereotactic treatment of primary renal cell carcinoma. VMAT plans were developed from the end-inhale (VMATinh) and the end-exhale (VMATexh) phases of the breathing cycle as well as a VMAT plan and 3-dimensional conformal radiation therapy plan based on an internal target volume (ITV) (VMATitv). An additional VMAT plan was created by giving the respective gated VMAT plan a 50% weighting and summing the inhale and exhale plans together to create a summed gated plan. Dosemore » to organs at risk (OARs) as well as comparison of intermediate and low-dose conformity was evaluated. There was no difference in the volume of healthy tissue receiving the prescribed dose for the planned target volume (PTV) (CI100%) for all the VMAT plans; however, the mean volume of healthy tissue receiving 50% of the prescribed dose for the PTV (CI50%) values were 4.7 (± 0.2), 4.6 (± 0.2), and 4.7 (± 0.6) for the VMATitv, VMATinh, and VMATexh plans, respectively. The VMAT plans based on the exhale and inhale breathing phases showed a 4.8% and 2.4% reduction in dose to 30 cm{sup 3} of the small bowel, respectively, compared with that of the ITV-based VMAT plan. The summed gated VMAT plans showed a 6.2% reduction in dose to 30 cm{sup 3} of the small bowel compared with that of the VMAT plans based on the ITV. Additionally, when compared with the inhale and the exhale VMAT plans, a 4% and 1.5%, respectively, reduction was observed. Gating VMAT was able to reduce the amount of prescribed, intermediate, and integral dose to healthy tissue when compared with VMAT plans based on an ITV. When summing the inhale and exhale plans together, dose to healthy tissue and OARs was optimized. However, gating VMAT plans would take longer to treat and is a factor that needs to be considered.« less

Modulation of distinct asthmatic phenotypes in mice by dose-dependent inhalation of microbial products.

PubMed

Whitehead, Gregory S; Thomas, Seddon Y; Cook, Donald N

2014-01-01

Humans with asthma display considerable heterogeneity with regard to T helper (Th) 2-associated eosinophilic and Th17-associated neutrophilic inflammation, but the impact of the environment on these different forms of asthma is poorly understood. We studied the nature and longevity of asthma-like responses triggered by inhalation of allergen together with environmentally relevant doses of inhaled lipopolysaccharide (LPS). Ovalbumin (OVA) was instilled into the airways of mice together with a wide range of LPS doses. Following a single OVA challenge, or multiple challenges, animals were assessed for pulmonary cytokine production, airway inflammation, and airway hyperresponsiveness (AHR). Mice instilled with OVA together with very low doses (≤10⁻³ μg) of LPS displayed modest amounts of Th2 cytokines, with associated airway eosinophilia and AHR after a single challenge, and these responses were sustained after multiple OVA challenges. When the higher but still environmentally relevant dose of 10⁻¹ μg LPS was used, mice initially displayed similar Th2 responses, as well as Th17-associated neutrophilia. After multiple OVA challenges, however, the 10⁻¹ μg LPS animals also accumulated large numbers of allergen-specific T regulatory (Treg) cells with high levels of inducible co-stimulatory molecule (ICOS). As a result, asthma-like features in these mice were shorter-lived than in mice sensitized using lower doses of LPS. The nature and longevity of Th2, Th17, and Treg immune responses to inhaled allergen are dependent on the quantity of LPS inhaled at the time of allergic sensitization. These findings might account in part for the heterogeneity of inflammatory infiltrates seen in lungs of asthmatics.

Quantitative dose-response assessment of inhalation exposures to toxic air pollutants

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

Jarabek, A.M.; Foureman, G.L.; Gift, J.S.

1997-12-31

Implementation of the 1990 Clean Air Act Amendments, including evaluation of residual risks. requires accurate human health risk estimates of both acute and chronic inhalation exposures to toxic air pollutants. The U.S. Environmental Protection Agency`s National Center for Environmental Assessment, Research Triangle Park, NC, has a research program that addresses several key issues for development of improved quantitative approaches for dose-response assessment. This paper describes three projects underway in the program. Project A describes a Bayesian approach that was developed to base dose-response estimates on combined data sets and that expresses these estimates as probability density functions. A categorical regressionmore » model has been developed that allows for the combination of all available acute data, with toxicity expressed as severity categories (e.g., mild, moderate, severe), and with both duration and concentration as governing factors. Project C encompasses two refinements to uncertainty factors (UFs) often applied to extrapolate dose-response estimates from laboratory animal data to human equivalent concentrations. Traditional UFs have been based on analyses of oral administration and may not be appropriate for extrapolation of inhalation exposures. Refinement of the UF applied to account for the use of subchronic rather than chronic data was based on an analysis of data from inhalation exposures (Project C-1). Mathematical modeling using the BMD approach was used to calculate the dose-response estimates for comparison between the subchronic and chronic data so that the estimates were not subject to dose-spacing or sample size variability. The second UF that was refined for extrapolation of inhalation data was the adjustment for the use of a LOAEL rather than a NOAEL (Project C-2).« less

Inhalation Anthrax: Dose Response and Risk Analysis

PubMed Central

Thran, Brandolyn; Morse, Stephen S.; Hugh-Jones, Martin; Massulik, Stacey

2008-01-01

The notion that inhalation of a single Bacillus anthracis spore is fatal has become entrenched nearly to the point of urban legend, in part because of incomplete articulation of the scientific basis for microbial risk assessment, particularly dose-response assessment. Risk analysis (ie, risk assessment, risk communication, risk management) necessitates transparency: distinguishing scientific facts, hypotheses, judgments, biases in interpretations, and potential misinformation. The difficulty in achieving transparency for biothreat risk is magnified by misinformation and poor characterization of both dose-response relationships and the driving mechanisms that cause susceptibility or resistance to disease progression. Regrettably, this entrenchment unnecessarily restricts preparedness planning to a single response scenario: decontaminate until no spores are detectable in air, water, or on surfaces—essentially forcing a zero-tolerance policy inconsistent with the biology of anthrax. We present evidence about inhalation anthrax dose-response relationships, including reports from multiple studies documenting exposures insufficient to cause inhalation anthrax in laboratory animals and humans. The emphasis of the article is clarification about what is known from objective scientific evidence for doses of anthrax spores associated with survival and mortality. From this knowledge base, we discuss the need for future applications of more formal risk analysis processes to guide development of alternative non-zero criteria or standards based on science to inform preparedness planning and other risk management activities. PMID:18582166

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...

ASSESSING THE HEALTH EFFECTS AND RISKS ASSOCIATED WITH CHILDREN’S INHALATION EXPOSURES – ASTHMA AND ALLERGY

EPA Science Inventory

Adults and children may have different reactions to inhalation exposures, which may be the result of differences in inhaled or target tissue doses following similar exposures, and/or due to growth and development of the lung which continues postnatally in distinct stages. Because...

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

Assessment of relative potential for Legionella species or surrogates inhalation exposure from common water uses.

PubMed

Hines, Stephanie A; Chappie, Daniel J; Lordo, Robert A; Miller, Brian D; Janke, Robert J; Lindquist, H Alan; Fox, Kim R; Ernst, Hiba S; Taft, Sarah C

2014-06-01

The Legionella species have been identified as important waterborne pathogens in terms of disease morbidity and mortality. Microbial exposure assessment is a tool that can be utilized to assess the potential of Legionella species inhalation exposure from common water uses. The screening-level exposure assessment presented in this paper developed emission factors to model aerosolization, quantitatively assessed inhalation exposures of aerosolized Legionella species or Legionella species surrogates while evaluating two generalized levels of assumed water concentrations, and developed a relative ranking of six common in-home uses of water for potential Legionella species inhalation exposure. Considerable variability in the calculated exposure dose was identified between the six identified exposure pathways, with the doses differing by over five orders of magnitude in each of the evaluated exposure scenarios. The assessment of exposure pathways that have been epidemiologically associated with legionellosis transmission (ultrasonic and cool mist humidifiers) produced higher estimated inhalation exposure doses than pathways where epidemiological evidence of transmission has been less strong (faucet and shower) or absent (toilets and therapy pool). With consideration of the large uncertainties inherent in the exposure assessment process used, a relative ranking of exposure pathways from highest to lowest exposure doses was produced using culture-based measurement data and the assumption of constant water concentration across exposure pathways. In this ranking, the ultrasonic and cool mist humidifier exposure pathways were estimated to produce the highest exposure doses, followed by the shower and faucet exposure pathways, and then the toilet and therapy pool exposure pathways. Published by Elsevier Ltd.

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…

Multivariate Analysis of Effects of Asthmatic Patient Respiratory Profiles on the In Vitro Performance of a Reservoir Multidose and a Capsule-Based Dry Powder Inhaler.

PubMed

Buttini, Francesca; Pasquali, Irene; Brambilla, Gaetano; Copelli, Diego; Alberi, Massimiliano Dagli; Balducci, Anna Giulia; Bettini, Ruggero; Sisti, Viviana

2016-03-01

The aim of this work was to evaluate the effect of two different dry powder inhalers, of the NGI induction port and Alberta throat and of the actual inspiratory profiles of asthmatic patients on in-vitro drug inhalation performances. The two devices considered were a reservoir multidose and a capsule-based inhaler. The formulation used to test the inhalers was a combination of formoterol fumarate and beclomethasone dipropionate. A breath simulator was used to mimic inhalatory patterns previously determined in vivo. A multivariate approach was adopted to estimate the significance of the effect of the investigated variables in the explored domain. Breath simulator was a useful tool to mimic in vitro the in vivo inspiratory profiles of asthmatic patients. The type of throat coupled with the impactor did not affect the aerodynamic distribution of the investigated formulation. However, the type of inhaler and inspiratory profiles affected the respirable dose of drugs. The multivariate statistical approach demonstrated that the multidose inhaler, released efficiently a high fine particle mass independently from the inspiratory profiles adopted. Differently, the single dose capsule inhaler, showed a significant decrease of fine particle mass of both drugs when the device was activated using the minimum inspiratory volume (592 mL).

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...

Stochastic rat lung dosimetry for inhaled radon progeny: a surrogate for the human lung for lung cancer risk assessment.

PubMed

Winkler-Heil, R; Hussain, M; Hofmann, W

2015-05-01

Laboratory rats are frequently used in inhalation studies as a surrogate for human exposures. The objective of the present study was therefore to develop a stochastic dosimetry model for inhaled radon progeny in the rat lung, to predict bronchial dose distributions and to compare them with corresponding dose distributions in the human lung. The most significant difference between human and rat lungs is the branching structure of the bronchial tree, which is relatively symmetric in the human lung, but monopodial in the rat lung. Radon progeny aerosol characteristics used in the present study encompass conditions typical for PNNL and COGEMA rat inhalation studies, as well as uranium miners and human indoor exposure conditions. It is shown here that depending on exposure conditions and modeling assumptions, average bronchial doses in the rat lung ranged from 5.4 to 7.3 mGy WLM(-1). If plotted as a function of airway generation, bronchial dose distributions exhibit a significant maximum in large bronchial airways. If, however, plotted as a function of airway diameter, then bronchial doses are much more uniformly distributed throughout the bronchial tree. Comparisons between human and rat exposures indicate that rat bronchial doses are slightly higher than human bronchial doses by about a factor of 1.3, while lung doses, averaged over the bronchial (BB), bronchiolar (bb) and alveolar-interstitial (AI) regions, are higher by about a factor of about 1.6. This supports the current view that the rat lung is indeed an appropriate surrogate for the human lung in case of radon-induced lung cancers. Furthermore, airway diameter seems to be a more appropriate morphometric parameter than airway generations to relate bronchial doses to bronchial carcinomas.

Clinical immunology review series: an approach to desensitization

PubMed Central

Krishna, M T; Huissoon, A P

2011-01-01

Allergen immunotherapy describes the treatment of allergic disease through administration of gradually increasing doses of allergen. This form of immune tolerance induction is now safer, more reliably efficacious and better understood than when it was first formally described in 1911. In this paper the authors aim to summarize the current state of the art in immunotherapy in the treatment of inhalant, venom and drug allergies, with specific reference to its practice in the United Kingdom. A practical approach has been taken, with reference to current evidence and guidelines, including illustrative protocols and vaccine schedules. A number of novel approaches and techniques are likely to change considerably the way in which we select and treat allergy patients in the coming decade, and these advances are previewed. PMID:21175592

Review and Design of Low-Dose Bacillus anthracis Inhalation ...

EPA Pesticide Factsheets

Report In July 2011, EPA NHSRC sponsored a Review and Design of Low-Dose Bacillus anthracis Inhalation Exposures meeting to review the research done to date and to identify gaps that future research should address regarding low-dose exposures. This effort brought together many organizations across the country, including EPA’s program offices, federal government agencies and laboratories, academia, and the private sector. Participants of the conference shared knowledge, explored differing opinions, and expanded understanding of the current state of research for low-dose exposure and future research needs. This report represents a summary of the presentations and discussions during the meeting.

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide

PubMed Central

Clearie, Karine L; Williamson, Peter A; Meldrum, Karen; Gillen, Michael; Carlsson, Lars-Goran; Carlholm, Marie; Ekelund, Jan; Lipworth, Brian J

2011-01-01

AIMS A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations. METHODS Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC24h[area under the concentration-time curve (0–24 h)], budesonide AUC0–12h and Cmax. Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC20 (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. RESULTS In the pharmacokinetic study, there were no differences in cortisol, AUC0–12h[area under the concentration-time curve (0–12 h)], Tmax (time to maximum concentration) or Cmax (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC24h was 1.02 (95% confidence interval 0.93–1.11) and budesonide AUC0–12h was 1.03 (90% confidence interval 0.9–1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC20 (provocative concentration of methacholine needed to produce a 20% fall in FEV1) with a relative potency ratio of 1.10 (95% confidence interval 0.49–2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables. CONCLUSIONS Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects. PMID:21395643

Requirements for radiation emergency urine bioassay techniques for the public and first responders.

PubMed

Li, Chunsheng; Vlahovich, Slavica; Dai, Xiongxin; Richardson, Richard B; Daka, Joseph N; Kramer, Gary H

2010-11-01

Following a radiation emergency, the affected public and the first responders may need to be quickly assessed for internal contamination by the radionuclides involved. Urine bioassay is one of the most commonly used methods for assessing radionuclide intake and radiation dose. This paper attempts to derive the sensitivity requirements (from inhalation exposure) for the urine bioassay techniques for the top 10 high-risk radionuclides that might be used in a terrorist attack. The requirements are based on a proposed reference dose to adults of 0.1 Sv (CED, committed effective dose). In addition, requirements related to sample turnaround time and field deployability of the assay techniques are also discussed. A review of currently available assay techniques summarized in this paper reveals that method development for ²⁴¹Am, ²²⁶Ra, ²³⁸Pu, and ⁹⁰Sr urine bioassay is needed.

Biomarkers of Dose and Effect of Inhaled Ozone in Resting versus Exercising Human Subjects: Comparison with Resting Rats

PubMed Central

Hatch, Gary E.; McKee, John; Brown, James; McDonnell, William; Seal, Elston; Soukup, Joleen; Slade, Ralph; Crissman, Kay; Devlin, Robert

2013-01-01

To determine the influence of exercise on pulmonary dose of inhaled pollutants, we compared biomarkers of inhaled ozone (O3) dose and toxic effect between exercise levels in humans, and between humans and rats. Resting human subjects were exposed to labeled O3 (18O3, 0.4 ppm, for 2 hours) and alveolar O3 dose measured as the concentration of excess 18O in cells and extracellular material of nasal, bronchial, and bronchoalveolar lavage fluid (BALF). We related O3 dose to effects (changes in BALF protein, LDH, IL-6, and antioxidant substances) measurable in the BALF. A parallel study of resting subjects examined lung function (FEV1) changes following O3. Subjects exposed while resting had 18O concentrations in BALF cells that were 1/5th of those of exercising subjects and directly proportional to the amount of O3 breathed during exposure. Quantitative measures of alveolar O3 dose and toxicity that were observed previously in exercising subjects were greatly reduced or non-observable in O3 exposed resting subjects. Resting rats and resting humans were found to have a similar alveolar O3 dose. PMID:23761957

OZONE UPTAKE IN THE INTACT HUMAN RESPIRATORY TRACT - RELATIONSHIP BETWEEN INHALED AND ACTUAL DOSE

EPA Science Inventory

Inhaled concentration (C), minute volume (MV), and exposure duration (T) are factors that may affect the uptake of ozone (03) within the respiratory tract. Ten healthy adult nonsmokers participated in four sessions, inhaling 0.2 or 0.4 ppm 03 through an oral mask while exercisi...

Empirical model for conveniently predicting total and regional lung deposition of inhaled aerosols

EPA Science Inventory

Accurate estimate of a dose of inhaled aerosols is a key factor for estimating potential health risks to exposure to ambient pollutant particulate matter on the one hand, and the therapeutic efficacy of inhaled drug aerosols on the other hand. Particle deposition in the lung is d...

Spotlight on fluticasone furoate/vilanterol trifenatate for the once-daily treatment of asthma: design, development and place in therapy

PubMed Central

Albertson, Timothy E; Bullick, Samuel W; Schivo, Michael; Sutter, Mark E

2016-01-01

The use of inhaled corticosteroids (ICSs) plays a key role in the treatment of asthmatic patients, and international guidelines have designated ICSs as an early maintenance therapy in controlling asthma symptoms. When asthmatic patients remain symptomatic on ICSs, one common option is to add a long-acting beta2 agonist (LABA) to the maintenance treatment. Fixed combination inhalers that contain both an ICS and a LABA have been popular for both chronic obstructive pulmonary disease (COPD) and asthma. Historically, these inhalers have been dosed twice daily. However, currently, there is a once-daily combination therapy with the ICS fluticasone furoate (FF) and the LABA vilanterol trifenatate (VI) with indications for use in both COPD and asthma. This dry powder inhaler (DPI) comes in two doses of FF (100 or 200 μg) both combined with VI (25 μg). This article reviews the clinical trial data for FF, VI and FF/VI combination inhalers and documents the efficacy and safety of once-daily inhaled maintenance therapy by DPI in asthmatic patients. PMID:28008228

Activity and Safety of Inhaled Itraconazole Nanosuspension in a Model Pulmonary Aspergillus fumigatus Infection in Inoculated Young Quails.

PubMed

Wlaź, Piotr; Knaga, Sebastian; Kasperek, Kornel; Wlaź, Aleksandra; Poleszak, Ewa; Jeżewska-Witkowska, Grażyna; Winiarczyk, Stanisław; Wyska, Elżbieta; Heinekamp, Thorsten; Rundfeldt, Chris

2015-08-01

Pulmonary aspergillosis is frequently reported in parrots, falcons, and other birds held in captivity. Inhalation is the main route of infection for Aspergillus fumigatus, resulting in both acute and chronic disease conditions. Itraconazole (ITRA) is an antifungal commonly used in birds, but its administration requires repeated oral dosing, and the safety margin is narrow. To investigate the efficacy of inhaled ITRA, six groups of ten young quails (Coturnix japonica) were inoculated intratracheally with 5 × 10(6) spores (3 groups) or 5 × 10(7) spores (3 groups). Animals were exposed to nebulized ITRA nanosuspension as 10 % suspension or 4 % suspension, once daily for 30 min, starting 2 h after inoculation for 6 days. Control groups were exposed to nebulized saline for the same period of time. Survival and clinical scores were evaluated, and animals were subjected to gross pathology. In control animals, aspergillosis resulted in systemic disease without pulmonary or air sac granulomas. Animals died from multiple organ failure. Inhalation of 10 % ITRA nanosuspension blocked lethality and prevented disease-related symptoms in the quails exposed to the low dose of spores, while the disease course in quails inoculated with the high-spore dose was retarded. Inhalation of 4 % ITRA nanosuspension was less effective. Both inhalations were well tolerated, and gross pathology did not reveal signs of local toxicity. The data indicate that inhaled administration of 10 % ITRA nanosuspension is capable of alleviating an acute A. fumigatus infection in quails. A lower ITRA concentration may be only active in chronic pulmonary aspergillosis.

Quadrupling Inhaled Glucocorticoid Dose to Abort Asthma Exacerbations.

PubMed

McKeever, Tricia; Mortimer, Kevin; Wilson, Andrew; Walker, Samantha; Brightling, Christopher; Skeggs, Andrew; Pavord, Ian; Price, David; Duley, Lelia; Thomas, Mike; Bradshaw, Lucy; Higgins, Bernard; Haydock, Rebecca; Mitchell, Eleanor; Devereux, Graham; Harrison, Timothy

2018-03-08

Asthma exacerbations are frightening for patients and are occasionally fatal. We tested the concept that a plan for patients to manage their asthma (self-management plan), which included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate, would reduce the incidence of severe asthma exacerbations among adults and adolescents with asthma. We conducted a pragmatic, unblinded, randomized trial involving adults and adolescents with asthma who were receiving inhaled glucocorticoids, with or without add-on therapy, and who had had at least one exacerbation in the previous 12 months. We compared a self-management plan that included an increase in the dose of inhaled glucocorticoids by a factor of 4 (quadrupling group) with the same plan without such an increase (non-quadrupling group), over a period of 12 months. The primary outcome was the time to a first severe asthma exacerbation, defined as treatment with systemic glucocorticoids or an unscheduled health care consultation for asthma. A total of 1922 participants underwent randomization, of whom 1871 were included in the primary analysis. The number of participants who had a severe asthma exacerbation in the year after randomization was 420 (45%) in the quadrupling group as compared with 484 (52%) in the non-quadrupling group, with an adjusted hazard ratio for the time to a first severe exacerbation of 0.81 (95% confidence interval, 0.71 to 0.92; P=0.002). The rate of adverse effects, which were related primarily to local effects of inhaled glucocorticoids, was higher in the quadrupling group than in the non-quadrupling group. In this trial involving adults and adolescents with asthma, a personalized self-management plan that included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate resulted in fewer severe asthma exacerbations than a plan in which the dose was not increased. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN15441965 .).

Evaluation of a novel nicotine inhaler device: part 1--arterial and venous pharmacokinetics.

PubMed

Moyses, Chris; Hearn, Alex; Redfern, Andrew

2015-01-01

In the United Kingdom, licensed nicotine-containing products can be recommended to reduce the harm associated with smoking. Many smokers find currently available nicotine replacement products unsatisfactory. The arterial and venous pharmacokinetics (PK) of nicotine delivered via a novel inhaler device were determined. Results are reported for Parts A (N = 18) and C (N = 18) of a 4-part (A-D) Phase I study. Participants (18-55 years, ≥ 10 cigarettes/day, smoking within 1 hr of waking, expired carbon monoxide >10 ppm on screening) orally inhaled 2 single doses of nicotine (2 of 3 dose levels [0.22, 0.45, and 0.67 mg]) (Part A) and repeated hourly doses of 0.67 mg nicotine for 12 hr (Part C), via the novel device. Arterial and venous PK and tolerability were assessed. In Part A, mean arterial plasma nicotine concentrations at 2 min after the start of inhalation were 1.10, 2.06, and 2.59 ng/mL for the 0.22, 0.45, and 0.67 mg doses, respectively. Mean maximum arterial plasma nicotine concentrations (C(max)) were 2.11, 3.73, and 4.38 ng/mL and mean times to C(max) were 10.2, 7.3, and 6.5 min after the start of inhalation for the 0.22, 0.45, and 0.67 mg doses, respectively. In Part C, the mean pre- and postdose venous plasma nicotine concentration increased steadily and fluctuated in the range 8-10 mg/mL after 9 hr. The novel device was well tolerated; most adverse events were mild. The novel inhaler device delivers nicotine rapidly into the systemic circulation and offers a viable alternative to cigarettes for those finding it difficult to quit the behavioral and sensorial aspects of smoking. © The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.

Comparison of modeled estimates of inhalation exposure to aerosols during use of consumer spray products.

PubMed

Park, Jihoon; Yoon, Chungsik; Lee, Kiyoung

2018-05-30

In the field of exposure science, various exposure assessment models have been developed to complement experimental measurements; however, few studies have been published on their validity. This study compares the estimated inhaled aerosol doses of several inhalation exposure models to experimental measurements of aerosols released from consumer spray products, and then compares deposited doses within different parts of the human respiratory tract according to deposition models. Exposure models, including the European Center for Ecotoxicology of Chemicals Targeted Risk Assessment (ECETOC TRA), the Consumer Exposure Model (CEM), SprayExpo, ConsExpo Web and ConsExpo Nano, were used to estimate the inhaled dose under various exposure scenarios, and modeled and experimental estimates were compared. The deposited dose in different respiratory regions was estimated using the International Commission on Radiological Protection model and multiple-path particle dosimetry models under the assumption of polydispersed particles. The modeled estimates of the inhaled doses were accurate in the short term, i.e., within 10 min of the initial spraying, with a differences from experimental estimates ranging from 0 to 73% among the models. However, the estimates for long-term exposure, i.e., exposure times of several hours, deviated significantly from the experimental estimates in the absence of ventilation. The differences between the experimental and modeled estimates of particle number and surface area were constant over time under ventilated conditions. ConsExpo Nano, as a nano-scale model, showed stable estimates of short-term exposure, with a difference from the experimental estimates of less than 60% for all metrics. The deposited particle estimates were similar among the deposition models, particularly in the nanoparticle range for the head airway and alveolar regions. In conclusion, the results showed that the inhalation exposure models tested in this study are suitable for estimating short-term aerosol exposure (within half an hour), but not for estimating long-term exposure. Copyright © 2018 Elsevier GmbH. All rights reserved.

Different effects of propofol and isoflurane on cochlear blood flow and hearing function in Guinea pigs.

PubMed

Xiao, Ying; Wen, Jian; Bai, Yanxia; Duan, Na; Jing, G X

2014-01-01

To investigate the effects of isoflurane and propofol on mean arterial pressure (MAP), cochlear blood flow (CoBF), distortion-product otoacoustic emission (DPOAE), and the ultrastructure of outer hair cells (OHCs) in guinea pig cochleae. Forty-eight male guinea pigs were randomly assigned to one of six treatment groups. Groups 1 to 3 were infused (i.v.) with a loading dose of propofol (5 mg/kg) for 5 min and three maintenance doses (10, 20, or 40 mg kg-1·h-1, respectively) for 115 min. Groups 4 to 6 were inhaled with isoflurane at concentrations of 1.15 vol%, 2.30 vol% or 3.45 vol% respectively for 120 min. CoBF and MAP were recorded prior to and at 5 min intervals during drug administration. DPOAE was measured before, immediately after, and 1 h after administration. Following the final DPOAE test, cochleae were examined using scanning electron microscopy. Propofol treatment reduced MAP in a dose-dependent manner. CoBF and DPOAE showed increases at propofol maintenance doses of 10 and 20 mg kg-1·h-1. Inhalation of isoflurane at concentrations of 2.30 vol% and 3.45 vol% reduced MAP and CoBF. DPOAE amplitude increased following inhalation of 1.15 vol% isoflurane, but decreased following inhalations of 2.30 vol% and 3.45 vol%. Cochlear structure was changed following inhalation of either 2.30 vol% or 3.45 vol% isoflurane. Propofol could decrease MAP and increase both CoBF and DPOAE without affecting OHC structure. Inhalation of isoflurane at concentrations >2.30 vol% decreased CoBF and DPOAE, and produced injury to OHCs.

Application of an inline dry powder inhaler to deliver high dose pharmaceutical aerosols during low flow nasal cannula therapy.

PubMed

Farkas, Dale; Hindle, Michael; Longest, P Worth

2018-05-05

Inline dry powder inhalers (DPIs) offer a potentially effective option to deliver high dose inhaled medications simultaneously with mechanical ventilation. The objective of this study was to develop an inline DPI that is actuated using a low volume of air (LV-DPI) to efficiently deliver pharmaceutical aerosols during low flow nasal cannula (LFNC) therapy. A characteristic feature of the new inline LV-DPIs was the use of hollow capillary tubes that both pierced the capsule and provided a pathway for inlet air and exiting aerosol. Aerosolization characteristics, LFNC depositional losses and emitted dose (ED) were determined using 10 mg powder masses of a small-particle excipient enhanced growth (EEG) formulation. While increasing the number of inlet capillaries from one to three did not improve performance, retracting the inlet and outlet capillaries did improve ED by over 30%. It was theorized that high quality performance requires both high turbulent energy to deaggregate the powder and high wall shear stresses to minimize capsule retention. Best case performance included a device ED of approximately 85% (of loaded dose) and device emitted mass median aerodynamic diameter of 1.77 µm. Maximum ED through the LFNC system and small diameter (4 mm) nasal cannula was approximately 65% of the loaded dose. Potential applications of this device include the delivery of high dose inhaled medications such as surfactants, antibiotics, mucolytics, and anti-inflammatories. Copyright © 2018 Elsevier B.V. All rights reserved.

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, ...

Air classifier technology (ACT) in dry powder inhalation Part 3. Design and development of an air classifier family for the Novolizer multi-dose dry powder inhaler.

PubMed

de Boer, A H; Hagedoorn, P; Gjaltema, D; Goede, J; Frijlink, H W

2006-03-09

In this study, the design of a multifarious classifier family for different applications is described. The main design and development steps are presented as well as some special techniques that have been applied to achieve preset objectives. It is shown by increasing the number of air supply channels to the classifier chamber (from 2 to 8), that the fine particle losses from adhesion onto the classifier walls can be reduced from 75% to less than 5% of the real dose for soft (spherical) agglomerates. By applying a bypass flow that is arranged as a co-axial sheath of clean air around the aerosol cloud from the classifier, the airflow resistance of the classifier can be controlled over a relatively wide range of values (0.023-0.041 kPa(0.5) min l(-1)). This, without affecting the fine particle dose or increasing the fine particle losses in the inhaler. Moreover, the sheath flow can be modelled to reduce the depositions in the induction port to the cascade impactor or in the patient's mouth, which are the result of back flows in these regions. The principle of powder induced pressure drop reduction across a classifier enables assessment of the amount of powder in the classifier at any moment during inhalation, from which classifier loading (from the dose system) and discharge rates can be derived. This principle has been applied to study the residence time of a dose in the classifier as function of the carrier size fraction and the flow rate. It has been found that this residence time can be controlled in order to obtain an optimal balance between the generated fine particle fraction and the inhalation manoeuvre of the patient. A residence time between 0.5 and 2 s at 60 l/min is considered favourable, as this yields a high fine particle dose (depending on the type of formulation used) and leaves sufficient inhaled volume for particle transport into the deep lung.

CERISE, a French radioprotection code, to assess the radiological impact and acceptance criteria of installations for material handling, and recycling or disposal of very low-level radioactive waste

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

Santucci, P.; Guetat, P.

1993-12-31

This document describes the code CERISE, Code d`Evaluations Radiologiques Individuelles pour des Situations en Enterprise et dans l`Environnement. This code has been developed in the frame of European studies to establish acceptance criteria of very low-level radioactive waste and materials. This code is written in Fortran and runs on PC. It calculates doses received by the different pathways: external exposure, ingestion, inhalation and skin contamination. Twenty basic scenarios are already elaborated, which have been determined from previous studies. Calculations establish the relation between surface, specific and/or total activities, and doses. Results can be expressed as doses for an average activitymore » unit, or as average activity limits for a set of reference doses (defined for each scenario analyzed). In this last case, the minimal activity values and the corresponding limiting scenarios, are selected and summarized in a final table.« less

The local and systemic side-effects of venom and inhaled-allergen subcutaneous immunotherapy.

PubMed

Adamic, Katja; Zidarn, Mihaela; Bajrovic, Nissera; Erzen, Renato; Kopac, Peter; Music, Ema

2009-01-01

Although immunotherapy is effective in allergic rhinitis, conjunctivitis, asthma and stinging insect hypersensitivity, it carries a risk of anaphylactic reactions. In a 4-year retrospective survey, we investigated 1257 adult patients who had received venom or inhaled-allergen subcutaneous immunotherapy. The dose-increase phase was performed as the 2-day rush protocol for venom immunotherapy and the 6-week protocol for inhaled-allergen immunotherapy. A total of 904 patients received venom immunotherapy and 353 patients inhaled-allergen immunotherapy. The prevalence of systemic reactions was 13.6%. The frequency of systemic reactions was higher during the maintenance phase than in the dose-increase phase (9.6% vs. 5.9%) and was highest in both phases of treatment with honeybee venom (P < 0.001). The majority of systemic reactions were mild. Five (0.4%) patients had reaction with a fall of blood pressure and were treated with adrenaline. There was no fatal outcome. The systemic side-effects during the dose-increase phase of venom immunotherapy occurred at a median dose of 46 microg (range 2-100 microg). Large local reactions occurred in 13.9% of patients without any significant difference between the allergens. We have shown that systemic reactions are not rare even during maintenance phase in patients with a well tolerated dose-increase phase of treatment. The most prominent risk factor for systemic reactions was immunotherapy with honeybee extract.

Acute respiratory toxicity following inhalation exposure to soman in guinea pigs.

PubMed

Perkins, Michael W; Pierre, Zdenka; Rezk, Peter; Sabnekar, Praveena; Kabra, Kareem; Chanda, Soma; Oguntayo, Samuel; Sciuto, Alfred M; Doctor, Bhupendra P; Nambiar, Madhusoodana P

2010-06-01

Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m(3) concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m(3) soman survived, while animals exposed to 841, and 1121 mg/m(3) resulted in 38% and 13% survival, respectively. The microinstillation inhalation exposure LCt(50) for soman determined by probit analysis was 827.2mg/m(3). A majority of the animals that died at 1121 mg/m(3) developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs. (c) 2010 Elsevier Inc. All rights reserved.

Tapering dose of inhaled budesonide in subjects with mild-to-moderate persistent asthma treated with montelukast: a 16-week single-blind randomized study.

PubMed

Riccioni, Graziano; Vecchia, Rosanna Della; Castronuovo, Marco; Di Ilio, Carmine; D'Orazio, Nicolantonio

2005-01-01

Pharmacological therapy with inhaled steroids (IS) is currently considered the gold-standard of treatment for mild-persistent asthma. Leukotriene receptor antagonist drugs (LTRAs) play an important role associated with IS, allowing dose tapering and maintaining control of asthma symptoms. The aim of this study was to determine the effectiveness of montelukast (MON) to allow tapering of the inhaled dose of budesonide (BUD) in patients with mild-moderate persistent asthma. This 16-wk single-blind randomized study included 40 asthmatic patients divided in 2 treatment groups. After a run-in period (4 wk), in which all patients inhaled 400 microg of BUD twice daily (bid), group A (20 patients) received MON (oral, 10 mg/day) combined with inhaled BUD (400 microg/bid), while group B (20 patients) was treated with BUD for the whole period of the study. In both groups, at every 4 wk the dose of BUD was halved. After 12 wk of treatment the mean value of forced expiratory volume during the first sec (FEV1, as % of predicted value) was significantly greater in group A compared with group B (94 +/- 7.5 vs 83.1 +/- 6.9; p<0.005). The mean values of peak expiratory flow (PEF), the percentages of asthmatic exacerbations, and the use of beta2-short-acting agonist (SABA) were similar in the 2 groups at 4, 8, and 12 wk. In conclusion, in patients with mild-moderate persistent asthma, MON therapy is useful in tapering the dose of IS in order to reduce its side effects and to maintain the clinical stability of the disease.

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.

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.

Efficacy and safety of budesonide/formoterol pMDI vs budesonide pMDI in asthmatic children (6-<12 years).

PubMed

Pearlman, David S; Eckerwall, Göran; McLaren, Julie; Lamarca, Rosa; Puu, Margareta; Gilbert, Ileen; Jorup, Carin; Sandin, Kristina; Lanz, Miguel J

2017-04-01

The efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler (pMDI) have been demonstrated in patients with asthma at least 12 years old. To evaluate the efficacy of 2 formoterol doses added to budesonide as fixed combinations vs budesonide alone in children 6 to younger than 12 years with asthma. This randomized, double-blinded, parallel-group, multicenter study (NCT02091986; CHASE 3) included children 6 to younger than 12 years with asthma previously receiving a medium-dose inhaled corticosteroid (ICS) or an ICS plus a long-acting β 2 -agonist. Children symptomatic during a 7-28-day run-in on low-dose ICS, 1 inhalation of budesonide dry powder inhaler 90 μg twice daily (BID), were randomized to receive 2 inhalations of budesonide/formoterol pMDI 80/4.5 μg (160/9 μg) BID (n = 92), budesonide/formoterol pMDI 80/2.25 μg (160/4.5 μg) BID (n = 95), or budesonide pMDI 80 μg (160 μg) BID (n = 92) for 12 weeks. Change in forced expiratory volume in 1 second from baseline to 1 hour after dosing (primary end point), change in forced expiratory volume in 1 second 15 minutes after dosing, and peak expiratory flow 1 hour after dosing at week 12 were statistically significantly greater for budesonide/formoterol 160/9 μg vs budesonide (P ≤ .015 for all comparisons), but not for budesonide/formoterol 160/4.5 μg vs budesonide. Bronchodilator effects, evident 15 minutes after the dose on day 1, were maintained at week 12. Incidence of protocol-defined asthma exacerbations and improvements in asthma symptom-related and quality-of-life outcomes were similar across treatments. There were no notable safety differences among treatments. Budesonide/formoterol pMDI 160/9 μg showed statistically significant and clinically meaningful lung function improvements vs budesonide pMDI 160 μg, demonstrating appropriateness as a therapeutic option for children 6 to younger than 12 years with asthma symptomatic on ICS alone. ClinicalTrials.gov Identifier: NCT02091986. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Activation of Antioxidative Functions by Radon Inhalation Enhances the Mitigation Effects of Pregabalin on Chronic Constriction Injury-Induced Neuropathic Pain in Mice

PubMed Central

Horie, Shunsuke; Etani, Reo; Kanzaki, Norie; Sasaoka, Kaori; Kobashi, Yusuke; Hanamoto, Katsumi; Yamaoka, Kiyonori

2016-01-01

Radon inhalation brings pain relief for chronic constriction injury- (CCI-) induced neuropathic pain in mice due to the activation of antioxidative functions, which is different from the mechanism of the pregabalin effect. In this study, we assessed whether a combination of radon inhalation and pregabalin administration is more effective against neuropathic pain than radon or pregabalin only. Mice were treated with inhaled radon at a concentration of 1,000 Bq/m3 for 24 hours and pregabalin administration after CCI surgery. In mice treated with pregabalin at a dose of 3 mg/kg weight, the 50% paw withdrawal threshold of mice treated with pregabalin or radon and pregabalin was significantly increased, suggesting pain relief. The therapeutic effects of radon inhalation or the combined effects of radon and pregabalin (3 mg/kg weight) were almost equivalent to treatment with pregabalin at a dose of 1.4 mg/kg weight or 4.1 mg/kg weight, respectively. Radon inhalation and the combination of radon and pregabalin increased antioxidant associated substances in the paw. The antioxidant substances increased much more in radon inhalation than in pregabalin administration. These findings suggested that the activation of antioxidative functions by radon inhalation enhances the pain relief of pregabalin and that this combined effect is probably an additive effect. PMID:26798431

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.

Activation of Antioxidative Functions by Radon Inhalation Enhances the Mitigation Effects of Pregabalin on Chronic Constriction Injury-Induced Neuropathic Pain in Mice.

PubMed

Kataoka, Takahiro; Horie, Shunsuke; Etani, Reo; Kanzaki, Norie; Sasaoka, Kaori; Kobashi, Yusuke; Hanamoto, Katsumi; Yamaoka, Kiyonori

2016-01-01

Radon inhalation brings pain relief for chronic constriction injury- (CCI-) induced neuropathic pain in mice due to the activation of antioxidative functions, which is different from the mechanism of the pregabalin effect. In this study, we assessed whether a combination of radon inhalation and pregabalin administration is more effective against neuropathic pain than radon or pregabalin only. Mice were treated with inhaled radon at a concentration of 1,000 Bq/m(3) for 24 hours and pregabalin administration after CCI surgery. In mice treated with pregabalin at a dose of 3 mg/kg weight, the 50% paw withdrawal threshold of mice treated with pregabalin or radon and pregabalin was significantly increased, suggesting pain relief. The therapeutic effects of radon inhalation or the combined effects of radon and pregabalin (3 mg/kg weight) were almost equivalent to treatment with pregabalin at a dose of 1.4 mg/kg weight or 4.1 mg/kg weight, respectively. Radon inhalation and the combination of radon and pregabalin increased antioxidant associated substances in the paw. The antioxidant substances increased much more in radon inhalation than in pregabalin administration. These findings suggested that the activation of antioxidative functions by radon inhalation enhances the pain relief of pregabalin and that this combined effect is probably an additive effect.

Determination of in vitro lung solubility and intake-to-dose conversion factor for tritiated lanthanum nickel aluminum alloy.

PubMed

Farfán, Eduardo B; Labone, Thomas R; Staack, Gregory C; Cheng, Yung-Sung; Zhou, Yue; Varallo, Thomas P

2012-09-01

A sample of tritiated lanthanum nickel aluminum alloy (LaNi4.25Al0.75 or LANA.75) similar to that used at the Savannah River Site Tritium Facilities was analyzed to estimate the particle size distribution of this metal tritide powder and the rate at which this material dissolves in the human respiratory tract after it is inhaled. This information is used to calculate the committed effective dose received by a worker after inhaling the material. These doses, which were calculated using the same methodology given in the U.S. Department of Energy Tritium Handbook, are presented as inhalation intake-to-dose conversion factors (DCF). The DCF for this metal tritide was determined to be 9.4 × 10 Sv Bq, which is less than the DCF for tritiated water. Therefore, the radiation worker bioassay programs designed for tritiated water are adequate to monitor for intakes of this material.

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.

Lung dosimetry for inhaled radon progeny in smokers.

PubMed

Baias, Paul F; Hofmann, Werner; Winkler-Heil, Renate; Cosma, Constantin; Duliu, Octavian G

2010-02-01

Cigarette smoking may change the morphological and physiological parameters of the lung. Thus the primary objective of the present study was to investigate to what extent these smoke-induced changes can modify deposition, clearance and resulting doses of inhaled radon progeny relative to healthy non-smokers (NSs). Doses to sensitive bronchial target cells were computed for four categories of smokers: (1) Light, short-term (LST) smokers, (2) light, long-term (LLT) smokers, (3) heavy, short-term (HST) smokers and (4) heavy, long-term (HLT) smokers. Because of only small changes of morphological and physiological parameters, doses for the LST smokers hardly differed from those for NSs. For LLT and HST smokers, even a protective effect could be observed, caused by a thicker mucus layer and increased mucus velocities. Only in the case of HLT smokers were doses higher by about a factor of 2 than those for NSs, caused primarily by impaired mucociliary clearance, higher breathing frequency, reduced lung volume and airway obstructions. These higher doses suggest that the contribution of inhaled radon progeny to the risk of lung cancer in smokers may be higher than currently assumed on the basis of NS doses.

Using smartphone as a motion detector to collect time-microenvironment data for estimating the inhalation dose.

PubMed

Hoi, Tran Xuan; Phuong, Huynh Truc; Van Hung, Nguyen

2016-09-01

During the production of iodine-131 from neutron irradiated tellurium dioxide by the dry distillation, a considerable amount of (131)I vapor is dispersed to the indoor air. People who routinely work at the production area may result in a significant risk of exposure to chronic intake by inhaled (131)I. This study aims to estimate the inhalation dose for individuals manipulating the (131)I at a radioisotope production. By using an application installed on smartphones, we collected the time-microenvironment data spent by a radiation group during work days in 2015. Simultaneously, we used a portable air sampler combined with radioiodine cartridges for grabbing the indoor air samples and then the daily averaged (131)I concentration was calculated. Finally, the time-microenvironment data jointed with the concentration to estimate the inhalation dose for the workers. The result showed that most of the workers had the annual internal dose in 1÷6mSv. We concluded that using smartphone as a motion detector is a possible and reliable way instead of the questionnaires, diary or GPS-based method. It is, however, only suitable for monitoring on fixed indoor environments and limited the targeted people. Copyright © 2016 Elsevier Ltd. All rights reserved.

Reliability of Current Biokinetic and Dosimetric Models for Radionuclides: A Pilot Study

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

Leggett, Richard Wayne; Eckerman, Keith F; Meck, Robert A.

2008-10-01

This report describes the results of a pilot study of the reliability of the biokinetic and dosimetric models currently used by the U.S. Nuclear Regulatory Commission (NRC) as predictors of dose per unit internal or external exposure to radionuclides. The study examines the feasibility of critically evaluating the accuracy of these models for a comprehensive set of radionuclides of concern to the NRC. Each critical evaluation would include: identification of discrepancies between the models and current databases; characterization of uncertainties in model predictions of dose per unit intake or unit external exposure; characterization of variability in dose per unit intakemore » or unit external exposure; and evaluation of prospects for development of more accurate models. Uncertainty refers here to the level of knowledge of a central value for a population, and variability refers to quantitative differences between different members of a population. This pilot study provides a critical assessment of models for selected radionuclides representing different levels of knowledge of dose per unit exposure. The main conclusions of this study are as follows: (1) To optimize the use of available NRC resources, the full study should focus on radionuclides most frequently encountered in the workplace or environment. A list of 50 radionuclides is proposed. (2) The reliability of a dose coefficient for inhalation or ingestion of a radionuclide (i.e., an estimate of dose per unit intake) may depend strongly on the specific application. Multiple characterizations of the uncertainty in a dose coefficient for inhalation or ingestion of a radionuclide may be needed for different forms of the radionuclide and different levels of information of that form available to the dose analyst. (3) A meaningful characterization of variability in dose per unit intake of a radionuclide requires detailed information on the biokinetics of the radionuclide and hence is not feasible for many infrequently studied radionuclides. (4) The biokinetics of a radionuclide in the human body typically represents the greatest source of uncertainty or variability in dose per unit intake. (5) Characterization of uncertainty in dose per unit exposure is generally a more straightforward problem for external exposure than for intake of a radionuclide. (6) For many radionuclides the most important outcome of a large-scale critical evaluation of databases and biokinetic models for radionuclides is expected to be the improvement of current models. Many of the current models do not fully or accurately reflect available radiobiological or physiological information, either because the models are outdated or because they were based on selective or uncritical use of data or inadequate model structures. In such cases the models should be replaced with physiologically realistic models that incorporate a wider spectrum of information.« less

Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach.

PubMed

Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kunz, Christina; Formella, Stephan; Kloft, Charlotte

2016-03-01

Olodaterol, a novel β2-adrenergic receptor agonist, is a long-acting, once-daily inhaled bronchodilator approved for the treatment of chronic obstructive pulmonary disease. The aim of the present study was to describe the plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers by population pharmacokinetic modelling and thereby to infer its pulmonary fate. Plasma and urine data after intravenous administration (0.5-25 μg) and oral inhalation (2.5-70 μg via the Respimat® inhaler) were available from a total of 148 healthy volunteers (single and multiple dosing). A stepwise model building approach was applied, using population pharmacokinetic modelling. Systemic disposition parameters were fixed to estimates obtained from intravenous data when modelling data after inhalation. A pharmacokinetic model, including three depot compartments with associated parallel first-order absorption processes (pulmonary model) on top of a four-compartment body model (systemic disposition model), was found to describe the data the best. The dose reaching the lung (pulmonary bioavailable fraction) was estimated to be 49.4% [95% confidence interval (CI) 46.1, 52.7%] of the dose released from the device. A large proportion of the pulmonary bioavailable fraction [70.1% (95% CI 66.8, 73.3%)] was absorbed with a half-life of 21.8 h (95% CI 19.7, 24.4 h). The plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers were adequately described. The key finding was that a high proportion of the pulmonary bioavailable fraction had an extended pulmonary residence time. This finding was not expected based on the physicochemical properties of olodaterol. © 2015 The British Pharmacological Society.

The electrospray and its application to targeted drug inhalation.

PubMed

Gomez, Alessandro

2002-12-01

This review explains the fundamentals of electrostatic spray (electrospray) atomization, with emphasis on operation in the so called cone-jet mode, which produces droplets with a very narrow size distribution. Since the control of droplet size is key to maximizing distal lung deposition, the electrospray should be well-suited to targeted drug inhalation. Electrospray droplets are a few micrometers in diameter, but they originate from a much larger nozzle, which allows nebulization of suspensions without clogging. Also discussed are: the physical principles of the break-up of the liquid ligament; droplet dispersion by Coulombic forces; and the most important scaling law linking the droplet size to liquid flow rate and liquid physical properties. The effects of the most critical of those properties may result in some restrictions on drug formulation. Droplets produced by electrospray are electrically charged, so to prevent electrostatic image forces from causing upper respiratory tract deposition. The charge is neutralized by generating a corona discharge of opposite polarity. Briefly discussed are the main differences between the laboratory systems (with which the electrospray has been quantitatively characterized during research in the past 10 years) and commercial electrospray inhalers under development at BattellePharma. Some remarkable miniaturization has incorporated liquid pump, power supply, breath activation, and dose counter into a palm-size portable device. The maximum flow rates dispersed from these devices are in the range of 8-16 microL/s, which makes them suitable for practical drug inhalation therapy. Fabrication is economically competitive with inexpensive nebulizers. Dramatic improvements in respirable dose efficiency (up to 78% by comparison with commercial metered-dose inhalers and dry powder inhalers) should ensure the commercialization of this promising technology for targeted drug inhalation.

Cross-sectional and prospective relation of cannabis potency, dosing and smoking behaviour with cannabis dependence: an ecological study.

PubMed

van der Pol, Peggy; Liebregts, Nienke; Brunt, Tibor; van Amsterdam, Jan; de Graaf, Ron; Korf, Dirk J; van den Brink, Wim; van Laar, Margriet

2014-07-01

Increased delta-9-tetrahydrocannabinol (THC) concentrations in cannabis may lead to higher THC exposure, cannabis dependence and treatment need, but users may also adapt the actual intake of THC through reduced inhalation of THC containing smoke (titration). We investigated whether consumers of stronger cannabis use less cannabis per joint or inhale less smoke than those using less potent cannabis and whether these factors predict cannabis dependence severity. Heavy cannabis users (n = 98) brought their own cannabis, rolled a joint and smoked it ad libitum in a naturalistic setting. We analysed the content of the joint, its association with smoking behaviour and the cross-sectional and prospective (1.5-year follow-up) relations between smoking behaviour and cannabis dependence severity (total number of DSM-IV dependence symptoms). THC concentration in cannabis (range 1.10-24.70%) was correlated positively with cannabis dose per joint (b = 0.008, P = 0.01), but the resulting THC concentration per joint (range 0.24-15.72%) was associated negatively with inhalation volume (b = -0.05, P = 0.03). Smoking behaviour measures (number of puffs, inhaled volume, reduction of puff volume and puff duration while smoking) predicted follow-up dependence severity, independently of baseline dependence severity and monthly THC dose (number of joints × cannabis dose × cannabis THC concentration). Monthly THC dose only predicted follow-up dependence severity when unadjusted for baseline severity. Cannabis users titrate their delta-9-tetrahydrocannabinol intake by inhaling lower volumes of smoke when smoking strong joints, but this does not fully compensate for the higher cannabis doses per joint when using strong cannabis. Thus, users of more potent cannabis are generally exposed to more delta-9-tetrahydrocannabinol. Smoking behaviour appears to be a stronger predictor for cannabis dependence severity than monthly delta-9-tetrahydrocannabinol dose. © 2014 Society for the Study of Addiction.

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2011 CFR

2011-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2010 CFR

2010-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2012 CFR

2012-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2014 CFR

2014-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

32 CFR 218.1 - Policies.

Code of Federal Regulations, 2013 CFR

2013-07-01

... radiation environment to which the veteran was exposed and shall include inhaled, ingested and neutron doses. In determining the veteran's dose, initial neutron, initial gamma, residual gamma, and internal... dose, neutron dose, and internal dose. The minimum standards for reporting dose estimates are set forth...

Treating Asthma in Children Ages 5 to 11

MedlinePlus

... a dry powder inhaler. This device requires a deep, rapid inhalation to get the full dose of ... critical part of managing your child's asthma is learning exactly what steps to take on a daily, ...

Asbestos: a perspective. I. An overview. II. An annotated literature collection, 1960--1974. III. A literature compilation, 1974--1977. [Health hazards

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

Huff, J.E.; Hammons, A.S.; Dinger, C.Y.

Although the general population is widely exposed to asbestos, both by inhalation and ingestion, the hazards of chronic, environmental exposure have not been determined. Reasons conflict but are attributed in part to a paucity of information on human dose response, effects of asbestos ingestion, ambient concentrations and distribution of asbestos in the environment, the environmental cycling of asbestos, and related biological interactions including transmission through foodchains. As distilled from the world's asbestos literature, conclusions representing a majority opinion on the pathological effects of asbestos on man are summarized. (38 references.)

Dose conversion factors for radon: recent developments.

PubMed

Marsh, James W; Harrison, John D; Laurier, Dominique; Blanchardon, Eric; Paquet, François; Tirmarche, Margot

2010-10-01

Epidemiological studies of the occupational exposure of miners and domestic exposures of the public have provided strong and complementary evidence of the risks of lung cancer following inhalation of radon progeny. Recent miner epidemiological studies, which include low levels of exposure, long duration of follow-up, and good quality of individual exposure data, suggest higher risks of lung cancer per unit exposure than assumed previously by the International Commission on Radiological Protection (ICRP). Although risks can be managed by controlling exposures, dose estimates are required for the control of occupational exposures and are also useful for comparing sources of public exposure. Currently, ICRP calculates doses from radon and its progeny using dose conversion factors from exposure (WLM) to dose (mSv) based on miner epidemiological studies, referred to as the epidemiological approach. Revision of these dose conversion factors using risk estimates based on the most recent epidemiological data gives values that are in good agreement with the results of calculations using ICRP biokinetic and dosimetric models, the dosimetric approach. ICRP now proposes to treat radon progeny in the same way as other radionuclides and to publish dose coefficients calculated using models, for use within the ICRP system of protection.

Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

PubMed

Devereux, Graham; Cotton, Seonaidh; Barnes, Peter; Briggs, Andrew; Burns, Graham; Chaudhuri, Rekha; Chrystyn, Henry; Davies, Lisa; De Soyza, Anthony; Fielding, Shona; Gompertz, Simon; Haughney, John; Lee, Amanda J; McCormack, Kirsty; McPherson, Gladys; Morice, Alyn; Norrie, John; Sullivan, Anita; Wilson, Andrew; Price, David

2015-06-10

Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014.

Anthriscus nemorosa essential oil inhalation prevents memory impairment, anxiety and depression in scopolamine-treated rats.

PubMed

Bagci, Eyup; Aydin, Emel; Ungureanu, Eugen; Hritcu, Lucian

2016-12-01

Anthriscus nemorosa (Bieb.) Sprengel is used for medicinal purposes in traditional medicine around the world, including Turkey. Ethnobotanical studies suggest that Anthriscus essential oil could improve memory in Alzheimer's disease. The current study was hypothesized to investigate the beneficial effects of inhaled Anthriscus nemorosa essential oil on memory, anxiety and depression in scopolamine-treated rats. Anthriscus nemorosa essential oil was administered by inhalation in the doses of 1% and 3% for 21 continuous days and scopolamine (0.7mg/kg) was injected intraperitoneally 30min before the behavioral testing. Y-maze and radial arm-maze tests were used for assessing memory processes. Also, the anxiety and depressive responses were studied by elevated plus-maze and forced swimming tests. As expected, the scopolamine alone-treated rats exhibited the following: decrease the percentage of the spontaneous alternation in Y-maze test, increase the number of working and reference memory errors in radial arm-maze test, decrease of the exploratory activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming time and increase of immobility time within forced swimming test. However, dual scopolamine and Anthriscus nemorosa essential oil-treated rats showed significant improvement of memory formation and exhibited anxiolytic- and antidepressant-like effects in scopolamine-treated rats. These results suggest that Anthriscus nemorosa essential oil inhalation can prevent scopolamine-induced memory impairment, anxiety and depression. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Lung dosimetry for inhaled long-lived radionuclides and radon progeny.

PubMed

Hussain, M; Winkler-Heil, R; Hofmann, W

2011-05-01

The current version of the stochastic lung dosimetry model IDEAL-DOSE considers deposition in the whole tracheobronchial (TB) and alveolar airway system, while clearance is restricted to TB airways. For the investigation of doses produced by inhaled long-lived radionuclides (LLR) together with short-lived radon progeny, alveolar clearance has to be considered. Thus, present dose calculations are based on the average transport rates proposed for the revision of the ICRP human respiratory tract model. The results obtained indicate that LLR cleared from the alveolar region can deliver up to two to six times higher doses to the TB region when compared with the doses from directly deposited particles. Comparison of LLR doses with those of short-lived radon progeny indicates that LLR in uranium mines can deliver up to 5 % of the doses predicted for the short-lived radon daughters.

Ventolin Diskus and Inspyril Turbuhaler: an in vitro comparison.

PubMed

Broeders, M E A C; Molema, J; Burnell, P K P; Folgering, H T M

2005-01-01

Dose delivery (total emitted dose, or TED) from dry powder inhalers (DPIs), pulmonary deposition, and the biological effects depend on drug formulation and device and patient characteristics. The aim of this study was to measure, in vitro, the relationship between parameters of inhalation profiles recorded from patients, the TED and fine particle mass (FPM) of Diskus and Turbuhaler inhalers. Inhalation profiles (IPs) of 25 patients, a representative sample of a wide range of 1500 IPs generated by 10 stable asthmatics, 3 x 16 (mild/moderate/severe) COPD patients and 15 hospitalized patients with an exacerbation asthma or COPD, were selected for each device. These 25 IPs were input IPs for the Electronic Lung (a computerdriven inhalation simulator) to determine particle size distribution from Ventolin Diskus and Inspyril Turbuhaler. The TED and FPM of Diskus and FPM of Turbuhaler were affected by the peak inspiratory flow (PIF) and not by slope of the pressure-time curve, inhaled volume and inhalation time. This flow-dependency was more marked at lower flows (PIF < 40 L/min). Both the TED and FPM of Diskus were significantly higher as compared to those of the Turbuhaler [mean (SD) TED(_diskus) (%label claim) 83.5 (13.9) vs. TED(_turbuhaler) (72.5 (11.1) (p = 0.004), FPM(_diskus) (%label claim) 36.8 (9.8) vs FPM(_turbuhaler) (28.7 (7.7) (p < 0.05)]. The TED and FPM of Diskus and FPM of Turbuhaler were affected by PIF, the flow-dependency being greater at PIF values below 40 L/min. Lower PIFs occurred more often when using Turbuhaler than Diskus, since Turbuhaler have a higher resistivity, requires substantially higher pressure in order to generate the same flow as Diskus. TED, dose consistency and the FPM were higher for Diskus as compared to Turbuhaler. The flow dependency of TED and FPM was substantially influenced by inhalation profiles when not only profiles of the usual outpatient population were included but also the real outliers from exacerbated patients.

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.

A review of ipratropium bromide/fenoterol hydrobromide (Berodual) delivered via Respimat Soft Mist Inhaler in patients with asthma and chronic obstructive pulmonary disease.

PubMed

Kässner, Frank; Hodder, Rick; Bateman, Eric D

2004-01-01

Asthma and chronic obstructive pulmonary disease (COPD) can be effectively treated by the use of bronchodilator therapies delivered by inhalation. Berodual is a fixed combination of the anticholinergic agent ipratropium bromide (IB) and the beta2-adrenergic agonist fenoterol hydrobromide (FEN). IB/FEN has been available for the treatment of asthma and COPD in a pressurised metered dose inhaler (MDI) [pMDI] formulation for many years. The pMDI is the most widely used device for the delivery of inhaled medications, such as IB/FEN. However, most conventional pMDIs contain chlorofluorocarbon (CFC) propellants, which are currently being withdrawn because of their detrimental effects on the environment. This has resulted in alternative methods of drug delivery being developed. Respimat Soft Mist Inhaler (SMI) is a new generation, propellant-free inhaler that generates a fine, slow-moving cloud (the Soft Mist) which can be easily inhaled. Scintigraphic studies have shown that this improves deposition of drugs in the lung and results in less oropharyngeal deposition than the CFC-MDI. A clinical development programme has been conducted to compare the efficacy and safety of IB/FEN delivered via Respimat SMI with that of IB/FEN via CFC-MDI in the treatment of patients with asthma or COPD. Five clinical studies (two phase II and three phase III) investigated dosages of IB/FEN 5/12.5 microg to 320/800 microg via Respimat SMI in single and multiple dose administration regimens. Four of the trials were conducted in patients with asthma (three in adults and one in children), while one phase III trial was conducted in patients with COPD. In phase III, 2058 patients participated, with a total of 1112 patients treated with IB/FEN via Respimat SMI. In the phase III studies, each dose from Respimat SMI was given in one actuation compared with two actuations with the CFC-MDI. In the paediatric asthma phase III study, all CFC-MDI doses were delivered via a spacer device. The results of the trials demonstrated that IB/FEN via Respimat SMI allows a reduction in the nominal dose of IB/FEN, while offering similar therapeutic efficacy and safety to a CFC-MDI. In children, Respimat SMI obviates the need for a spacer.

Dermal and inhalation acute toxic class methods: test procedures and biometric evaluations for the Globally Harmonized Classification System.

PubMed

Holzhütter, H G; Genschow, E; Diener, W; Schlede, E

2003-05-01

The acute toxic class (ATC) methods were developed for determining LD(50)/LC(50) estimates of chemical substances with significantly fewer animals than needed when applying conventional LD(50)/LC(50) tests. The ATC methods are sequential stepwise procedures with fixed starting doses/concentrations and a maximum of six animals used per dose/concentration. The numbers of dead/moribund animals determine whether further testing is necessary or whether the test is terminated. In recent years we have developed classification procedures for the oral, dermal and inhalation routes of administration by using biometric methods. The biometric approach assumes a probit model for the mortality probability of a single animal and assigns the chemical to that toxicity class for which the best concordance is achieved between the statistically expected and the observed numbers of dead/moribund animals at the various steps of the test procedure. In previous publications we have demonstrated the validity of the biometric ATC methods on the basis of data obtained for the oral ATC method in two-animal ring studies with 15 participants from six countries. Although the test procedures and biometric evaluations for the dermal and inhalation ATC methods have already been published, there was a need for an adaptation of the classification schemes to the starting doses/concentrations of the Globally Harmonized Classification System (GHS) recently adopted by the Organization for Economic Co-operation and Development (OECD). Here we present the biometric evaluation of the dermal and inhalation ATC methods for the starting doses/concentrations of the GHS and of some other international classification systems still in use. We have developed new test procedures and decision rules for the dermal and inhalation ATC methods, which require significantly fewer animals to provide predictions of toxicity classes, that are equally good or even better than those achieved by using the conventional LD(50)/LC(50) methods. In order to cope with rather narrow dose/concentration classes of the GHS we have, as in our previous publications, combined the outcome of all results that can be obtained during testing for the allocation to one of the defined toxicity classes of the GHS. Our results strongly recommend the deletion of the dermal LD(50) and the inhalation LC(50) test as regulatory tests and the adoption of the dermal and inhalation ATC methods as internationally accepted alternatives.

Biopersistence of inhaled organic and inorganic fibers in the lungs of rats.

PubMed Central

Warheit, D B; Hartsky, M A; McHugh, T A; Kellar, K A

1994-01-01

Fiber dimension and durability are recognized as important features in influencing the development of pulmonary carcinogenic and fibrogenic effects. Using a short-term inhalation bioassay, we have studied pulmonary deposition and clearance patterns and evaluated and compared the pulmonary toxicity of two previously tested reference materials, an inhaled organic fiber, Kevlar para-aramid fibrils, and an inorganic fiber, wollastonite. Rats were exposed for 5 days to aerosols of Kevlar fibrils (900-1344 f/cc; 9-11 mg/m3) or wollastonite fibers (800 f/cc; 115 mg/m3). The lungs of exposed rats were digested to quantify dose, fiber dimensional changes over time, and clearance kinetics. The results showed that inhaled wollastonite fibers were cleared rapidly with a retention half-time of < 1 week. Mean fiber lengths decreased from 11 microns to 6 microns over a 1-month period, and fiber diameters increased from 0.5 micron to 1.0 micron in the same time. Fiber clearance studies with Kevlar showed a transient increase in the numbers of retained fibrils at 1 week postexposure, with rapid clearance of fibers thereafter, and retention half-time of 30 days. A progressive decrease in the mean lengths from 12.5 microns to 7.5 microns and mean diameters from 0.33 micron to 0.23 micron was recorded 6 months after exposure to inhaled Kevlar fibrils. The percentages of fibers > 15 microns in length decreased from 30% immediately after exposure to 5% after 6 months; the percentages of fibers in the 4 to 7 microns range increased from 25 to 55% in the same period.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 4. A Figure 4. B Figure 6. A Figure 6. B PMID:7882921

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).

Comparison of particulate matter dose and acute heart rate variability response in cyclists, pedestrians, bus and train passengers.

PubMed

Nyhan, Marguerite; McNabola, Aonghus; Misstear, Bruce

2014-01-15

Exposure to airborne particulate matter (PM) has been linked to cardiovascular morbidity and mortality. Heart rate variability (HRV) is a measure of the change in cardiac autonomic function, and consistent links between PM exposure and decreased HRV have been documented in studies. This study quantitatively assesses the acute relative variation of HRV with predicted PM dose in the lungs of commuters. Personal PM exposure, HR and HRV were monitored in 32 young healthy cyclists, pedestrians, bus and train passengers. Inhaled and lung deposited PM doses were determined using a numerical model of the human respiratory tract which accounted for varying ventilation rates between subjects and during commutes. Linear mixed models were used to examine air pollution dose and HRV response relationships in 122 commutes sampled. Elevated PM2.5 and PM10 inhaled and lung deposited doses were significantly (p<0.05) associated with decreased HRV indices. Percent declines in SDNN (standard deviation of normal RR intervals) relative to resting, due to an inter-quartile range increase in PM10 lung deposited dose were stronger in cyclists (-6.4%, 95% CI: -11.7, -1.3) and pedestrians (-5.8%, 95% CI: -11.3, -0.5), in comparison to bus (-3.2%, 95% CI: -6.4, -0.1) and train (-1.8%, -7.5, 3.8) passengers. A similar trend was observed in the case of PM2.5 lung deposited dose and results for rMSSD (the square root of the squared differences of successive normal RR intervals) followed similar trends to SDNN. Inhaled and lung deposited doses accounting for varying ventilation rates between modes, individuals and during commutes have been neglected in other studies relating PM to HRV. The findings here indicate that exercise whilst commuting has an influence on inhaled PM and PM lung deposited dose, and these were significantly associated with acute declines in HRV, especially in pedestrians and cyclists. © 2013.

Incorporation of dosimetry in the derivation of reference concentrations for ambient or workplace air: a conceptual approach.

PubMed

Oller, Adriana R; Oberdörster, Günter

2016-09-01

Dosimetric models are essential tools to refine inhalation risk assessments based on local respiratory effects. Dosimetric adjustments to account for differences in aerosol particle size and respiratory tract deposition and/or clearance among rodents, workers, and the general public can be applied to experimentally- and epidemiologically-determined points of departure (PODs) to calculate size-selected (e.g., PM 10 , inhalable aerosol fraction, respirable aerosol fraction) equivalent concentrations (e.g., HEC or Human Equivalent Concentration; REC or Rodent Equivalent Concentration). A modified POD (e.g., HEC) can then feed into existing frameworks for the derivation of occupational or ambient air concentration limits or reference concentrations. HECs that are expressed in terms of aerosol particle sizes experienced by humans but are derived from animal studies allow proper comparison of exposure levels and associated health effects in animals and humans. This can inform differences in responsiveness between animals and humans, based on the same deposited or retained doses and can also allow the use of both data sources in an integrated weight of evidence approach for hazard and risk assessment purposes. Whenever possible, default values should be replaced by substance-specific and target population-specific parameters. Assumptions and sources of uncertainty need to be clearly reported.

Incorporation of dosimetry in the derivation of reference concentrations for ambient or workplace air: a conceptual approach

PubMed Central

Oberdörster, Günter

2016-01-01

Dosimetric models are essential tools to refine inhalation risk assessments based on local respiratory effects. Dosimetric adjustments to account for differences in aerosol particle size and respiratory tract deposition and/or clearance among rodents, workers, and the general public can be applied to experimentally- and epidemiologically-determined points of departure (PODs) to calculate size-selected (e.g., PM10, inhalable aerosol fraction, respirable aerosol fraction) equivalent concentrations (e.g., HEC or Human Equivalent Concentration; REC or Rodent Equivalent Concentration). A modified POD (e.g., HEC) can then feed into existing frameworks for the derivation of occupational or ambient air concentration limits or reference concentrations. HECs that are expressed in terms of aerosol particle sizes experienced by humans but are derived from animal studies allow proper comparison of exposure levels and associated health effects in animals and humans. This can inform differences in responsiveness between animals and humans, based on the same deposited or retained doses and can also allow the use of both data sources in an integrated weight of evidence approach for hazard and risk assessment purposes. Whenever possible, default values should be replaced by substance-specific and target population-specific parameters. Assumptions and sources of uncertainty need to be clearly reported. PMID:27721518

Radiation Dose to Post-Chernobyl Cleanup Workers

Cancer.gov

Radiation dose calculation for post-Chernobyl Cleanup Workers in Ukraine - both external radiation exposure due to fallout and internal doses due to inhalation (I131 intake) or ingestion of contaminated foodstuffs.

Effects of Δ9-THC and cannabidiol vapor inhalation in male and female rats.

PubMed

Javadi-Paydar, Mehrak; Nguyen, Jacques D; Kerr, Tony M; Grant, Yanabel; Vandewater, Sophia A; Cole, Maury; Taffe, Michael A

2018-06-16

Previous studies report sex differences in some, but not all, responses to cannabinoids in rats. The majority of studies use parenteral injection; however, most human use is via smoke inhalation and, increasingly, vapor inhalation. To compare thermoregulatory and locomotor responses to inhaled ∆ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination using an e-cigarette-based model in male and female rats METHODS: Male and female Wistar rats were implanted with radiotelemetry devices for the assessment of body temperature and locomotor activity. Animals were then exposed to THC or CBD vapor using a propylene glycol (PG) vehicle. THC dose was adjusted via the concentration in the vehicle (12.5-200 mg/mL) and the CBD (100, 400 mg/mL) dose was also adjusted by varying the inhalation duration (10-40 min). Anti-nociception was evaluated using a tail-withdrawal assay following vapor inhalation. Plasma samples obtained following inhalation in different groups of rats were compared for THC content. THC inhalation reduced body temperature and increased tail-withdrawal latency in both sexes equivalently and in a concentration-dependent manner. Female temperature, activity, and tail-withdrawal responses to THC did not differ between estrus and diestrus. CBD inhalation alone induced modest hypothermia and suppressed locomotor activity in both males and females. Co-administration of THC with CBD, in a 1:4 ratio, significantly decreased temperature and activity in an approximately additive manner and to similar extent in each sex. Plasma THC varied with the concentration in the PG vehicle but did not differ across rat sex. In summary, the inhalation of THC or CBD, alone and in combination, produces approximately equivalent effects in male and female rats. This confirms the efficacy of the e-cigarette-based method of THC delivery in female rats.

Relative bioavailability of salbutamol to the lung following inhalation via a novel dry powder inhaler and a standard metered dose inhaler

PubMed Central

Hindle, M.; Peers, E. M.; Parry-Billings, M.; Chrystyn, H.

1997-01-01

Aims The number of dry powder inhaler (DPI) devices could increase because they are easier to use than a metered dose inhaler (MDI). Using urinary excretion, the relative bioavailability of salbutamol to the lungs and the body for a prototype DPI has been compared with an MDI. Methods A randomized, double-blind, two way crossover study compared the amount of salbutamol in the urine 30 min following inhalation of 2×100 μg salbutamol from a prototype DPI (Innovata Biomed Ltd, UK) and a Ventolin® (Allen and Hanburys Ltd, UK) MDI in 10 volunteers. The amount of salbutamol and its metabolite, the ester sulphate conjugate, renally excreted up to 24 h post inhalation was also determined to evaluate the relative bioavailability of salbutamol to the body. Results The mean (s.d.) 30 min post-treatment urinary excretion for the prototype DPI and MDI was 8.4 (2.6) and 5.0 (1.9) μg, respectively (P<0.001). The total amount of salbutamol and its ester metabolite excreted in the urine over the 24 h period after inhalation was 187.9 (77.6) and 137.6 (40.0) μg (P<0.05). Conclusions The prototype DPI delivered more salbutamol to the body and the lungs than a conventional MDI. This finding supports further development of the prototype DPI. The urinary salbutamol method is able to discriminate between two different inhalation systems. PMID:9088593

Inhaled Treprostinil-Prodrug Lipid Nanoparticle Formulations Provide Long-Acting Pulmonary Vasodilation.

PubMed

Leifer, Franziska G; Konicek, Donna M; Chen, Kuan-Ju; Plaunt, Adam J; Salvail, Dany; Laurent, Charles E; Corboz, Michel R; Li, Zhili; Chapman, Richard W; Perkins, Walter R; S Malinin, Vladimir

2018-05-23

Treprostinil (TRE), a prostanoid analogue approved in the USA for the treatment of pulmonary arterial hypertension, requires continuous infusion or multiple dosing sessions per day for inhaled and oral routes of administration due to its short half-life. The inhaled drug is known to induce adverse systemic and local effects including headache, nausea, cough, and throat irritation which may be due at least in part to transiently high drug concentrations in the lungs and plasma immediately following administration [1]. To ameliorate these side effects and reduce dosing frequency we designed an inhaled slow-release TRE formulation. TRE was chemically modified to be an alkyl prodrug (TPD) which was then packaged into a lipid nanoparticle (LNP) carrier. Preclinical screening in a rat model of hypoxia-induced pulmonary vasoconstriction led to selection of a 16-carbon alkyl ester derivative of TRE. The TPD-LNP demonstrated approximately 10-fold lower TRE plasma C max compared to inhaled TRE solution while maintaining an extended vasodilatory effect. The favorable PK profile is attributed to gradual dissociation of TPD from the LNP and subsequent conversion to TRE. Together, this sustained presentation of TRE to the lungs and plasma is consistent with a once- or twice-daily dosing schedule in the absence of high C max -associated adverse events which could provide patients with an improved treprostinil therapy. © Georg Thieme Verlag KG Stuttgart · New York.

Ciclesonide for the treatment of asthma

PubMed Central

Dahl, Ronald

2006-01-01

Ciclesonide is a nonhalogenated corticosteroid that is converted to its clinically active metabolite, desisobutyryl-ciclesonide, by esterases in the airways. Pharmacodynamic studies have shown that inhaled ciclesonide has potent antiinflammatory activity in patients with asthma, and does not appear to have clinically relevant systemic effects, even at high doses. It is highly protein-bound and rapidly metabolized by the liver, and thus has a low oral bioavailability. Ciclesonide is formulated as a solution for inhalation using a hydrofluoroalkane pressurized metered-dose inhaler. This formulation delivers a high fraction of respirable particles that yield high lung deposition with even distribution throughout the lungs and minimal oropharyngeal deposition. Results from numerous 12-week trials in patients (including children) with varying degrees of asthma show that morning or evening dosing with ciclesonide is more effective than placebo, and at least equivalent to other inhaled corticosteroids such as budesonide and fluticasone, with regard to improved spirometry, symptom scores, and less need for rescue medication. Results with once-daily ciclesonide are similar to those with twice-daily budesonide or fluticasone. At the dosages used in clinical trials, ciclesonide did not exert any untoward adverse effects and did not affect cortisol production. The favorable pharmacological properties of ciclesonide help explain the low incidence of adverse events, which are mostly mild to moderate in nature. Once-daily ciclesonide offers an efficacious treatment option for stepwise asthma management when inhaled corticosteroids are required. PMID:18360579

A methodology for the assessment of inhalation exposure to aluminium from antiperspirant sprays.

PubMed

Schwarz, Katharina; Pappa, Gerlinde; Miertsch, Heike; Scheel, Julia; Koch, Wolfgang

2018-04-01

Inhalative exposure can occur accidentally when using cosmetic spray products. Usually, a tiered approach is applied for exposure assessment, starting with rather conservative, simplistic calculation models that may be improved with measured data and more refined modelling. Here we report on an advanced methodology to mimic in-use conditions for antiperspirant spray products to provide a more accurate estimate of the amount of aluminium possibly inhaled and taken up systemically, thus contributing to the overall body burden. Four typical products were sprayed onto a skin surrogate in defined rooms. For aluminium, size-related aerosol release fractions, i.e. inhalable, thoracic and respirable, were determined by a mass balance method taking droplet maturation into account. These data were included into a simple two-box exposure model, allowing calculation of the inhaled aluminium dose over 12 min. Systemic exposure doses were calculated for exposure of the deep lung and the upper respiratory tract using the Multiple Path Particle Deposition Model (MPPD) model. The total systemically available dose of aluminium was in all cases found to be less than 0.5 µg per application. With this study it could be demonstrated that refinement of the input data of the two-box exposure model with measured data of released airborne aluminium is a valuable approach to analyse the contribution of antiperspirant spray inhalation to total aluminium exposure as part of the overall risk assessment. We suggest the methodology which can also be applied to other exposure modelling approaches for spray products, and further is adapted to other similar use scenarios.

Inhalation devices: from basic science to practical use, innovative vs generic products.

PubMed

Pirozynski, Michal; Sosnowski, Tomasz R

2016-11-01

Inhalation therapy is a convenient method of treating respiratory diseases. The key factors required for inhalation are the preparation of drug carriers (aerosol particles) allowing reproducible dosing during administration. These technical challenges are accomplished with a variety of inhalation devices (inhalers) and medicinal formulations, which are optimized to be easily converted into inhalable aerosols. Areas covered: This review is focused on the most important, but often overlooked, effects, which are required for the reliable and reproducible inhalable drug administration. The effects of patient-related issues that influence inhalation therapy, such as proper selection of inhalers for specific cases is discussed. We also discuss factors that are the most essential if generic inhalation product should be considered equivalent to the drugs with the clinically confirmed efficacy. Expert opinion: Proper device selection is crucial in clinical results of inhalation therapy. The patients' ability to coordinate inhalation with actuation, generation of optimal flow through the device, use of optimal inspiratory volume, all produces crucial effects on disease control. Also the severity of the disease process effects proper use of inhalers. Interchanging of inhalers can produce potentially conflicting problem regarding efficacy and safety of inhalation therapy.

HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT ...

EPA Pesticide Factsheets

Health and Environmental Effects Documents (HEEDS) are prepared for the Office of Solid Waste and Emergency Response (OSWER). This document series is intended to support listings under the Resource Conservation and Recovery Act (RCRA) as well as to provide health-related limits and goals for emergency and remedial actions under the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA). Both published literature and information obtained from Agency Program Office files are evaluated as they pertain to potential human health, aquatic life and environmental effects of hazardous waste constituents. Several quantitative estimates are presented provided sufficient data are available. For systemic toxicants, these include Reference Doses (RfDs) for chronic and subchronic exposures for both the inhalation and oral exposures. In the case of suspected carcinogens, RfDs may not be estimated. Instead, a carcinogenic potency factor, or q1*, is provided. These potency estimates are derived for both oral and inhalation exposures where possible. In addition, unit risk estimates for air and drinking water are presented based on inhalation and oral data, respectively. Reportable quantities (RQs) based on both chronic toxicity and carcinogenicity are derived. The RQ is used to determine the quantity of a hazardous substance for which notification is required in the event of a release as specified under CERCLA.

Development of a Zealand White Rabbit Deposition Model to Study Inhalation Anthrax

PubMed Central

Asgharian, Bahman; Price, Owen; Kabilan, Senthil; Jacob, Richard E.; Einstein, Daniel R.; Kuprat, A.P.; Corley, Richard A.

2016-01-01

Despite using rabbits in several inhalation exposure experiments to study diseases such as anthrax, there is a lack of understanding regarding deposition characteristics and fate of inhaled particles (bio-aerosols and viruses) in the respiratory tracts of rabbits. Such information allows dosimetric extrapolation to humans to inform human outcomes. The lung geometry of the New Zealand white rabbit (referred to simply as rabbits throughout the article) was constructed using recently acquired scanned images of the conducting airways of rabbits and available information on its acinar region. In addition, functional relationships were developed for the lung and breathing parameters of rabbits as a function of body weight. The lung geometry and breathing parameters were used to extend the existing deposition model for humans and several other species to rabbits. Evaluation of the deposition model for rabbits was made by comparing predictions with available measurements in the literature. Deposition predictions in the lungs of rabbits indicated smaller deposition fractions compared to those found in humans across various particle diameter ranges. The application of the deposition model for rabbits was demonstrated by extrapolating deposition predictions in rabbits to find equivalent human exposure concentrations assuming the same dose-response relationship between the two species. Human equivalent exposure concentration levels were found to be much smaller than those for rabbits. PMID:26895308

Performance of dry powder inhalers with single dosed capsules in preschool children and adults using improved upper airway models.

PubMed

Lindert, Sandra; Below, Antje; Breitkreutz, Joerg

2014-02-06

The pulmonary administration of pharmaceutical aerosols to patients is affected by age-dependent variations in the anatomy of the upper airways and the inhalation pattern. Considering this aspect, different upper airway models, representing the geometries of adults and preschool children, and a conventional induction port according to the European Pharmacopeia were used for in vitro testing of dry powder inhalers with single dosed capsules (Cyclohaler®, Handihaler® and Spinhaler®). Deposition measurements were performed using steady flow rates of 30 and 60 L/min for the Handihaler®/Spinhaler® and 30, 60 and 75 L/min for the Cyclohaler®. The inhalation volume was set at 1 L. For the Cyclohaler®, the in vitro testing was supplemented by a pediatric inhalation profile. Slight differences of pulmonary deposition between the idealized adult (11%-15%) and pediatric (9%-11%) upper airway model were observed for the Cyclohaler®. The applied pediatric inhalation profile resulted in a reduction of pulmonary deposition by 5% compared to steady conditions and indicated the influence of the inhalation pattern on the amount of pulmonary deposited particles. The comparison of two pediatric upper airway models showed no differences. The performance of the Handihaler® was similar to the Cyclohaler®. The Spinhaler® showed an insufficient performance and limited reproducibility in our investigations.

STUDY OF RADIATION EXPOSURE DUE TO RADON, THORON AND PROGENY IN THE INDOOR ENVIRONMENT OF YAMUNA AND TONS VALLEYS OF GARHWAL HIMALAYA.

PubMed

Prasad, Mukesh; Rawat, Mukesh; Dangwal, Anoop; Prasad, Ganesh; Mishra, Rosaline; Ramola, R C

2016-10-01

Long-term measurements of indoor radon, thoron and their progeny concentrations have been carried out in dwellings of Yamuna and Tons Valleys of Uttarkashi, Garhwal Himalaya to investigate the health risk associated with inhalation of radon, thoron and progeny. The experimentally determined values of radon, thoron and progeny concentrations were used to estimate the annual inhalation doses and annual effective doses. The annual inhalation dose has been found to vary from 0.8 to 3.9 mSv y -1 with an average of 1.8 mSv y -1 The annual effective dose from the exposure to radon and its progeny in the study area has been found to vary from 0.1 to 2.4 mSv with an average of 1.2±0.6 mSv. Similarly, the annual effective dose due to thoron and its progeny has been found to vary from 0.2 to 1.5 mSv with an average of 0.6±0.4. The measurement techniques and results obtained are discussed in detail. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Comparative study on the inhibitory effects of α-tocopherol and radon on carbon tetrachloride-induced renal damage.

PubMed

Kataoka, Takahiro; Yamato, Keiko; Nishiyama, Yuichi; Morii, Yuji; Etani, Reo; Takata, Yuji; Hanamoto, Katsumi; Kawabe, Atsuishi; Sakoda, Akihiro; Ishimori, Yuu; Taguchi, Takehito; Yamaoka, Kiyonori

2012-01-01

Since the 2011 nuclear accident in Fukushima, the effects of low-dose irradiation, especially internal exposure, are at the forefront of everyone's attention. However, low-dose radiation induced various stimulating effects such as activation of antioxidative and immune functions. In this study, we attempted to evaluate the quantitative effects of the activation of antioxidative activities in kidney induced by radon inhalation on carbon tetrachloride (CCl4)-induced renal damage. Mice were subjected to intraperitoneal (i.p.) injection of CCl4 after inhaling approximately 1000 or 2000 Bq/m3 radon for 24 h, or immediately after i.p. injection of α-tocopherol (100, 300, or 500 mg/kg bodyweight). In case of renal function, radon inhalation at a concentration of 2000 Bq/m3 has the inhibitory effects similar to α-tocopherol treatment at a dose of 300-500 mg/kg bodyweight. The activities of superoxide dismutase and catalase in kidneys were significantly higher in mice exposed to radon as compared to mice treated with CCl4 alone. These findings suggest that radon inhalation has an antioxidative effect against CCl4-induced renal damage similar to the antioxidative effects of α-tocopherol due to induction of antioxidative functions.

Ingestion, inhalation, and dermal exposures to chloroform and trichloroethene from tap water.

PubMed Central

Weisel, C P; Jo, W K

1996-01-01

Individuals are exposed to volatile compounds present in tap water by ingestion, inhalation, and dermal absorption. Traditional risk assessments for water often only consider ingestion exposure to toxic chemicals, even though showering has been shown to increase the body burden of certain chemicals due to inhalation exposure and dermal absorption. We collected and analyzed time-series samples of expired alveolar breath to evaluate changes in concentrations of volatile organic compounds being expired, which reflects the rate of change in the bloodstream due to expiration, metabolism, and absorption into tissues. Analysis of chloroform and trichloethene in expired breath, compounds regulated in water, was also used to determine uptake from tap water by each route (inhalation, ingestion, or absorption). Each route of exposure contributed to the total exposure of these compounds from daily water use. Further, the ingestion dose was completely metabolized before entering the bloodstream, whereas the dose from the other routes was dispersed throughout the body. Thus, differences in potential biologically effective doses depend on route, target organ, and whether the contaminant or metabolite is the biologically active agent. Images Figure 1. A Figure 1. B Figure 1. C Figure 2. A Figure 2. B PMID:8834861

Achieving Consistent Multiple Daily Low-Dose Bacillus anthracis Spore Inhalation Exposures in the Rabbit Model

DTIC Science & Technology

2012-06-13

plethysmography. Overall, the presented results show that the animal aerosol system was stable and highly reproducible between different studies and over...develop and deliver low-doses of B. anthracis spores via inhalation in a reproducible manner. The pilot feasibility study (see Table 1 for results) enabled...results presented in Figure 3 show that exposures produced by the aerosol system were stable and reproducible from day-to-day. In all testing, the

Fluticasone furoate and vilanterol inhalation powder for the treatment of chronic obstructive pulmonary disease.

PubMed

Matera, Maria Gabriella; Capuano, Annalisa; Cazzola, Mario

2015-02-01

Fluticasone furoate/vilanterol (FF/VI) is a novel inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) fixed dose combination that, by simplifying the dosing schedule, allows, for the first time in a member of the ICS/LABA class, a shift from twice-daily to once-daily treatment. FF/VI is delivered via a novel, single-step activation, multi-dose dry powder inhaler for oral inhalation, Ellipta. Regrettably, there are no head-to-head trials that have shown superiority in the safety or efficacy of FF versus other ICSs, but evidence shows that VI has a quicker onset of effect versus salmeterol. However, the clinical utility of this effect in a maintenance medication is still questionable. Furthermore, benefits of FF/VI over twice-daily ICS/LABA comparator have not been shown yet and, in addition, its adverse event profile is generally consistent with the known class effects of an ICS/LABA fixed dose combination. In particular, there is an increase in the risk of pneumonia among patients treated with FF/VI relative to VI, mainly among those who benefit most from FF/VI. Nevertheless, the interesting pharmacological profiles of both FF and VI, the possibility that FF/VI can be administered once-daily, and the attractive characteristics of Ellipta are important features that could help FF/VI to be a successful combination in the treatment of chronic obstructive pulmonary disease.

Impact of the new nuclear decay data of ICRP publication 107 on inhalation dose coefficients for workers

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

Manabe, K.; Endo, Akira; Eckerman, Keith F

2010-03-01

The impact a revision of nuclear decay data had on dose coefficients was studied using data newly published in ICRP Publication 107 (ICRP 107) and existing data from ICRP Publication 38 (ICRP 38). Committed effective dose coefficients for occupational inhalation of radionuclides were calculated using two sets of decay data with the dose and risk calculation software DCAL for 90 elements, 774 nuclides and 1572 cases. The dose coefficients based on ICRP 107 increased by over 10 % compared with those based on ICRP 38 in 98 cases, and decreased by over 10 % in 54 cases. It was foundmore » that the differences in dose coefficients mainly originated from changes in the radiation energy emitted per nuclear transformation. In addition, revisions of the half-lives, radiation types and decay modes also resulted in changes in the dose coefficients.« less

Range-Finding Risk Assessment of Inhalation Exposure to Nanodiamonds in a Laboratory Environment

PubMed Central

Koivisto, Antti J.; Palomäki, Jaana E.; Viitanen, Anna-Kaisa; Siivola, Kirsi M.; Koponen, Ismo K.; Yu, Mingzhou; Kanerva, Tomi S.; Norppa, Hannu; Alenius, Harri T.; Hussein, Tareq; Savolainen, Kai M.; Hämeri, Kaarle J.

2014-01-01

This study considers fundamental methods in occupational risk assessment of exposure to airborne engineered nanomaterials. We discuss characterization of particle emissions, exposure assessment, hazard assessment with in vitro studies, and risk range characterization using calculated inhaled doses and dose-response translated to humans from in vitro studies. Here, the methods were utilized to assess workers’ risk range of inhalation exposure to nanodiamonds (NDs) during handling and sieving of ND powder. NDs were agglomerated to over 500 nm particles, and mean exposure levels of different work tasks varied from 0.24 to 4.96 µg·m−3 (0.08 to 0.74 cm−3). In vitro-experiments suggested that ND exposure may cause a risk for activation of inflammatory cascade. However, risk range characterization based on in vitro dose-response was not performed because accurate assessment of delivered (settled) dose on the cells was not possible. Comparison of ND exposure with common pollutants revealed that ND exposure was below 5 μg·m−3, which is one of the proposed exposure limits for diesel particulate matter, and the workers’ calculated dose of NDs during the measurement day was 74 ng which corresponded to 0.02% of the modeled daily (24 h) dose of submicrometer urban air particles. PMID:24840353

Non-linear relationship of cell hit and transformation probabilities in a low dose of inhaled radon progenies.

PubMed

Balásházy, Imre; Farkas, Arpád; Madas, Balázs Gergely; Hofmann, Werner

2009-06-01

Cellular hit probabilities of alpha particles emitted by inhaled radon progenies in sensitive bronchial epithelial cell nuclei were simulated at low exposure levels to obtain useful data for the rejection or support of the linear-non-threshold (LNT) hypothesis. In this study, local distributions of deposited inhaled radon progenies in airway bifurcation models were computed at exposure conditions characteristic of homes and uranium mines. Then, maximum local deposition enhancement factors at bronchial airway bifurcations, expressed as the ratio of local to average deposition densities, were determined to characterise the inhomogeneity of deposition and to elucidate their effect on resulting hit probabilities. The results obtained suggest that in the vicinity of the carinal regions of the central airways the probability of multiple hits can be quite high, even at low average doses. Assuming a uniform distribution of activity there are practically no multiple hits and the hit probability as a function of dose exhibits a linear shape in the low dose range. The results are quite the opposite in the case of hot spots revealed by realistic deposition calculations, where practically all cells receive multiple hits and the hit probability as a function of dose is non-linear in the average dose range of 10-100 mGy.

The impact of expired and empty quick-relief asthma inhalers: The Asthma and Allergy Foundation of America's Asthma Inhaler Design Survey.

PubMed

Storms, William W; Tringale, Mike; Ferro, Thomas J

2015-01-01

Despite the available treatments, asthma remains a serious illness, with a considerable socioeconomic burden associated with a high number of unscheduled visits to the emergency department (ED). Poor adherence and inadequate inhaler technique are contributing factors to poor asthma management and control. The Asthma Inhaler Design Survey assessed the behaviors, attitudes, needs, and preferences of patients with asthma and their caregivers with regard to quick-relief inhaler usage and device design. The Asthma and Allergy Foundation of America invited 19,157 adult patients and parents of children with asthma to take part in an online survey that focused on previous asthma diagnosis, symptom severity, and quick-relief and controller medication use. Opinions were also collected. Data from 590 respondents (366 adults; 224 children) were included in the final analysis. Relief inhalers were needed and found to be past the expiration date by 284 of 561 (50.6%) and relief inhalers were found to be empty by 270 of 560 (48.2%). Of the empty inhaler group, 28 of 270 (10.4%) had to visit the ED for treatment, 18 of 270 (6.7%) missed work or school for an unscheduled physician office visit, and 54 of 270 (20%) went without treatment. Although 78.5% indicated that they had at least two quick-relief inhalers nearby, these were not always easily accessible. Few respondents (194/578 [33.6%]) indicated that they and/or their child were very confident that they were using their inhaler properly, even though the majority had received some instruction. When asked what they would do to improve satisfaction with their quick-relief inhalers, 173 of 558 (31%) responded that they would add a dose counter. Unnecessary health care utilization and avoidable loss of time at work or school were associated with the lack of full availability of properly functioning quick-relief inhalers when needed. Adding a dose counter was the most frequently cited response for improving satisfaction with quick-relief inhalers. Confidence about proper inhaler use was low, despite previous instruction.

Radon and Thoron Measured in Petrol and Gas-oil Exhaust Fumes by Using CR-39 and LR-115 II Nuclear Track Detectors: Radiation Doses to the Respiratory Tract of Mechanic Workers.

PubMed

Misdaq, M A; Chaouqi, A; Ouguidi, J; Touti, R; Mortassim, A

2015-06-01

Mechanic workers are exposed to exhaust fumes when controlling vehicle engines in motion inside repair shops. To assess radiation doses due to radon short-lived progeny from the inhalation of exhaust fumes by mechanic workers, concentrations of these radionuclides were measured in petrol (gasoline) and gas-oil exhaust fumes by evaluating mean critical angles of etching of the CR-39 and LR-115 type II SSNTDs for alpha particles emitted by the radon and thoron decay series. Committed effective doses due to ²¹⁸Po and ²¹⁴Po short-lived radon decay products from the inhalation of petrol and gas-oil exhaust fumes by workers were evaluated. A maximum value of 1.35 mSv y⁻¹ due to radon short-lived decay products from the inhalation of gas-oil exhaust fumes by mechanic workers was found, which is lower than the (3-10 mSv y⁻¹) dose limit interval for workers.

AGE-DEPENDENT INHALATION DOSE DUE TO EXPOSURE OF SHORT LIVED PROGENY OF RADON AND THORON FOR DIFFERENT AGE GROUPS IN JAMMU & KASHMIR, HIMALAYAS.

PubMed

Sharma, Sumit; Kumar, Ajay; Mehra, Rohit

2018-05-16

Dosimetric approach is used in this study for the assessment of doses due to inhalation of short lived radon/thoron progeny to the inhabitants of Udhampur district of Jammu & Kashmir. This paper also presents the activity concentrations and unattached fraction of radon and thoron progeny. The observed annual concentration of attached and unattached 222Rn and 220Rn progeny has been found to vary from 8 to 32 and 0.09 to 14 Bq/m3, 0.75 to 3.16 and 0.01 to 1.13 Bq/m3, respectively. The inhalation doses from radon progeny to different body organs of different age groups have been calculated by using the age dependent biokinetic model. The attachment rate of 222Rn and indoor aerosol concentration of 222Rn and 220Rn have been estimated and their relation between them has also been studied. The dose conversion factor for mouth and nasal breathing to different exposure conditions has been obtained from Porstendorfer model.

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)

Inhalation toxicity of methanol/gasoline in rats: effects of 13-week exposure.

PubMed

Poon, R; Park, G; Viau, C; Chu, I; Potvin, M; Vincent, R; Valli, V

1998-01-01

The subchronic inhalation toxicity of a methanol/gasoline blend (85% methanol, 15% gasoline, v/v) was studied in rats. Sprague Dawley rats (10 animals per group) of both sexes were exposed to vapours of methanol/gasoline at 50/3, 500/30 and 5000/300ppm for 6 hours per day, 5 days per week, for 13 weeks. Control animals inhaled filtered room air only. Control recovery and high dose recovery groups were also included which inhaled room air for an extra 4 weeks following the treatment period. No clinical signs of toxicity were observed in the treatment group and their growth curves were not significantly different from the control. Except for decreased forelimb grip strength in high dose females, no treatment-related neurobehavioural effects (4-6 hours post inhalation) were observed using screening tests which included cage-side observations, righting reflex, open field activities, and forelimb and hindlimb grip strength. At necropsy, the organ to body weight ratios for the liver, spleen, testes, thymus and lungs were not significantly different from the control group. There were no treatment-related effects in the hematological endpoints and no elevation in serum formate levels. Minimal serum biochemical changes were observed with the only treatment-related change being the decreased creatinine in the females. A dose-related increase in urinary ascorbic acid was detected in males after 2, 4 and 8 weeks of exposure, but not after the 12th week, and in females only at week-2. Increased urinary albumin was observed in treated males starting at the lowest dose and at all exposure periods, but not in females. A treatment-related increase in urinary beta 2-microglobulin was detected in males at week-2 only. Except for mild to moderate mucous cell metaplasia in nasal septum B, which occurred more often and with a slightly higher degree of severity in the low dose groups of both sexes, and presence of a minimal degree of interstitial lymphocyte infiltration in the prostate glands in the high dose males. No other significant microscopic changes were observed in the tissues of treated animals. Based on the marked increase in urinary ascorbic acid and albumin in the high dose males and the decreased forelimb grip strength in the high dose females, we concluded that the no-observed adverse effect level (NOAEL) of methanol/gasoline vapour is 500/30 ppm.

Toxicity of inhaled plutonium dioxide in beagle dogs

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

Muggenburg, M.A.; Guilmette, R.A.; Mewhinney, J.A.

This study was conducted to determine the biological effects of inhaled {sup 238}PuO{sub 2} over the life spans of 144 beagle dogs. The dogs inhaled one of two sizes of monodisperse aerosols of {sup 238}PuO{sub 2} to achieve graded levels of initial lung burden (ILB). The aerosols also contained {sup 169}Yb to provide a {gamma}-ray-emitting label for the {sup 238}Pu inhaled by each dog. Excreta were collected periodically over each dog`s life span to estimate plutonium excretion; at death, the tissues were analyzed radiochemically for plutonium activity. The tissue content and the amount of plutonium excreted were used to estimatemore » the ILB. These data for each dog were used in a dosimetry model to estimate the ILB. These data for each dog were used in a dosimetry model to estimate tissue doses. The lung, skeleton and liver received the highest {alpha}-particle doses, ranging from 0.16-68 Gy for the liver. At death, all dogs were necropsied, and all organs and lesions were sampled and examined by histopathology. Findings of non-neoplastic changes included neutropenia and lymphopenia that developed in a dose-related fashion soon after inhalation exposure. These effects persisted for up to 5 years in some animals, but no other health effects could be related to the blood changes observed. Radiation pneumonitis was observed among the dogs with the highest ILBs. Deaths from radiation pneumonitis occurred from 1.5 to 5.4 years after exposure. Tumors of the lung, skeleton and liver occurred beginning at about 3 years after exposure. These findings in dogs suggest that similar dose-related biological effects could be expected in humans accidentally exposed to {sup 238}PuO{sub 2}. 89 refs., 10 figs., 11 tab.« less

Optimizing the Entrainment Geometry of a Dry Powder Inhaler: Methodology and Preliminary Results.

PubMed

Kopsch, Thomas; Murnane, Darragh; Symons, Digby

2016-11-01

For passive dry powder inhalers (DPIs) entrainment and emission of the aerosolized drug dose depends strongly on device geometry and the patient's inhalation manoeuvre. We propose a computational method for optimizing the entrainment part of a DPI. The approach assumes that the pulmonary delivery location of aerosol can be determined by the timing of dose emission into the tidal airstream. An optimization algorithm was used to iteratively perform computational fluid dynamic (CFD) simulations of the drug emission of a DPI. The algorithm seeks to improve performance by changing the device geometry. Objectives were to achieve drug emission that was: A) independent of inhalation manoeuvre; B) similar to a target profile. The simulations used complete inhalation flow-rate profiles generated dependent on the device resistance. The CFD solver was OpenFOAM with drug/air flow simulated by the Eulerian-Eulerian method. To demonstrate the method, a 2D geometry was optimized for inhalation independence (comparing two breath profiles) and an early-bolus delivery. Entrainment was both shear-driven and gas-assisted. Optimization for a delay in the bolus delivery was not possible with the chosen geometry. Computational optimization of a DPI geometry for most similar drug delivery has been accomplished for an example entrainment geometry.

Pulmonary cellular effects in rats following aerosol exposures to ultrafine Kevlar aramid fibrils: evidence for biodegradability of inhaled fibrils.

PubMed

Warheit, D B; Kellar, K A; Hartsky, M A

1992-10-01

Previous chronic inhalation studies have shown that high concentrations of Kevlar fibrils produced fibrosis and cystic keratinizing tumors in rats following 2-year inhalation exposures. The current studies were undertaken to evaluate mechanisms and to assess the toxicity of inhaled Kevlar fibrils relative to other reference materials. Rats were exposed to ultrafine Kevlar fibers (fibrils) for 3 or 5 days at concentrations ranging from 600-1300 fibers/cc (gravimetric concentrations ranging from 2-13 mg/m3). A complete characterization of the fiber aerosol and dose was carried out. These measurements included gravimetric concentrations, mass median aerodynamic diameter, fiber number, and count median lengths and diameters of the aerosol. Following exposures, cells and fluids from groups of sham- and fiber-exposed animals were recovered by bronchoalveolar lavage (BAL). Alkaline phosphatase, lactate dehydrogenase (LDH), protein, and N-acetyl glucosaminidase (NAG) values were measured in BAL fluids at several time points postexposure. Alveolar macrophages were cultured and studied for morphology, chemotaxis, and phagocytosis by scanning electron microscopy. The lungs of additional exposed animals were processed for deposition, cell labeling, retained dose, and lung clearance studies, as well as fiber dimensions (from digested lung tissue), histopathology, and transmission electron microscopy. Five-day exposures to Kevlar fibrils elicited a transient granulocytic inflammatory response with concomitant increases in BAL fluid levels of alkaline phosphatase, NAG, LDH, and protein. Unlike the data from silica and asbestos exposures where inflammation persisted, biochemical parameters returned to control levels at time intervals between 1 week and 1 month postexposure. Macrophage function in Kevlar-exposed alveolar macrophages was not significantly different from sham controls at any time period. Cell labeling studies were carried out immediately after exposure, as well as 1 week and 1 month postexposure. Increased pulmonary cell labeling was measured in terminal bronchiolar cells immediately after exposure but returned to control values 1 week later. Fiber clearance studies demonstrated a transient increase in the numbers of retained fibers at 1 week postexposure, with rapid clearance of fibers thereafter. The transient increase in the number of fibers could be due to transverse cleaving of the fibers, since the average lengths of retained fibers continued to decrease over time. In this regard, a progressive decrease in the mean lengths and diameters of inhaled fibers was measured over a 6-month postexposure period.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Fluticasone and Vilanterol Oral Inhalation

MedlinePlus

... glaucoma (an eye disease), cataracts (clouding of the lens of the eyes), any condition that affects your immune system, or ... after every blister has been used (when the dose indicator reads 0), whichever ... and those for eye drops, creams, patches, and inhalers) are not child- ...

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.

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.

Pulmonary Bovine-Type Tuberculosis in Rabbits: Bacillary Virulence, Inhaled Dose Effects, Tuberculin Sensitivity, and Mycobacterium vaccae Immunotherapy

PubMed Central

Converse, P. J.; Dannenberg, A. M.; Shigenaga, T.; McMurray, D. N.; Phalen, S. W.; Stanford, J. L.; Rook, G. A. W.; Koru-Sengul, T.; Abbey, Helen; Estep, J. E.; Pitt, M. L. M.

1998-01-01

This report elucidates four aspects of the immunology of pulmonary tuberculosis produced in rabbits: (i) the virulence of bovine-type tubercle bacilli, strain Ravenel S, (ii) systemic factors influencing the generation of visible primary pulmonary tubercles, (iii) differences in tuberculin sensitivity of rabbits and humans, and (iv) the effect of Mycobacterium vaccae immunotherapy on cavitary tuberculosis. Laboratory strain Ravenel S (ATCC 35720) was not fully virulent. Fully virulent strains produce one visible primary pulmonary tubercle for each three bacillary units inhaled. Strain ATCC 35720 produced one such tubercle for each 18 to 107 bacillary units inhaled, indicating that its virulence was reduced by 6- to 36-fold. When a low dose of this Ravenel S strain was inhaled, the host resistance (measured by the number of inhaled bacilli needed to generate one visible primary pulmonary tubercle) was increased at least 3.5-fold compared to the host resistance when a high dose was inhaled. Rabbits and humans differ in the degree and in the maintenance of their dermal sensitivities to tuberculin. Compared to rabbits, humans are 100 times more sensitive to tuberculin. Also, at 33 weeks rabbits with well-controlled cavitary tuberculosis usually showed a decrease in their tuberculin reactions of about 50% from peak values, whereas humans with such well-controlled tuberculosis are thought to maintain strong reactions for many years. These species differences may be due to desensitization to group II mycobacterial antigens in the rabbits because they have a different diet and a different type of digestive tract. M. vaccae immunotherapy of rabbits with cavitary tuberculosis produced no statistically significant effects. Experiments with many more rabbits would be required to prove whether or not such immunotherapy is beneficial. PMID:9801350

Assessing Inhalation Exposures Associated with Contamination Events in Water Distribution Systems

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

Davis, Michael J.; Janke, Robert; Taxon, Thomas N.

When a water distribution system (WDS) is contaminated, short-term inhalation exposures to airborne contaminants could occur as the result of domestic water use. The most important domestic sources of such exposures are likely to be showering and the use of aerosol-producing humidifiers, i.e., ultrasonic and impeller (cool-mist) units. A framework is presented for assessing the potential effects of short-term, system-wide inhalation exposures that could result from such activities during a contamination event. This framework utilizes available statistical models for showering frequency and duration, available exposure models for showering and humidifier use, and experimental results on both aerosol generation and themore » volatilization of chemicals during showering. New models for the times when showering occurs are developed using time-use data for the United States. Given a lack of similar models for how humidifiers are used, or the information needed to develop them, an analysis of the sensitivity of results to assumptions concerning humidifier use is presented. The framework is applied using network models for three actual WDSs. Simple models are developed for estimating upper bounds on the potential effects of system-wide inhalation exposures associated with showering and humidifier use. From a system-wide, population perspective, showering could result in significant inhalation doses of volatile chemical contaminants, and humidifier use could result in significant inhalation doses of microbial contaminants during a contamination event. From a system-wide perspective, showering is unlikely to be associated with significant doses of microbial contaminants. In conclusion, given the potential importance of humidifiers as a source of airborne contaminants during a contamination event, an improved understanding of the nature of humidifier use is warranted.« less

Assessing Inhalation Exposures Associated with Contamination Events in Water Distribution Systems

DOE PAGES

Davis, Michael J.; Janke, Robert; Taxon, Thomas N.

2016-12-08

When a water distribution system (WDS) is contaminated, short-term inhalation exposures to airborne contaminants could occur as the result of domestic water use. The most important domestic sources of such exposures are likely to be showering and the use of aerosol-producing humidifiers, i.e., ultrasonic and impeller (cool-mist) units. A framework is presented for assessing the potential effects of short-term, system-wide inhalation exposures that could result from such activities during a contamination event. This framework utilizes available statistical models for showering frequency and duration, available exposure models for showering and humidifier use, and experimental results on both aerosol generation and themore » volatilization of chemicals during showering. New models for the times when showering occurs are developed using time-use data for the United States. Given a lack of similar models for how humidifiers are used, or the information needed to develop them, an analysis of the sensitivity of results to assumptions concerning humidifier use is presented. The framework is applied using network models for three actual WDSs. Simple models are developed for estimating upper bounds on the potential effects of system-wide inhalation exposures associated with showering and humidifier use. From a system-wide, population perspective, showering could result in significant inhalation doses of volatile chemical contaminants, and humidifier use could result in significant inhalation doses of microbial contaminants during a contamination event. From a system-wide perspective, showering is unlikely to be associated with significant doses of microbial contaminants. In conclusion, given the potential importance of humidifiers as a source of airborne contaminants during a contamination event, an improved understanding of the nature of humidifier use is warranted.« less

Investigation of endothelial function by pulse contour analysis: a protocol for drug administration and timing of pulse contour assessment

PubMed Central

Gordon, Sarah E; Cartwright, Neil; Griffiths, Mark J D

2009-01-01

AIMS Pulse contour analysis (PCA) obtained by finger photoplethysmography produces a digital volume pulse (DVP) including an inflection point in its down-slope. The reflection index (RI: ratio of the inflection point height over the maximal DVP) is responsive to vasodilatation. We aimed to optimize the drug dose and time interval for assessing endothelial function using PCA in healthy volunteers and patients with severe coronary artery disease. METHODS Time and dose to RI response relationships were constructed in 16 volunteers and nine patients to inhaled salbutamol (100–400 µg) or sublingual nitroglycerin (NTG; 25–400 µg). RESULTS For the volunteers, the time to maximum RI response to inhaled salbutamol and sublingual NTG was 10.73 ± 0.41 and 3.66 ± 0.21 min, respectively. A plateau in the RI response to salbutamol occurred between 5 and 15 min after inhalation and results were averaged over this period. A dose-dependent response was observed to inhaled salbutamol and sublingual NTG (P= 0.05 and P < 0.001 by repeated-measures anova, respectively) in healthy volunteers. By contrast, in patients with severe coronary artery disease inhaled salbutamol (100–400 µg) did not cause a significant change in RI. CONCLUSIONS In healthy volunteers the RI response to inhaled salbutamol (100–200 µg) averaged over 5–15 min after administration may be used to investigate endothelial function by PCA. The response to sublingual NTG (50 µg) should be determined at 4 min. This technique may not be suitable for the assessment of endothelial function in subjects with extensive coronary artery disease owing to the small responses observed and potential confounding effect of vasoactive medication. PMID:19843066

Assessing Inhalation Exposures Associated with Contamination Events in Water Distribution Systems

PubMed Central

Davis, Michael J.; Janke, Robert; Taxon, Thomas N.

2016-01-01

When a water distribution system (WDS) is contaminated, short-term inhalation exposures to airborne contaminants could occur as the result of domestic water use. The most important domestic sources of such exposures are likely to be showering and the use of aerosol-producing humidifiers, i.e., ultrasonic and impeller (cool-mist) units. A framework is presented for assessing the potential effects of short-term, system-wide inhalation exposures that could result from such activities during a contamination event. This framework utilizes available statistical models for showering frequency and duration, available exposure models for showering and humidifier use, and experimental results on both aerosol generation and the volatilization of chemicals during showering. New models for the times when showering occurs are developed using time-use data for the United States. Given a lack of similar models for how humidifiers are used, or the information needed to develop them, an analysis of the sensitivity of results to assumptions concerning humidifier use is presented. The framework is applied using network models for three actual WDSs. Simple models are developed for estimating upper bounds on the potential effects of system-wide inhalation exposures associated with showering and humidifier use. From a system-wide, population perspective, showering could result in significant inhalation doses of volatile chemical contaminants, and humidifier use could result in significant inhalation doses of microbial contaminants during a contamination event. From a system-wide perspective, showering is unlikely to be associated with significant doses of microbial contaminants. Given the potential importance of humidifiers as a source of airborne contaminants during a contamination event, an improved understanding of the nature of humidifier use is warranted. PMID:27930709

Are We Done with Respiratory Deposition and Dosimetry of Inhaled Particles?

EPA Science Inventory

Deposition of inhaled particles and subsequent dose estimation in the respiratory airways is an essential information needed for assessing potential health hazard of airborne pollutant particles on the one hand and therapeutic efficacy of drug aerosols on the other hand. Over sev...

LOW-DOSE AIRBORNE ENDOTOXIN EXPOSURE ENHANCES BRONCHIAL RESPONSIVENESS TO INHALED ALLERGEN IN ATOPIC ASTHMATICS

EPA Science Inventory

Endotoxin exposure has been associated with both protection against development of TH2-immune responses during childhood and exacerbation of asthma in persons who already have allergic airway inflammation.1 Occupational and experimental inhalation exposures to endotoxin have been...

Osteosarcoma development following single inhalation exposure to americium-241 in beagle dogs.

PubMed

Gillett, N A; Hahn, F F; Mewhinney, J A; Muggenberg, B A

1985-10-01

Young, mature Beagle dogs underwent single inhalation exposure to respirable aerosols of 241AmO2 to determine the radiation dose distribution to tissues. The dogs were serially sacrificed to assess the clearance of 241Am from the lung, the rate of translocation to internal organs, the pattern of retention in the organs, and the rates and modes of excretion. Americium dioxide was relatively soluble in the lung, leading to the translocation of significant quantities of 241Am to bone and liver, thus delivering radiation doses to these tissues nearly equal to that received by the lung. Osteoblastic osteosarcomas developed in four dogs surviving more than 1000 days after exposure. Histologically, all of the osteosarcomas were associated with areas of radiation osteodystrophy characterized by bone infarction, peritrabecular new bone formation, marrow fibrosis, and microresorptive cavities. The retention and translocation of inhaled 241Am in dogs is similar to that of man, indicating that 241Am inhaled by humans may potentially result in significant risk of bone tumor development.

Treatment outcomes of using inhalation sedation for comprehensive dental care.

PubMed

Madouh, M; BaniHani, A; Tahmassebi, J F

2018-02-01

To assess the outcomes of dental treatment under inhalation sedation within a UK specialist hospital setting. This was a retrospective cohort study of the case notes of patients under 17 years of age who received dental treatment using inhalation sedation at a UK specialist setting during the period 2006-2011. Treatment outcomes were categorised into five groups: (1) treatment completed as planned, (2) modified treatment completed, (3) treatment abandoned in sedation unit and patient referred for treatment under general analgesia (GA), (4) treatment abandoned in sedation unit and patient referred for treatment under local analgesia (LA), (5) child failed to return to complete treatment. In total, the case notes of 453 patients were evaluated. The mean age of the patients was 10.3 ± 2.9 years. Treatment was completed successfully in 63.6% of the cases, 15.9% were referred for treatment under GA, 11.2% failed to return to complete the treatment, 7.1% received modified treatment completed, and only 2.2% were referred for treatment under LA. Treatment outcomes were significantly associated with patient`s age (p = 0.002). The treatment outcome "treatment abandoned and child referred to be treated under GA" had significantly lower mean patient ages than the other outcomes. The majority of children referred for inhalation sedation, completed their course of treatment. A significantly higher proportion of those in the younger age group required GA to complete their treatment.

Formulation and Development of Metered Dose Inhalations of Salbutamol in Solution Form

PubMed Central

Khale, Anubha; Bajaj, Amrita

2011-01-01

In the present study attempts were made to prepare metered dose inhalation of salbutamol in solution form and compared it with the marketed metered dose inhalation in suspension form. Solution form of the drug was found better than marketed suspension formulation with respect to homogeneity and content uniformity. Propellant blend P-11 and P-12 in the proportion 30:70 was selected as it gave optimum vapour pressure. Surfactant oleic acid in concentration 10 mg per can was selected as it gave best results with clarity, spray pattern, vapour pressure, content per spray and rate of evaporation. Ethyl alcohol 2 ml per can was used as a cosolvent to give a clear solution, optimum vapour pressure, maximum content per spray and fair rate of evaporation. The selected formulation was subjected to the physico-chemical evaluation tests as per the standard pharmacopoeial procedures and the characteristics of the formulations were further compared with a conventional marketed formulation. In vitro study reveled the net respirable fraction was better than marketed preparation. PMID:22923867

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

Asthma: non-responsiveness to conventional therapy.

PubMed

Rebuck, A S

1986-01-01

Despite regular inhalation of beta-agonists, topical steroids and anticholinergic aerosols and the achievement of therapeutic blood levels of theophylline, some asthmatics have rapidly fluctuating levels of peak flow measurements throughout the day. Often little or no improvement is obtained with larger doses of corticosteroids. Before embarking on more intense drug therapy, attention should be paid to conscientious adherence to the prescribed regimen and avoidance of aspirin and tartrazine, as well as to exposure to allergens such as those associated with household pets. A number of newer therapeutic options are related to the use of air jet or ultrasonic nebulizers, that allow liquid forms of inhalation agents to be taken slowly in the home environment. In this regard, combination therapy with a beta-agonist and the anticholinergic ipratropium has been shown to have bronchodilating properties superior to either agent used alone. Secondly, sodium cromoglycate in its liquid form appears to have bronchodilator properties; taken on a regular basis, four times per day, it appears to have a steroid-sparing effect. Two alternatives are available for increasing the intensity of corticosteroid therapy, other than by prolonged, high-dose prednisone. The first is that of high-dose inhaled beclomethasone (up to 2000 micrograms/day) using the 250 micrograms/puff inhaler. The second is that of intravenous therapy with methylprednisolone, recently shown to have lung permeability superior to that of prednisolone. Office patients can be treated with occasional or even regular 'pulse' doses of methylprednisolone, an approach that is now finding acceptance in the management of the inflammatory alveolitides.

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.

Inhalation dose assessment of indoor radon progeny using biokinetic and dosimetric modeling and its application to Jordanian population.

PubMed

Al-Jundi, J; Li, W B; Abusini, M; Tschiersch, J; Hoeschen, C; Oeh, U

2011-06-01

High indoor radon concentrations in Jordan result in internal exposures of the residents due to the inhalation of radon and its short-lived progeny. It is therefore important to quantify the annual effective dose and further the radiation risk to the radon exposure. This study describes the methodology and the biokinetic and dosimetric models used for calculation of the inhalation doses exposed to radon progeny. The regional depositions of aerosol particles in the human respiratory tract were firstly calculated. For the attached progeny, the activity median aerodynamic diameters of 50 nm, 230 nm and 2500 nm were chosen to represent the nucleation, accumulation and coarse modes of the aerosol particles, respectively. For the unattached progeny, the activity median thermodynamic diameter of 1 nm was chosen to represent the free progeny nuclide in the room air. The biokinetic models developed by the International Commission on Radiological Protection (ICRP) were used to calculate the nuclear transformations of radon progeny in the human body, and then the dosimetric model was applied to estimate the organ equivalent doses and the effective doses with the specific effective energies derived from the mathematical anthropomorphic phantoms. The dose conversion coefficient estimated in this study was 15 mSv WLM(-1) which was in the range of the values of 6-20 mSv WLM(-1) reported by other investigators. Implementing the average indoor radon concentration in Jordan, the annual effective doses were calculated to be 4.1 mSv y(-1) and 0.08 mSv y(-1) due to the inhalation of radon progeny and radon gas, respectively. The total annual effective dose estimated for Jordanian population was 4.2 mSv y(-1). This high annual effective dose calculated by the dosimetric approach using ICRP biokinetic and dosimetric models resulted in an increase of a factor of two in comparison to the value by epidemiological study. This phenomenon was presented by the ICRP in its new published statement on radon. Copyright © 2011 Elsevier Ltd. All rights reserved.

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...

IRIS Toxicological Review of 1,4-Dioxane (with Inhalation Update) (External Review Draft)

EPA Science Inventory

EPA is conducting a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of 1,4-Dioxane (with inhalation update) that when finalized will appear on the Integrated Risk Information System (IRIS) database.

Comparison of Physician-, Biomarker-, and Symptom-Based Strategies for Adjustment of Inhaled Corticosteroid Therapy in Adults With Asthma

PubMed Central

Calhoun, William J.; Ameredes, Bill T.; King, Tonya S.; Icitovic, Nikolina; Bleecker, Eugene R.; Castro, Mario; Cherniack, Reuben M.; Chinchilli, Vernon M.; Craig, Timothy; Denlinger, Loren; DiMango, Emily A.; Engle, Linda L.; Fahy, John V.; Grant, J. Andrew; Israel, Elliot; Jarjour, Nizar; Kazani, Shamsah D.; Kraft, Monica; Kunselman, Susan J.; Lazarus, Stephen C.; Lemanske, Robert F.; Lugogo, Njira; Martin, Richard J.; Meyers, Deborah A.; Moore, Wendy C.; Pascual, Rodolfo; Peters, Stephen P.; Ramsdell, Joe; Sorkness, Christine A.; Sutherland, E. Rand; Szefler, Stanley J.; Wasserman, Stephen I.; Walter, Michael J.; Wechsler, Michael E.; Boushey, Homer A.

2013-01-01

Context No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms. Objective To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment–based adjustment in preventing treatment failure in adults with mild to moderate asthma. Design, Setting, and Participants A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n=114 assigned to physician assessment–based adjustment [101 completed], n=115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n=113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010. Interventions For physician assessment–based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use. Main Outcome Measure The primary outcome was time to treatment failure. Results There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment–based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment–based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment–based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3). Conclusion Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment–based adjustment of inhaled corticosteroids in time to treatment failure. Trial Registration clinicaltrials.gov Identifier: NCT00495157 PMID:22968888

Methodologies for the quantitative estimation of toxicant dose to cigarette smokers using physical, chemical and bioanalytical data.

PubMed

St Charles, Frank Kelley; McAughey, John; Shepperd, Christopher J

2013-06-01

Methodologies have been developed, described and demonstrated that convert mouth exposure estimates of cigarette smoke constituents to dose by accounting for smoke spilled from the mouth prior to inhalation (mouth-spill (MS)) and the respiratory retention (RR) during the inhalation cycle. The methodologies are applicable to just about any chemical compound in cigarette smoke that can be measured analytically and can be used with ambulatory population studies. Conversion of exposure to dose improves the relevancy for risk assessment paradigms. Except for urinary nicotine plus metabolites, biomarkers generally do not provide quantitative exposure or dose estimates. In addition, many smoke constituents have no reliable biomarkers. We describe methods to estimate the RR of chemical compounds in smoke based on their vapor pressure (VP) and to estimate the MS for a given subject. Data from two clinical studies were used to demonstrate dose estimation for 13 compounds, of which only 3 have urinary biomarkers. Compounds with VP > 10(-5) Pa generally have RRs of 88% or greater, which do not vary appreciably with inhalation volume (IV). Compounds with VP < 10(-7) Pa generally have RRs dependent on IV and lung exposure time. For MS, mean subject values from both studies were slightly greater than 30%. For constituents with urinary biomarkers, correlations with the calculated dose were significantly improved over correlations with mouth exposure. Of toxicological importance is that the dose correlations provide an estimate of the metabolic conversion of a constituent to its respective biomarker.

Effective Dose Radon 222 of the Tap Water in Children and Adults People; Minab City, Iran.

PubMed

Fakhri, Yadolah; Kargosha, Morteza; Langarizadeh, Ghazaleh; Zandsalimi, Yahya; Rasouli Amirhajeloo, Leila; Moradi, Mahboobeh; Moradi, Bigard; Mirzaei, Maryam

2015-09-01

(222)Rn is a radioactive, odorless, and colorless element which has a half-life of 3.83 days. One of (222)Rn main resources are Groundwater (wells, springs, etc.). Hence, the use of groundwater with high concentration of (222)Rn can increase the risk of lung and stomach cancers. Concentration of (222)Rn in tap water of Minab city in two temperatures 5 and 15 ºC was measured by radon meter model RTM1668-2. The effective dose was calculated by equations proposed by UNSCEAR. Geometric mean concentration of (222)Rn in drinking water was found to be 0.78±0.06 and 0.46±0.04 Bq/l at 5 and 15 ̊C (p value<0.05), respectively. The effective doses were 0.006 and 0.003 mSv/y for adults, and 0.011 and 0.007 mSv/y for the children, respectively (p value<0.05). Besides, the effective dose for adult through inhaling (222)Rn at 5 and 15 ̊C were estimated 0.0021 and 0.0012mSv/y, respectively. Geometric mean concentration in (222)Rn drinking water and effective dose received from drinking water and inhalation of (222)Rn is lower than WHO and EPA standard limits. Increasing temperature of drinking water will decrease the effective dose received. Annual Effective dose received from inhalation and consumption of (222)Rn in drinking water in children is more than adults.

Effective Dose Radon 222 of the Tap Water in Children and Adults People; Minab City, Iran

PubMed Central

Fakhri, Yadolah; Kargosha, Morteza; Langarizadeh, Ghazaleh; Zandsalimi, Yahya; Amirhajeloo, Leila Rasouli; Moradi, Mahboobeh; Moradi, Bigard; Mirzaei, Maryam

2016-01-01

222Rn is a radioactive, odorless, and colorless element which has a half-life of 3.83 days. One of 222Rn main resources are Groundwater (wells, springs, etc.). Hence, the use of groundwater with high concentration of 222Rn can increase the risk of lung and stomach cancers. Concentration of 222Rn in tap water of Minab city in two temperatures 5 and 15 ºC was measured by radon meter model RTM1668-2. The effective dose was calculated by equations proposed by UNSCEAR. Geometric mean concentration of 222Rn in drinking water was found to be 0.78±0.06 and 0.46±0.04 Bq/l at 5 and 15 °C (p value<0.05), respectively. The effective doses were 0.006 and 0.003 mSv/y for adults, and 0.011 and 0.007 mSv/y for the children, respectively (p value<0.05). Besides, the effective dose for adult through inhaling 222Rn at 5 and 15 °C were estimated 0.0021 and 0.0012mSv/y, respectively. Geometric mean concentration in 222Rn drinking water and effective dose received from drinking water and inhalation of 222Rn is lower than WHO and EPA standard limits. Increasing temperature of drinking water will decrease the effective dose received. Annual Effective dose received from inhalation and consumption of 222Rn in drinking water in children is more than adults. PMID:26573047

Mercury study report to Congress. Volume 4. Health effects of mercury and mercury compounds. Sab review draft

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

Schoeny, R.

1996-06-01

This volume of the draft Mercury Study Report to Congress summarizes the available information on human health effects and animal data for hazard identification and dose-response assessment for three forms of mercury: elemental mercury, mercury chloride (inorganic mercury), and methylmercury (organic mercury). Effects are summarized by endpoint. The risk assessment evaluates carcinogenicity, mutagenicity, developmental toxicity and general systemic toxicity of these chemical species of mercury. Toxicokinetics (absorption, distribution, metabolism and excretion) are described for each of the three mercury species. PBPK models are described, but not applied in risk assessment. Reference doses are calculated for inorganic and methylmercury; a referencemore » concentration for inhaled elemental mercury is provided. A quantitiative analysis of factors contributing to variability and uncertainty in the methylmercury RfD is provided in an appendix. Interations and sensitive populations are described.« less

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

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

Perkins, Michael W.; Pierre, Zdenka; Rezk, Peter

Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m{sup 3} concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m{sup 3} soman survived, while animals exposed to 841, and 1121 mg/m{sup 3} resulted in 38% and 13% survival,more » respectively. The microinstillation inhalation exposure LCt{sub 50} for soman determined by probit analysis was 827.2 mg/m{sup 3}. A majority of the animals that died at 1121 mg/m{sup 3} developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24 h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs.« less

Development of a Zealand white rabbit deposition model to study inhalation anthrax

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

Asgharian, Bahman; Price, Owen; Kabilan, Senthil

Despite using rabbits in several inhalation exposure experiments to study diseases such as anthrax, there is a lack of understanding regarding deposition characteristics and fate of inhaled particles (bio-aerosols and viruses) in the respiratory tracts of rabbits. Such information allows dosimetric extrapolation to humans to inform human outcomes. The lung geometry of the New Zealand white rabbit (referred to simply as rabbits throughout the article) was constructed using recently acquired scanned images of the conducting airways of rabbits and available information on its acinar region. In addition, functional relationships were developed for the lung and breathing parameters of rabbits asmore » a function of body weight. The lung geometry and breathing parameters were used to extend the existing deposition model for humans and several other species to rabbits. Evaluation of the deposition model for rabbits was made by comparing predictions with available measurements in the literature. Deposition predictions in the lungs of rabbits indicated smaller deposition fractions compared to those found in humans across various particle diameter ranges. The application of the deposition model for rabbits was demonstrated by extrapolating deposition predictions in rabbits to find equivalent human exposure concentrations assuming the same dose-response relationship between the two species. Human equivalent exposure concentration levels were found to be much smaller than those for rabbits.« less

The US and EU regulatory landscapes for locally acting generic/hybrid inhalation products intended for treatment of asthma and COPD.

PubMed

Fuglsang, Anders

2012-08-01

This is a review of the current regulatory requirements associated with development and submission of abridged dossiers for locally acting inhalation drugs intended for the treatment of asthma and chronic obstructive pulmonary disease. The current EU law does not provide for submission of such products as generics due to the definition of bioequivalence and bioavailability; instead they must be submitted as hybrids. A guideline from 2009 is available that suggests a stepwise approach toward approval. An applicant should first consider the degree of in vitro match with the reference product; provided that the match is extensive, approval may be granted. If the in vitro match cannot be proven, the next step is comparison of lung deposition and systemic exposure. If this match is proven, approval may be granted; otherwise, the final step is pharmacodynamic evaluation. In the United States, submission as a generic is possible, but only a single specific guidance document from 1989 is in force. It describes in vitro requirements for comparison of albuterol and metaproterenol pressurized metered dose inhalers. Applicants are encouraged to seek dialogue with regulators prior to and during development. Although parallel scientific advice procedures have been established between the US Food and Drug Administration and the European Medicines Agency, the two authorities give independent and individual advice.

IRIS Toxicological Review of 1,4-Dioxane (with Inhalation Update) (Final Report)

EPA Science Inventory

The final IRIS Toxicological Review of 1,4-dioxane (with inhalation update) provides scientific support and rationale for the hazard and dose-response assessment pertaining to chronic exposure to 1,4-dioxane. Human health risk concerns for 1,4-dioxane are primarily relat...

Predicting the acute behavioral effects in rats inhaling toluene (or up to 24 hrs: Inhaled vs. internal dose metrics.

EPA Science Inventory

The acute toxicity oftoluene, a model volatile organic compound (VOC), depends on the concentration (C) and duration (t) ofexposure, and guidelines for acute exposures have traditionally used ext relationships to extrapolate protective and/or effective concentrations across durat...

Which inhaled corticosteroid and long-acting β-agonist combination is better in patients with moderate-to-severe asthma, a dry powder inhaler or a pressurized metered-dose inhaler?

PubMed

Muraki, Masato; Gose, Kyuya; Hanada, Soichiro; Sawaguchi, Hirochiyo; Tohda, Yuji

2017-11-01

Two main types of devices are used to facilitate the administration of inhaled corticosteroid (ICS) and long-acting β-agonist (LABA) in combination, dry powder inhalers (DPIs) and pressurized metered-dose inhalers (pMDIs). There are few reports comparing the effects of the two devices, and it is unknown which should be recommended for asthma patients with given sets of characteristics. In the current study, the beneficial effects and side effects associated with DPIs and pMDIs were compared, and the question of which device should be recommended for asthma patients was investigated. A prospective, randomized, crossover, comparative study in adult outpatients with asthma was conducted using salmeterol/fluticasone propionate combination (SFC) 50 μg/250 μg, one inhalation of Adoair ® 250 Diskus ® twice daily or two inhalations of Adoair ® 125 Aerosol twice daily, for 8 weeks. Questionnaires, exhaled nitric oxide (FeNO) tests and pulmonary function tests were administered after the use of each device for 8 weeks, and the results derived from each device were compared. Sixty-eight subjects were included in the final analysis. There were no significant differences between quality-of-life scores, FeNO, spirometry test results and forced oscillation results. With regard to patient preferences, 57.4% preferred the Adoair ® Aerosol and 35.3% preferred the Adoair ® Diskus ® , as determined via the comparative evaluation questionnaire. Although DPI prescription accounts for the predominant market share of combined ICS/LABA in Japan, patients preferred a pMDI device to a DPI device. Compared to DPIs, pMDIs may be the preferential choice for patients with asthma.

Use of lung toxicity and lung particle clearance to estimate the maximum tolerated dose (MTD) for a fiber glass chronic inhalation study in the rat.

PubMed

Hesterberg, T W; McConnel, E E; Miiller, W C; Chevalier, J; Everitt, J; Thevenaz, P; Fleissner, H; Oberdörster, G

1996-07-01

Short-term toxicity and lung clearance were assessed in rats exposed by inhalation to size-selected fibrous glass (FG) for 13 weeks. Results from this study and from a recent FG chronic inhalation study are presented here as guidelines for the selection of a maximum tolerated dose (MTD) for chronic inhalation studies of fibers. Fischer 344 rats were exposed using nose-only inhalation chambers, 6 hr/day, 5 days/week, for 13 weeks to one of five concentrations of FG (36, 206, 316, 552, or 714 fibers/cc; expressed gravimetrically, 3, 16, 30, 45, or 60 mg/m3) or to filtered air. Rats were then held for an additional 10 weeks of postexposure recovery. Test fiber was size-selected from glass wool having a chemical composition representative of building insulation. Rats were terminated at 7, 13, 19, and 23 weeks after the onset of exposure to evaluate pulmonary pathology, lung epithelium cell proliferation, lung fiber burden, and lung lavage cells and chemistry. The effect of fiber inhalation on lung clearance of innocuous microspheres was also evaluated: following fiber exposure, six rats/group were exposed to 85Sr-labeled 3.0-microns polystyrene microspheres by intratracheal inhalation and then monitored for whole-body radioactivity during the 10-week recovery period. Data from the short-term study support the choice of 30 mg/m3 as the MTD for the previous chronic FG study and also provide indicators of long-term lung toxicity and functional impairment that can be used to estimate the MTD for future chronic fiber inhalation studies.

Dosimetric assessment from 212Pb inhalation at a thorium purification plant.

PubMed

Campos, M P; Pecequilo, B R S

2004-01-01

At the Instituto de Pesquisas Energeticas e Nucleares (IPEN), Sao Paulo, Brazil, there is a facility (thorium purification plant) where materials with high thorium concentrations are manipulated. In order to estimate afterwards the lung cancer risk for the workers, the thoron daughter (212Pb) levels were assessed and the committed effective and lung committed equivalent doses for workers in place. A total of 28 air filter samples were measured by total alpha counting through the modified Kusnetz method, to determine the 212Pb concentraion. The committed effective dose and lung committed equivalent dose due to 212Pb inhalation were derived from compartmental analysis following the ICRP 66 lung compartmental model, and ICRP 67 lead metabolic model.

Awareness of environmental issues and the acceptance of CFC-free inhalers.

PubMed

Goh, S Y; Arulanandam, S; Ho, C L; Zhang, L; Goh, D Y; Chew, F T; Lee, B W

1998-09-01

With the recent availability of a chlorofluorocarbon (CFC)-free metered dose inhaler (MDI) (Airomir), a patient survey was carried out to evaluate awareness of the role of CFCs in our environment and acceptance of this new inhaler. A questionnaire survey was conducted on parents and guardians of 201 children. Depending on respondents' preference, the interview was conducted in English (71%), Chinese (23%), Malay (5%) or Tamil (1%). A 'taste' test was also conducted on 103 of these children. Only 13% (26/201) of parents/guardians were aware that MDIs contained CFCs. Although 70% of children were in favour of the new taste of the CFC-free inhaler, the cost of the new inhaler was an important consideration for parents and guardians in their decision to switch to the new inhaler. The majority (93%) were willing to switch if its cost were equivalent to their current inhaler. This study has provided pertinent information with regard to acceptance of CFC-free inhalers which should be considered when making the inevitable switch to environmentally friendly inhalers.

Computational modeling of nanoscale and microscale particle deposition, retention and dosimetry in the mouse respiratory tract.

PubMed

Asgharian, B; Price, O T; Oldham, M; Chen, Lung-Chi; Saunders, E L; Gordon, T; Mikheev, V B; Minard, K R; Teeguarden, J G

2014-12-01

Comparing effects of inhaled particles across rodent test systems and between rodent test systems and humans is a key obstacle to the interpretation of common toxicological test systems for human risk assessment. These comparisons, correlation with effects and prediction of effects, are best conducted using measures of tissue dose in the respiratory tract. Differences in lung geometry, physiology and the characteristics of ventilation can give rise to differences in the regional deposition of particles in the lung in these species. Differences in regional lung tissue doses cannot currently be measured experimentally. Regional lung tissue dosimetry can however be predicted using models developed for rats, monkeys, and humans. A computational model of particle respiratory tract deposition and clearance was developed for BALB/c and B6C3F1 mice, creating a cross-species suite of available models for particle dosimetry in the lung. Airflow and particle transport equations were solved throughout the respiratory tract of these mice strains to obtain temporal and spatial concentration of inhaled particles from which deposition fractions were determined. Particle inhalability (Inhalable fraction, IF) and upper respiratory tract (URT) deposition were directly related to particle diffusive and inertial properties. Measurements of the retained mass at several post-exposure times following exposure to iron oxide nanoparticles, micro- and nanoscale C60 fullerene, and nanoscale silver particles were used to calibrate and verify model predictions of total lung dose. Interstrain (mice) and interspecies (mouse, rat and human) differences in particle inhalability, fractional deposition and tissue dosimetry are described for ultrafine, fine and coarse particles.

Tennessee Valley region study: potential year 2000 radiological dose to population resulting from nuclear facility operations. [Includes glossary

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

None

A companion report, DOE/ET-0064/1, presents a geographic, cultural, and demographic profile of the Tennessee Valley Region study area. This report describes the calculations of radionuclide release and transport and of the resultant dose to the regional population, assuming a projected installed capacity of 220,000 MW in the year 2000, of which 144,000 MW would be nuclear. All elements of the fuel cycle were assumed to be in operation. The radiological dose was calculated as a one-year dose based on ingestion of 35 different food types as well as for nine non-food pathways, and was reported as dose to the totalmore » body and for six specific organs for each of four age groups (infant, child, teen, and adult). Results indicate that the average individual would receive an incremental dose of 7 x 10/sup -4/ millirems in the year 2000 from the operation of nuclear facilities within and adjacent to the region, five orders of magnitude smaller than the dose from naturally occurring radiation in the area. The major contributor to dose was found to be tritium, and the most significant pathways were immersion in air, inhalation of air, transpiration of tritium (absorption through the skin), and exposure radionuclide-containing soil. 60 references.« less

Corrigendum to "Chemical composition and acidity of size-fractionated inorganic aerosols of 2013-14 winter haze in Shanghai and associated health risk of toxic elements" [Atmos. Environ. (2015) 259-271

NASA Astrophysics Data System (ADS)

Behera, Sailesh N.; Cheng, Jinping; Huang, Xian; Zhu, Qiongyu; Liu, Ping; Balasubramanian, Rajasekhar

2018-03-01

The authors regret that the sources from which the RfC (reference concentration) and the IUR (inhalation unit risk) values were obtained for estimation of RfD (reference dose, presented in Table 2) and SF (slope factor, presented in Table 3) were not clearly indicated in the published article due to an oversight. The revised tables with improved clarity are given below. a The Risk Assessment Information System (https://rais.ornl.gov/) b USEPA Integrated Risk Information System (IRIS) (http://www.epa.gov/iris) c The California EPA, the office of Environmental Health Hazard Assessment (OEHHA) (https://www.oehha.gov.gov/) d Behera, S.N., Xian, H. and Balasubramanian, R., 2014. Human health risk associated with exposure to toxic elements in mainstream and sidestream cigarette smoke. Science of the Total Environment, 472, pp.947-956.

Effect of adjusting the combination of budesonide/formoterol on the alleviation of asthma symptoms.

PubMed

Souma, Ryosuke; Sugiyama, Kumiya; Masuda, Hiroyuki; Arifuku, Hajime; Nakano, Kentaro; Watanabe, Hiroyoshi; Wakayama, Tomoshige; Tokita, Shingo; Tatewaki, Masamitsu; Satoh, Hideyuki; Koyama, Kenya; Hayashi, Yumeko; Fukushima, Fumiya; Hirata, Hirokuni; Arima, Masafumi; Kurasawa, Kazuhiro; Fukuda, Takeshi; Fukushima, Yasutsugu

2018-01-01

The combination of budesonide + formoterol (BFC) offers the advantages of dose adjustment in a single inhaler according to asthma symptoms. We analyzed the relationship between asthma symptoms in terms of peak expiratory flow (PEF) and dose adjustment by the patient. Twenty-eight patients with asthma who used BFC for alleviation of their symptoms (12 men, 16 women; 60 years old) were instructed that the inhaled BFC dose could be increased to a maximum of 8 inhalations per day according to symptom severity. Patients measured and recorded PEF every morning and evening in their asthma diary along with their symptoms and the dose of drugs taken. Sixteen of the 28 patients increased their dose for asthma symptoms. The time to recovery from the asthma symptoms was significantly shorter when cough was the only symptom present compared with dyspnea or wheeze (1.4 vs. 5.3 or 6.6 days, p  < 0.05) and when they had only one symptom compared with two or three symptoms (1.3 vs. 5.7 or 10.5, p  < 0.01). The relationship between PEF (% of personal best) when the dose was increased (Y) and the days for the increased dose to achieve a PEF greater than PEF in the symptom-free state (X) was determined to be Y = - 0.591X + 89.2 (r 2  = 0.299, p  < 0.001). As a guide for increasing the BFC dose when patients with mild asthma have asthma symptoms, the dose should be increased when cough is present or PEF is decreased to 88.9% (i.e., X = 0.5).

SU-E-T-797: Variations of Cardiac Dose at Different Respiratory Status in CyberKnife M6â„¢ Treatment Plans for Accelerated Partial Breast Irradiation (APBI)

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

Long, S; Shang, C; Evans, G

2015-06-15

Purpose: Cyberknife robotic assisted radiation delivery has become a choice for accelerated breast RT, while a slightly increased cardiac dose has been reported. The dose dynamics throughout the respiration cycle has scarcely been explored. This study was designed to investigate the dose changes at each respiratory phase or status during respiration cycle. Methods: Six patients with 4DCT studies and six patients with a pair of free-breathing and deep breath-hold CT sets were used for dosimetry comparisons. 4DCT sets were obtained by Siemens™ CT and its respiratory gating system, comprising of 8 phases. Standard APBI plan at 340 cGy was donemore » per fraction per NSABP B-39/RTOG 0413 and modulated with Cyberknife M6™ on MultiPlan™5.1.2. For the purpose of this study, the tumor volume was outlined in the media-lower quadrant of the left breast. Results: Except for D5cc in plans with 4DCT, cardiac doses are significantly different between respiratory phases in well inhaled breathing phases, and more significantly in plans with BH CT. Mean cardiac doses in 100% inhalation phase were often found to be 5–15% (p< 0.02) less than those in other phases. Conclusion: Although ineligible cardiac doses are noted in APBI plans using 4D free-breathing CT and instantaneous free breathing CT series, a reduction in cardiac dose was seen for the well-inhaled phases. This provides practical guidance for cardiac dose reduction applicable with CK M6 APBR.« less

SUDOQU, a new dose-assessment methodology for radiological surface contamination.

PubMed

van Dillen, Teun; van Dijk, Arjan

2018-06-12

A new methodology has been developed for the assessment of the annual effective dose resulting from removable and fixed radiological surface contamination. It is entitled SUDOQU (SUrface DOse QUantification) and it can for instance be used to derive criteria for surface contamination related to the import of non-food consumer goods, containers and conveyances, e.g., limiting values and operational screening levels. SUDOQU imposes mass (activity)-balance equations based on radioactive decay, removal and deposition processes in indoor and outdoor environments. This leads to time-dependent contamination levels that may be of particular importance in exposure scenarios dealing with one or a few contaminated items only (usually public exposure scenarios, therefore referred to as the 'consumer' model). Exposure scenarios with a continuous flow of freshly contaminated goods also fall within the scope of the methodology (typically occupational exposure scenarios, thus referred to as the 'worker model'). In this paper we describe SUDOQU, its applications, and its current limitations. First, we delineate the contamination issue, present the assumptions and explain the concepts. We describe the relevant removal, transfer, and deposition processes, and derive equations for the time evolution of the radiological surface-, air- and skin-contamination levels. These are then input for the subsequent evaluation of the annual effective dose with possible contributions from external gamma radiation, inhalation, secondary ingestion (indirect, from hand to mouth), skin contamination, direct ingestion and skin-contact exposure. The limiting effective surface dose is introduced for issues involving the conservatism of dose calculations. SUDOQU can be used by radiation-protection scientists/experts and policy makers in the field of e.g. emergency preparedness, trade and transport, exemption and clearance, waste management, and nuclear facilities. Several practical examples are worked out demonstrating the potential applications of the methodology. . Creative Commons Attribution license.

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.

Protection of rhesus macaques against inhalational anthrax with a Bacillus anthracis capsule conjugate vaccine.

PubMed

Chabot, Donald J; Ribot, Wilson J; Joyce, Joseph; Cook, James; Hepler, Robert; Nahas, Debbie; Chua, Jennifer; Friedlander, Arthur M

2016-07-25

The efficacy of currently licensed anthrax vaccines is largely attributable to a single Bacillus anthracis immunogen, protective antigen. To broaden protection against possible strains resistant to protective antigen-based vaccines, we previously developed a vaccine in which the anthrax polyglutamic acid capsule was covalently conjugated to the outer membrane protein complex of Neisseria meningitidis serotype B and demonstrated that two doses of 2.5μg of this vaccine conferred partial protection of rhesus macaques against inhalational anthrax . Here, we demonstrate complete protection of rhesus macaques against inhalational anthrax with a higher 50μg dose of the same capsule conjugate vaccine. These results indicate that B. anthracis capsule is a highly effective vaccine component that should be considered for incorporation in future generation anthrax vaccines. Published by Elsevier Ltd.

Efficacy of Formoterol Fumarate Delivered by Metered Dose Inhaler Using Co-Suspension™ Delivery Technology Versus Foradil® Aerolizer® in Moderate-To-Severe COPD: A Randomized, Dose-Ranging Study.

PubMed

Sethi, Sanjay; Fogarty, Charles; Hanania, Nicola A; Martinez, Fernando J; Rennard, Stephen; Fries, Michael; Orevillo, Chad; Darken, Patrick; St Rose, Earl; Strom, Shannon; Fischer, Tracy; Golden, Michael; Dwivedi, Sarvajna; Reisner, Colin

2016-11-17

Background: Co-Suspension™ Delivery Technology offers a novel pharmaceutical platform for inhaled drug therapy. This randomized, double-blind, placebo-controlled, single-dose study (NCT01349868) evaluated the efficacy of a range of doses for formoterol fumarate (FF) delivered using Co-Suspension delivery technology via a pressurized metered dose inhaler (MDI) versus placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Secondary objectives included determination of non-inferior efficacy and systemic exposure compared with open-label Foradil ® 12 μg (Foradil ® Aerolizer ® ; formoterol fumarate dry powder inhaler). Methods: Patients received each of the 6 study treatments (FF MDI [7.2, 9.6 and 19.2μg], placebo MDI and open-label Foradil ® [12 and 24µg]), separated by 3-10 days. Spirometry was performed 60 and 30 minutes prior to and at regular intervals up to 12 hours post-administration of study drug. The primary outcome measure was the change in forced expiratory volume in 1 second (FEV 1 ) area under the curve between 0 and 12 hours (AUC 0-12 ) relative to test day baseline. Results: A total of 50 patients were randomized to study treatment sequences. All doses of FF MDI demonstrated superiority to placebo ( p <0.0001) and non-inferiority to Foradil ® 12μg, on bronchodilator outcome measures. No serious adverse events were reported during the study. Conclusions: This study demonstrates non-inferiority of bronchodilator response and bioequivalent exposure of FF MDI 9.6μg to Foradil ® 12μg, with both agents exhibiting a similar safety profile in patients with moderate-to-severe COPD. This study supports the selection of FF MDI 9.6µg for further evaluation in Phase III trials.

Speed of onset of bronchodilator response to salbutamol inhaled via different devices in asthmatics: a bioassay based on functional antagonism

PubMed Central

Lavorini, Federico; Geri, Pietro; Mariani, Laura; Marmai, Cecilia; Maluccio, Nazzarena Maria; Pistolesi, Massimo; Fontana, Giovanni A

2006-01-01

Aims To evaluate the speed of onset of bronchodilation following salbutamol administered via a metered-dose inhaler with a spacer (pMDI + Volumatic) and a dry-powder inhaler (Diskus), as well as the relative potencies of these devices in asthmatic patients with methacholine-induced bronchoconstriction. Methods Eighteen patients inhaled methacholine (MCh) until FEV1 decreased by 35% of control. Following administration of placebo, 200 µg salbutamol or 400 µg salbutamol through the pMDI + Volumatic or the Diskus, we calculated the time elapsed from drug administration and the appearance of a 90% increase in post-MCh forced vital capacity (FVC), FEV1 and volume-adjusted mid-expiratory flow (recovery times). The salbutamol doses to be delivered by the two inhalation devices to achieve similar recovery times and the relative potencies of the devices were calculated by using the 2-by-2 Finney parallel regression method. Results For all functional variables, recovery times were significantly (P < 0.01) shorter in pMDI + Volumatic than Diskus trials. The salbutamol doses to be delivered by the Diskus to achieve recovery times for FVC, FEV1 and volume-adjusted mid-expiratory flow similar to those obtained with 200 µg salbutamol administered via the pMDI + Volumatic were 558 (95% CI 537, 579) µg, 395 (95% CI 388, 404) µg and 404 (95% CI 393, 415) µg, respectively, and corresponded to relative potencies of 2.79 (95% CI 2.68, 2.90), 1.98 (95% CI 1.94, 2.02), and 2.02 (95% CI 1.96, 2.07). Conclusions Administration of salbutamol via the pMDI + Volumatic provides faster reversal of induced bronchoconstriction than via the Diskus. The salbutamol dose targeting the lungs with the pMDI + Volumatic is approximately twice that with the Diskus. PMID:16995861

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

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.

Exposure of infants to budesonide through breast milk of asthmatic mothers.

PubMed

Fält, Anette; Bengtsson, Thomas; Kennedy, Britt-Marie; Gyllenberg, Ann; Lindberg, Bengt; Thorsson, Lars; Stråndgarden, Kerstin

2007-10-01

Maintenance treatment with inhaled corticosteroids is often required for asthmatic nursing women. Data on the transfer of inhaled corticosteroids from plasma to breast milk and the subsequent exposure of the breast-feeding infant has been unavailable. We sought to assess budesonide concentrations in milk and plasma of asthmatic nursing women receiving maintenance treatment with the Pulmicort Turbuhaler and estimate the exposure of their breast-fed infants. Milk and plasma samples were collected up to 8 hours after dosing from 8 mothers receiving budesonide maintenance treatment (200 or 400 microg twice daily). Pharmacokinetic parameters were calculated from budesonide milk and plasma concentrations. Infant exposure was estimated based on average milk budesonide concentrations. A single blood sample was obtained from 5 infants close to expected infant maximum concentration. Budesonide concentrations in milk reflected those in maternal plasma, supporting passive diffusion of budesonide between plasma and milk, and was always lower than that in plasma. The mean milk/plasma ratio was 0.46. The estimated daily infant dose was 0.3% of the daily maternal dose for both dose levels, and the average plasma concentration in infants was estimated to be 1/600th of the concentrations observed in maternal plasma, assuming complete infant oral bioavailability. Budesonide concentrations in infant plasma samples were all less than the limit of quantification. Maintenance treatment with inhaled budesonide (200 or 400 microg twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants. These data support continued use of inhaled budesonide during breast-feeding.

Postmarketing surveillance study of a non-chlorofluorocarbon inhaler according to the safety assessment of marketed medicines guidelines

PubMed Central

Ayres, J G; Frost, C D; Holmes, W F; Williams, D R R; Ward, S M

1998-01-01

Objective To evaluate the safety of a non-chlorofluorocarbon metered dose salbutamol inhaler. Design This was a postmarketing surveillance study, conducted under formal guidelines for company sponsored safety assessment of marketed medicines (SAMM). A non-randomised, non-interventional, observational design compared patients prescribed metered doses of salbutamol delivered by inhalers using either hydrofluoroalkane or chlorofluorocarbon as the propellant. Follow up was three months. Setting 646 general practices throughout the United Kingdom. Subjects 6614 patients with obstructive airways disease (1667 patient years of exposure). Main outcome measures Proportions of patients who were: admitted to hospital for respiratory diseases, reported adverse side effects, or withdrew because of adverse affects. Results There were no significant differences between the hydrofluoroalkane (HFA 134a) and chlorofluorocarbon inhaler groups in relation to the proportions of patients admitted to hospital for respiratory diseases (odds ratio 0.75; 95% confidence interval 0.51 to 1.08) or the proportions who reported adverse events (1.01; 0.88 to 1.17). However, more patients using the hydrofluoroalkane inhaler than the chlorofluorocarbon inhaler withdrew because of adverse events (3.8% and 0.9% respectively). Conclusion The hydrofluoroalkane inhaler was as safe as the chlorofluorocarbon inhaler when judged by hospital admissions and adverse affects. The study design successfully fulfilled the recommendations of the guidelines. Differences between postmarketing surveillance studies and randomised clinical trials in assessing safety were identified. These may lead to difficulties in the design of postmarketing surveillance studies. Key messagesCredibility of postmarketing surveillance studies is expected to increase after the introduction of guidelines covering their conduct The study design successfully fulfilled the requirements of these guidelines in terms of the number, rate, and geographical spread of patients recruitedSafety of salbutamol inhalers using hydrofluoroalkane and chlorofluorocarbon as propellants is similarImportant differences in study design/conduct and outcome between a postmarketing surveillance study and a randomised clinical trial merit further consideration. PMID:9756813

A dose-responsive model of smoke inhalation injury. Severity-related alteration in cardiopulmonary function.

PubMed Central

Shimazu, T; Yukioka, T; Hubbard, G B; Langlinais, P C; Mason, A D; Pruitt, B A

1987-01-01

The dose responsiveness of selected physiologic indices was studied in a sheep model of smoke inhalation injury. In this model, graded severity of injury was achieved by changing the contact time with smoke (defined by "unit"), whereas other variables were kept constant. Blood gas and cardiopulmonary indices were measured in 70 sheep, including 12 controls, either 24 or 72 hours after exposure to 3, 6, 9, 12, 15, or 18 units of smoke. A 12-unit dose of smoke was fatal within 72 hours and an 18-unit dose was fatal within 24 hours. The best correlation between smoke dose and response was observed in arterial oxygen tension 24 hours after exposure. At 24 hours, most of the cardiopulmonary indices showed significant change only after a 12-unit exposure. Although the exact shape of the dose-response curve could not be defined, sigmoid or curved linear shape was suggested, reflecting the progressive deterioration. Images Fig. 3. Fig. 4A. Fig. 4B. PMID:3606236

Predicting the acute behavioral effects in rats inhaling toluene for up to 24 hrs: Inhaled vs, internal dose metrics and tolerance.

EPA Science Inventory

The acute toxicity of toluene, a model volatile organic compound (VOC), depends on the concentration (C) and duration (t) of exposure, and guidelines for acute exposures have traditionally used extrelationships to extrapolate protective and/or effective concentrations across dura...

Effects of Endogenous Formaldehyde in Nasal Tissues on Inhaled Formmaldehyde Dosimetry Predictions in the Rat, Monkey, and Human Nasal Passages

EPA Science Inventory

ABSTRACT Formaldehyde, a nasal carcinogen, is also an endogenous compound that is present in all living cells. Due to its high solubility and reactivity, quantitative risk estimates for inhaled formaldehyde rely on internal dose calculations in the upper respiratory tract which ...

The effect of providing feedback on inhaler technique and adherence from an electronic audio recording device, INCA®, in a community pharmacy setting: study protocol for a randomised controlled trial.

PubMed

O'Dwyer, Susan Mary; MacHale, Elaine; Sulaiman, Imran; Holmes, Martin; Hughes, Cian; D'Arcy, Shona; Rapcan, Viliam; Taylor, Terence; Boland, Fiona; Bosnic-Anticevich, Sinthia; Reilly, Richard B; Ryder, Sheila A; Costello, Richard W

2016-05-04

Poor adherence to inhaled medication may lead to inadequate symptom control in patients with respiratory disease. In practice it can be difficult to identify poor adherence. We designed an acoustic recording device, the INCA® (INhaler Compliance Assessment) device, which, when attached to an inhaler, identifies and records the time and technique of inhaler use, thereby providing objective longitudinal data on an individual's adherence to inhaled medication. This study will test the hypothesis that providing objective, personalised, visual feedback on adherence to patients in combination with a tailored educational intervention in a community pharmacy setting, improves adherence more effectively than education alone. The study is a prospective, cluster randomised, parallel-group, multi-site study conducted over 6 months. The study is designed to compare current best practice in care (i.e. routine inhaler technique training) with the use of the INCA® device for respiratory patients in a community pharmacy setting. Pharmacies are the unit of randomisation and on enrolment to the study they will be allocated by the lead researcher to one of the three study groups (intervention, comparator or control groups) using a computer-generated list of random numbers. Given the nature of the intervention neither pharmacists nor participants can be blinded. The intervention group will receive feedback from the acoustic recording device on inhaler technique and adherence three times over a 6-month period along with inhaler technique training at each of these times. The comparator group will also receive training in inhaler use three times over the 6-month study period but no feedback on their habitual performance. The control group will receive usual care (i.e. the safe supply of medicines and advice on their use). The primary outcome is the rate of participant adherence to their inhaled medication, defined as the proportion of correctly taken doses of medication at the correct time relative to the prescribed interval. Secondary outcomes include exacerbation rates and quality of life measures. Differences in the timing and technique of inhaler use as altered by the interventions will also be assessed. Data will be analysed on an intention-to-treat and a per-protocol basis. Sample size has been calculated with reference to comparisons to be made between the intervention and comparator clusters and indicates 75 participants per cluster. With an estimated 10 % loss to follow-up we will be able to show a 20 % difference between the population means of the intervention and comparator groups with a power of 0.8. The Type I error probability associated with the test of the null hypothesis is 0.05. This clinical trial will establish whether providing personalised feedback to individuals on their inhaler use improves adherence. It may also be possible to enhance the role of pharmacists in clinical care by identifying patients in whom alteration of either therapy or inhaler device is appropriate. ClinicalTrials.gov NCT02203266 .

A brief history of inhaled asthma therapy over the last fifty years.

PubMed

Crompton, Graham

2006-12-01

This year is the 50th anniversary of the introduction into clinical use of the first modern inhaler for the management of asthma--the pressurised metered-dose inhaler (pMDI). The pMDI was initially used for the administration of the non-selective beta-agonists adrenaline and isoprenaline. However, the epidemic of asthma deaths which occurred in the 1960s led to these drugs being superseded by the selective short-acting beta-agonist salbutamol, and the first inhaled corticosteroid (ICS) beclomethasone. At the same time, sodium cromoglycate was introduced, to be administered via the first dry-powder inhaler--the Spinhaler--but owing to its relatively weak anti-inflammatory action its use is now very limited. Over the last 10 years, the long-acting beta-agonists (LABAs) have become an important add-on therapy for the management of asthma, and they are now often used with ICS in a single ICS/LABA combination inhaler.

Modeling intersubject variability of bronchial doses for inhaled radon progeny.

PubMed

Hofmann, Werner; Winkler-Heil, Renate; Hussain, Majid

2010-10-01

The main sources of intersubject variations considered in the present study were: (1) size and structure of nasal and oral passages, affecting extrathoracic deposition and, in further consequence, the fraction of the inhaled activity reaching the bronchial region; (2) size and asymmetric branching of the human bronchial airway system, leading to variations of diameters, lengths, branching angles, etc.; (3) respiratory parameters, such as tidal volume, and breathing frequency; (4) mucociliary clearance rates; and (5) thickness of the bronchial epithelium and depth of target cells, related to airway diameters. For the calculation of deposition fractions, retained surface activities, and bronchial doses, parameter values were randomly selected from their corresponding probability density functions, derived from experimental data, by applying Monte Carlo methods. Bronchial doses, expressed in mGy WLM-1, were computed for specific mining conditions, i.e., for defined size distributions, unattached fractions, and physical activities. Resulting bronchial dose distributions could be approximated by lognormal distributions. Geometric standard deviations illustrating intersubject variations ranged from about 2 in the trachea to about 7 in peripheral bronchiolar airways. The major sources of the intersubject variability of bronchial doses for inhaled radon progeny are the asymmetry and variability of the linear airway dimensions, the filtering efficiency of the nasal passages, and the thickness of the bronchial epithelium, while fluctuations of the respiratory parameters and mucociliary clearance rates seem to compensate each other.

Estimation of inhaled airborne particle number concentration by subway users in Seoul, Korea.

PubMed

Kim, Minhae; Park, Sechan; Namgung, Hyeong-Gyu; Kwon, Soon-Bark

2017-12-01

Exposure to airborne particulate matter (PM) causes several diseases in the human body. The smaller particles, which have relatively large surface areas, are actually more harmful to the human body since they can penetrate deeper parts of the lungs or become secondary pollutants by bonding with other atmospheric pollutants, such as nitrogen oxides. The purpose of this study is to present the number of PM inhaled by subway users as a possible reference material for any analysis of the hazards to the human body arising from the inhalation of such PM. Two transfer stations in Seoul, Korea, which have the greatest number of users, were selected for this study. For 0.3-0.422 μm PM, particle number concentration (PNC) was highest outdoors but decreased as the tester moved deeper underground. On the other hand, the PNC between 1 and 10 μm increased as the tester moved deeper underground and showed a high number concentration inside the subway train as well. An analysis of the particles to which subway users are actually exposed to (inhaled particle number), using particle concentration at each measurement location, the average inhalation rate of an adult, and the average stay time at each location, all showed that particles sized 0.01-0.422 μm are mostly inhaled from the outdoor air whereas particles sized 1-10 μm are inhaled as the passengers move deeper underground. Based on these findings, we expect that the inhaled particle number of subway users can be used as reference data for an evaluation of the hazards to health caused by PM inhalation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Methodologies for the quantitative estimation of toxicant dose to cigarette smokers using physical, chemical and bioanalytical data

PubMed Central

McAughey, John; Shepperd, Christopher J.

2013-01-01

Methodologies have been developed, described and demonstrated that convert mouth exposure estimates of cigarette smoke constituents to dose by accounting for smoke spilled from the mouth prior to inhalation (mouth-spill (MS)) and the respiratory retention (RR) during the inhalation cycle. The methodologies are applicable to just about any chemical compound in cigarette smoke that can be measured analytically and can be used with ambulatory population studies. Conversion of exposure to dose improves the relevancy for risk assessment paradigms. Except for urinary nicotine plus metabolites, biomarkers generally do not provide quantitative exposure or dose estimates. In addition, many smoke constituents have no reliable biomarkers. We describe methods to estimate the RR of chemical compounds in smoke based on their vapor pressure (VP) and to estimate the MS for a given subject. Data from two clinical studies were used to demonstrate dose estimation for 13 compounds, of which only 3 have urinary biomarkers. Compounds with VP > 10−5 Pa generally have RRs of 88% or greater, which do not vary appreciably with inhalation volume (IV). Compounds with VP < 10−7 Pa generally have RRs dependent on IV and lung exposure time. For MS, mean subject values from both studies were slightly greater than 30%. For constituents with urinary biomarkers, correlations with the calculated dose were significantly improved over correlations with mouth exposure. Of toxicological importance is that the dose correlations provide an estimate of the metabolic conversion of a constituent to its respective biomarker. PMID:23742081

[Assessment of knowledge in the use of metered dose inhalers in parents of asthmatic school children].

PubMed

Aquino-Pérez, Dulce María; Peña-Cadena, Daniel; Trujillo-García, José Ubaldo; Jiménez-Sandoval, Jaime Omar; Machorro-Muñoz, Olga Stephanie

2013-01-01

The use of metered dose inhaler (MDI) is key in the treatment of asthma; its effectiveness is related to proper technique. The purpose of this study is to evaluate the use of the technique of metered dose inhalers for the parents or guardians of school children with asthma. In this cross-sectional study, we used a sample of 221 individual caregivers (parent or guardian) of asthmatic children from 5 to 12 years old, who use MDI. We designed a validated questionnaire consisting of 27 items which addressed the handling of inhaler technique. Descriptive statistics was used. Caregivers were rated as "good technique" in 41 fathers (18.6%), 77 mothers (34.8%) and 9 tutors (4.1%), and with a "regular technique" 32 fathers (14.5%), 48 mothers (21.2%) and 14 guardians (6.3%). Asthmatic children aged 9 were rated as with "good technique" in 24 (10.9%). According to gender, we found a "good technique" in 80 boys (36.2%) and 47 girls (21.3%) and with a "regular technique" in 59 boys (26.7%) and 35 girls (15.8%), P 0.0973, RP 0.9. We found with a "regular technique" mainly those asthmatic children diagnosed at ages between 1 to 3 years. Most of the participants had a good technical qualification; however major mistakes were made at key points in the performance of it.

Halogenated flame retardants in building and decoration materials in China: Implications for human exposure via inhalation and dust ingestion.

PubMed

Hou, Minmin; Wang, Yan; Zhao, Hongxia; Zhang, Qiaonan; Xie, Qing; Zhang, Xiaojing; Chen, Ruize; Chen, Jingwen

2018-07-01

In this study, polybrominated diphenyl ethers (PBDEs), novel brominated flame retardants (NBFRs), and dechlorane plus (DPs) were analyzed in seven categories of building and decoration materials. The total concentrations of analyzed FRs ranged from 1.19 ng/g (diatomite powder) to 9532 ng/g (expanded polystyrene panel). Relatively high concentrations were detected in foam samples and PVC materials, followed by sealing materials, boards, wallpaper, paints, and wall decoration powders. BDE209 was the most detected compound with the highest concentrations in almost all materials, followed by decabromodiphenyl ethane (DBDPE), which was consistent with their productions and consumptions in China. The estimated PBDE concentrations in air and dust based on material concentration and emission rate were comparable with those detected in real samples. Adult and infant exposures via inhalation and dust ingestion were assessed. The estimated exposures to BDE209 via dust ingestion were 1.36 and 0.12 ng/(kg bw d), which were 19- and 4-fold higher than those via inhalation for infants and adults, respectively. This suggested that dust ingestion was a significant pathway of human BDE209 exposure, especially for infants. For the other PBDE congeners (∑ 7 PBDEs), the estimated exposures via inhalation were 2.60 and 1.32 ng/(kg bw d) for infants and adults, respectively. Despite the low estimated human exposures to PBDEs compared to the oral reference doses, the exposure associated with building and decoration materials still requires more attention because of the potential risks from other exposure pathways and undetected FRs in those materials. Copyright © 2018 Elsevier Ltd. All rights reserved.

Cyanotoxins in desert environments may present a risk to human health.

PubMed

Metcalf, J S; Richer, R; Cox, P A; Codd, G A

2012-04-01

There have been few studies concerning cyanotoxins in desert environments, compared with the multitude of studies of cyanotoxins in aquatic environments. However, cyanobacteria are important primary producers in desert environments, where after seasonal rains they can grow rapidly both stabilising and fertilising arid habitats. Samples of cyanobacteria from wadis - dry, ephemeral river beds - and sabkha - supertidal salt flats - in Qatar were analysed for the presence of microcystins, nodularin, anatoxin-a, cylindrospermopsin and anatoxin-a(S). Microcystins were detected by HPLC-PDA and ELISA at concentrations between 1.5 and 53.7ngg(-1) dry wt of crust. PCR products for the mycD gene for microcystin biosynthesis were detected after amplification of DNA from desert crust samples at two out of three sample sites. The presence of anatoxin-a(S) was also indicated by acetylcholine esterase inhibition assay. As a function of area of desert crust, microcystin concentrations were between 3 and 56μgm(-2). Based on the concentration of microcystins detected in crust, with reference to the published inhalation NOAEL and LOAEL values via nasal spray inhalation of purified microcystin-LR in aqueous solution, and the amount of dust potentially inhaled by a person from these dried crusts, the dose of microcystins could exceed a calculated TDI value of 1-2ngkg(-1)day(-1) for an average adult. The presence of microcystins, and potentially of anatoxin-a(S), in desert crusts has important implications for human health. Further studies are required to monitor desert dust storms for the presence of cyanotoxins. An understanding of the risks of inhaling particles containing cyanotoxins is also warranted. Copyright © 2012 Elsevier B.V. All rights reserved.

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

Measurement of (222)Rn concentration levels in drinking water and the associated health effects in the Southern part of West Bank - Palestine.

PubMed

Thabayneh, Khalil M

2015-09-01

Radon concentration and annual effective doses were measured in drinking water in the Southern Part of West Bank - Palestine, by using both passive and active techniques. 184 samples were collected from various sources i.e. tap water, groundwater, rain waters and mineral waters. It is found that the annual effective dose resulting from inhalation and ingestion of radon emanated from all types of drinking water is negligible compared to the total annual effective dose from indoor radon in the region. Results reveal that there is no significant public health risk from radon ingested and inhalation with drinking water in the study region. Copyright © 2015. Published by Elsevier Ltd.

The expanding role of aerosols in systemic drug delivery, gene therapy, and vaccination.

PubMed

Laube, Beth L

2005-09-01

Aerosolized medications have been used for centuries to treat respiratory diseases. Until recently, inhalation therapy focused primarily on the treatment of asthma and chronic obstructive pulmonary disease, and the pressurized metered-dose inhaler was the delivery device of choice. However, the role of aerosol therapy is clearly expanding beyond that initial focus. This expansion has been driven by the Montreal protocol and the need to eliminate chlorofluorocarbons (CFCs) from traditional metered-dose inhalers, by the need for delivery devices and formulations that can efficiently and reproducibly target the systemic circulation for the delivery of proteins and peptides, and by developments in medicine that have made it possible to consider curing lung diseases with aerosolized gene therapy and preventing epidemics of influenza and measles with aerosolized vaccines. Each of these drivers has contributed to a decade or more of unprecedented research and innovation that has altered how we think about aerosol delivery and has expanded the role of aerosol therapy into the fields of systemic drug delivery, gene therapy, and vaccination. During this decade of innovation, we have witnessed the coming of age of dry powder inhalers, the development of new soft mist inhalers, and improved pressurized metered-dose inhaler delivery as a result of the replacement of CFC propellants with hydrofluoroalkane. The continued expansion of the role of aerosol therapy will probably depend on demonstration of the safety of this route of administration for drugs that have their targets outside the lung and are administered long term (eg, insulin aerosol), on the development of new drugs and drug carriers that can efficiently target hard-to-reach cell populations within the lungs of patients with disease (eg, patients with cystic fibrosis or lung cancer), and on the development of devices that improve aerosol delivery to infants, so that early intervention in disease processes with aerosol therapy has a high probability of success.

32 CFR 218.4 - Dose estimate reporting standards.

Code of Federal Regulations, 2013 CFR

2013-07-01

...) MISCELLANEOUS GUIDANCE FOR THE DETERMINATION AND REPORTING OF NUCLEAR RADIATION DOSE FOR DOD PARTICIPANTS IN THE ATMOSPHERIC NUCLEAR TEST PROGRAM (1945-1962) § 218.4 Dose estimate reporting standards. The following minimum... of the radiation environment to which the veteran was exposed and shall include inhaled, ingested...

32 CFR 218.4 - Dose estimate reporting standards.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) MISCELLANEOUS GUIDANCE FOR THE DETERMINATION AND REPORTING OF NUCLEAR RADIATION DOSE FOR DOD PARTICIPANTS IN THE ATMOSPHERIC NUCLEAR TEST PROGRAM (1945-1962) § 218.4 Dose estimate reporting standards. The following minimum... of the radiation environment to which the veteran was exposed and shall include inhaled, ingested...

32 CFR 218.4 - Dose estimate reporting standards.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) MISCELLANEOUS GUIDANCE FOR THE DETERMINATION AND REPORTING OF NUCLEAR RADIATION DOSE FOR DOD PARTICIPANTS IN THE ATMOSPHERIC NUCLEAR TEST PROGRAM (1945-1962) § 218.4 Dose estimate reporting standards. The following minimum... of the radiation environment to which the veteran was exposed and shall include inhaled, ingested...

32 CFR 218.4 - Dose estimate reporting standards.

Code of Federal Regulations, 2012 CFR

2012-07-01

...) MISCELLANEOUS GUIDANCE FOR THE DETERMINATION AND REPORTING OF NUCLEAR RADIATION DOSE FOR DOD PARTICIPANTS IN THE ATMOSPHERIC NUCLEAR TEST PROGRAM (1945-1962) § 218.4 Dose estimate reporting standards. The following minimum... of the radiation environment to which the veteran was exposed and shall include inhaled, ingested...

32 CFR 218.4 - Dose estimate reporting standards.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) MISCELLANEOUS GUIDANCE FOR THE DETERMINATION AND REPORTING OF NUCLEAR RADIATION DOSE FOR DOD PARTICIPANTS IN THE ATMOSPHERIC NUCLEAR TEST PROGRAM (1945-1962) § 218.4 Dose estimate reporting standards. The following minimum... of the radiation environment to which the veteran was exposed and shall include inhaled, ingested...

Association of Inhaled Corticosteroids and Long-Acting β-Agonists as Controller and Quick Relief Therapy With Exacerbations and Symptom Control in Persistent Asthma: A Systematic Review and Meta-analysis.

PubMed

Sobieraj, Diana M; Weeda, Erin R; Nguyen, Elaine; Coleman, Craig I; White, C Michael; Lazarus, Stephen C; Blake, Kathryn V; Lang, Jason E; Baker, William L

2018-04-10

Combined use of inhaled corticosteroids and long-acting β-agonists (LABAs) as the controller and the quick relief therapy termed single maintenance and reliever therapy (SMART) is a potential therapeutic regimen for the management of persistent asthma. To conduct a systematic review and meta-analysis of the effects of SMART in patients with persistent asthma. The databases of MEDLINE via OVID, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews were searched from database inception through August 2016 and updated through November 28, 2017. Two reviewers selected randomized clinical trials or observational studies evaluating SMART vs inhaled corticosteroids with or without a LABA used as the controller therapy and short-acting β-agonists as the relief therapy for patients aged 5 years or older with persistent asthma and reporting on an outcome of interest. Meta-analyses were conducted using a random-effects model to calculate risk ratios (RRs), risk differences (RDs), and mean differences with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength of evidence grading were completed by 2 independent reviewers. Asthma exacerbations. The analyses included 16 randomized clinical trials (N = 22 748 patients), 15 of which evaluated SMART as a combination therapy with budesonide and formoterol in a dry-powder inhaler. Among patients aged 12 years or older (n = 22 524; mean age, 42 years; 14 634 [65%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.68 [95% CI, 0.58 to 0.80]; RD, -6.4% [95% CI, -10.2% to -2.6%]) and a higher dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.77 [95% CI, 0.60 to 0.98]; RD, -2.8% [95% CI, -5.2% to -0.3%]). Similar results were seen when SMART was compared with inhaled corticosteroids alone as the controller therapy. Among patients aged 4 to 11 years (n = 341; median age, 8 [range, 4-11] years; 69 [31%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with a higher dose of inhaled corticosteroids as the controller therapy (RR, 0.55 [95% CI, 0.32 to 0.94]; RD, -12.0% [95% CI, -22.5% to -1.5%]) or the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.38 [95% CI, 0.23 to 0.63]; RD, -23.2% [95% CI, -33.6% to -12.1%]). In this meta-analysis of patients with persistent asthma, the use of single maintenance and reliever therapy compared with inhaled corticosteroids as the controller therapy (with or without a long-acting β-agonist) and short-acting β-agonists as the relief therapy was associated with a lower risk of asthma exacerbations. Evidence for patients aged 4 to 11 years was limited.

MPC and ALI: their basis and their comparison

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

Kennedy, W.E. Jr.; Watson, E.C.

Radiation protection regulations in the United States have evolved from the recommendations of the International Commission on Radiological Protection (ICRP) and the National Council on Radiation Protection and Measurements (NCRP). In 1959, the ICRP issued Publication 2 which contained specific recommendations on dose rate limits, permissible body burdens, metabolic data for radionuclides, and maximum permissible concentrations (MPC) in air or water. Over the next 20 years, new information became available concerning the effects of radiation, the uptake and retention of radionuclides, and the radioactive decay schemes of parent radionuclides. To include this newer information, the ICRP issued Publication 30 inmore » 1978 to supersede Publication 2. One of the secondary limits defined in Publication 30 is the annual limit of intake (ALI). Radionuclide specific ALI values are intended to replace MPC values in determining whether or not ambient air and water concentrations are sufficiently low to maintain the dose to workers within accepted dose rate limits. In this paper, we discuss the derivation of MPC and ALI values, compare inhalation committed dose equivalent factors derived from ICRP Publications 2 and 30, and discuss the practical implications of using either MPC or ALI in determining compliance with occupational exposure limits. 6 references.« less

Single dosing comparison of the relative cardiac beta 1/beta 2 activity of inhaled fenoterol and salbutamol in normal subjects.

PubMed Central

Newnham, D M; Wheeldon, N M; Lipworth, B J; McDevitt, D G

1993-01-01

BACKGROUND--The aim of the present study was to compare the dose related effects of fenoterol and salbutamol on cardiac beta 1 and beta 2 receptors using the beta 1 selective antagonist atenolol, in order to dissect out relative beta 1/beta 2 mediated responses. METHODS--Fourteen normal volunteers were randomised to receive pretreatment with either atenolol 25 mg or placebo, followed by inhaled fenoterol or salbutamol in equal doses by weight (cumulative doses of 1 mg and 4 mg). Measurements were made 30 minutes after inhaling each dose of beta 2 agonist. Values (mean and 95% CI) were expressed as a change from baseline. RESULTS--At 4 mg fenoterol produced equivalent falls in serum potassium and increases in tremor to salbutamol. The mean (95% CI) increase in heart rate (beats/min) with fenoterol at 4 mg after placebo was 47 (41-53) and after atenolol was 34 (28-40), with values for salbutamol being 46 (40-52) after placebo and 30 (24-36) after atenolol. The inotropic response (stroke distance) after atenolol at the 4 mg dose was 5.0 (3.9-6.1) cm for fenoterol and 4.7 (3.5-5.9) cm for salbutamol. There were no significant differences in heart rate or stroke distance response between the two drugs after either placebo or atenolol. Furthermore, ECG effects (Q-Tc and T wave) of fenoterol and salbutamol were comparable at both doses. CONCLUSIONS--These results show that there is no difference in the respective chronotropic or inotropic activities of fenoterol and salbutamol on cardiac beta 1 or beta 2 receptors when given at higher than conventional doses. PMID:8102213

Using physiologically based pharmacokinetic modeling and benchmark dose methods to derive an occupational exposure limit for N-methylpyrrolidone.

PubMed

Poet, T S; Schlosser, P M; Rodriguez, C E; Parod, R J; Rodwell, D E; Kirman, C R

2016-04-01

The developmental effects of NMP are well studied in Sprague-Dawley rats following oral, inhalation, and dermal routes of exposure. Short-term and chronic occupational exposure limit (OEL) values were derived using an updated physiologically based pharmacokinetic (PBPK) model for NMP, along with benchmark dose modeling. Two suitable developmental endpoints were evaluated for human health risk assessment: (1) for acute exposures, the increased incidence of skeletal malformations, an effect noted only at oral doses that were toxic to the dam and fetus; and (2) for repeated exposures to NMP, changes in fetal/pup body weight. Where possible, data from multiple studies were pooled to increase the predictive power of the dose-response data sets. For the purposes of internal dose estimation, the window of susceptibility was estimated for each endpoint, and was used in the dose-response modeling. A point of departure value of 390 mg/L (in terms of peak NMP in blood) was calculated for skeletal malformations based on pooled data from oral and inhalation studies. Acceptable dose-response model fits were not obtained using the pooled data for fetal/pup body weight changes. These data sets were also assessed individually, from which the geometric mean value obtained from the inhalation studies (470 mg*hr/L), was used to derive the chronic OEL. A PBPK model for NMP in humans was used to calculate human equivalent concentrations corresponding to the internal dose point of departure values. Application of a net uncertainty factor of 20-21, which incorporates data-derived extrapolation factors, to the point of departure values yields short-term and chronic occupational exposure limit values of 86 and 24 ppm, respectively. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Efficacy of budesonide/formoterol maintenance and reliever therapy compared with higher-dose budesonide as step-up from low-dose inhaled corticosteroid treatment.

PubMed

Jenkins, Christine R; Eriksson, Göran; Bateman, Eric D; Reddel, Helen K; Sears, Malcolm R; Lindberg, Magnus; O'Byrne, Paul M

2017-04-20

Asthma management may involve a step up in treatment when symptoms are not well controlled. We examined whether budesonide/formoterol maintenance and reliever therapy (MRT) is as effective as higher, fixed-dose budesonide plus as-needed terbutaline in patients requiring step-up from Step 2 treatment (low-dose inhaled corticosteroids), stratified by baseline reliever use. A post-hoc analysis utilized data from three clinical trials of 6-12 months' duration. Patients aged ≥12 years with symptomatic asthma uncontrolled despite Step 2 treatment were included. Severe exacerbation rate, lung function and reliever use were analysed, stratified by baseline reliever use (<1, 1-2 and >2 occasions/day). Overall, 1239 patients were included. Reductions in severe exacerbation rate with budesonide/formoterol MRT versus fixed-dose budesonide were similar across baseline reliever use levels, and were statistically significant in patients using 1-2 (42%, p = 0.01) and >2 (39%, p = 0.02) reliever occasions/day, but not <1 reliever occasion/day (35%, p = 0.11). Both treatments significantly increased mean FEV 1 from baseline; improvements were significantly greater for budesonide/formoterol MRT in all reliever use groups. Reductions in reliever use from baseline were significantly greater with budesonide/formoterol MRT versus fixed-dose budesonide in patients using 1-2 and >2 reliever occasions/day (-0.33 and -0.74 occasions/day, respectively). Treatment benefit with budesonide/formoterol MRT versus higher, fixed-dose budesonide plus short-acting β 2 -agonist was found in Step 2 patients with relatively low reliever use, supporting the proposal that budesonide/formoterol MRT may be useful when asthma is uncontrolled with low-dose inhaled corticosteroid.

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.

Estimation of thyroid equivalent doses during evacuation based on body surface contamination levels in the nuclear accident of FDNPS in 2011

NASA Astrophysics Data System (ADS)

Ohba, Takashi; Hasegawa, Arifumi; Kohayakawa, Yoshitaka; Kondo, Hisayoshi; Suzuki, Gen

2017-09-01

To reduce uncertainty in thyroid dose estimation, residents' radiation protection behavior should be reflected in the estimation. Screening data of body surface contamination provide information on exposure levels during evacuation. Our purpose is to estimate thyroid equivalent doses based on body surface contamination levels using a new methodology. We obtained a record of 7,539 residents/evacuees. Geiger-Mueller survey meter measurement value in cpm was translated into Bq/cm2 according to the nuclides densities obtained by measuring clothing from two persons by germanium γ-spectrometer. The measurement value of body surface contamination on head was adjusted by a natural removal rate of 15 hours and radionuclides' physical half-life. Thyroid equivalent dose of 1-year-old children by inhalation was estimated by two-dimensional Monte Carlo simulation. The proportions of evacuees/residents with measurement value in cpm of Namie and Minamisoma groups were higher than those of other groups during both periods (p<0.01, Kruskal-Wallis). During 12-14 March period, 50 and 95 percentiles of thyroid equivalent doses by inhalation were estimated as 2.7 and 86.0 mSv, respectively, for Namie group, and 4.2 and 17.2 mSv, respectively, for Minamisoma group, 0.1 and 1.0 mSv, respectively, for Tomioka/Okuma/Futaba/Naraha group, and 0.2 and 2.1 mSv, respectively, for the other group. During 15- 17 March period, 50 and 95 percentiles of thyroid equivalent doses by inhalation were 0.8 and 15.7 mSv, respectively, for Namie group, and 1.6 and 8.4 mSv, respectively, for Minamisoma group, 0.2 and 13.2 mSv, respectively, for Tomioka/Okuma/Futaba/Naraha group, and 1.2 and 12.7 mSv, respectively, for the other group. It was indicated that inhalation dose was generally higher in Namie and Minamisoma groups during 12-14 March than those during 15-17 March might reflect different self-protective behavior to radioactive plumes from other groups.

Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery.

PubMed

Liu, Sha; Watts, Alan B; Du, Ju; Bui, Amanda; Hengsawas, Soraya; Peters, Jay I; Williams, Robert O

2015-10-01

Co-administration of an inhaled corticosteroid and long acting beta agonist for chronic obstructive pulmonary disease has reduced mortality compared to either drug alone. This combination reduces exacerbations, hospitalization, emergency department visits and health care costs. A novel fixed-dose combination of the long acting beta-2 agonist salmeterol xinafoate (SX) and the corticosteroid mometasone furoate (MF) were prepared in a composite particle formulation as brittle matrix powder (BMP) and investigated for suitability as an inhaled combination product. In this study, BMP fixed dose combinations of SX and MF with or without stabilizing excipients (lactose, mannitol, glycine and trehalose) were prepared and characterized with respect to their thermal properties, morphology, aerodynamic performance and physical stability. BMP combination formulations of SX and MF exhibited improved aerodynamic properties when delivered by dry powder inhalation as compared to the micronized blends of the same substances. Aerodynamic evaluation was carried out by next generation pharmaceutical impactor (NGI) with a marketed DPI device. Results demonstrated that co-deposition occurred when SX and MF were formulated together as composite particles in a BMP, while physical blends resulted in inconsistent deposition and dose uniformity. As a result of the bottom-up particle engineering approach, combination BMP formulations allow for dual API composite formulations to be dispersed as aerosolized particles. Aerosolized BMP combination formulations resulted in delivered dose uniformity and co-deposition of each API. Further, an excipient-free formulation, BMP SXMF, delivered approximately 50% of the loaded dose in the respirable range and demonstrated stability at ambient conditions for 6months. Single dose 24-h pharmacokinetic studies in rats demonstrated that lung tissue deposition and blood circulation (AUC0-24h) of two APIs were higher for the BMP combination group exhibiting a significantly higher lung concentration of drugs than for the crystalline physical blend. While high system drug levels are generally undesirable in lung targeted therapies, high blood levels in this rodent study could be indicative of increased pulmonary tissue exposure using BMP formulations. Copyright © 2015 Elsevier B.V. All rights reserved.

Influence of inspiratory flow rate, particle size, and airway caliber on aerosolized drug delivery to the lung.

PubMed

Dolovich, M A

2000-06-01

A number of studies in the literature support the use of fine aerosols of drug, inhaled at low IFRs to target peripheral airways, with the objective of improving clinical responses to inhaled therapy (Fig. 8). Attempts have been made to separate response due to changes in total administered dose or the surface concentration of the dose from response due to changes in site of deposition--both are affected by the particle size of the aerosol, with IFR additionally influencing the latter. The tools for measuring dose and distribution have improved over the last 10-15 years, and thus we should expect greater accuracy in these measurements for assessing drug delivery to the lung. There are still issues, though, in producing radiolabeled (99m)technetium aerosols that are precise markers for the pharmaceutical product being tested and in quantitating absolute doses deposited in the lung. PET isotopes may provide the means for directly labelling a drug and perhaps can offer an alternative for making these measurements in the future, but deposition measurements should not be used in isolation; protocols should incorporate clinical tests to provide parallel therapeutic data in response to inhalation of the drug by the various patient populations being studied.

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.

Statistical analysis of nonmonotonic dose-response relationships: research design and analysis of nasal cell proliferation in rats exposed to formaldehyde.

PubMed

Gaylor, David W; Lutz, Werner K; Conolly, Rory B

2004-01-01

Statistical analyses of nonmonotonic dose-response curves are proposed, experimental designs to detect low-dose effects of J-shaped curves are suggested, and sample sizes are provided. For quantal data such as cancer incidence rates, much larger numbers of animals are required than for continuous data such as biomarker measurements. For example, 155 animals per dose group are required to have at least an 80% chance of detecting a decrease from a 20% incidence in controls to an incidence of 10% at a low dose. For a continuous measurement, only 14 animals per group are required to have at least an 80% chance of detecting a change of the mean by one standard deviation of the control group. Experimental designs based on three dose groups plus controls are discussed to detect nonmonotonicity or to estimate the zero equivalent dose (ZED), i.e., the dose that produces a response equal to the average response in the controls. Cell proliferation data in the nasal respiratory epithelium of rats exposed to formaldehyde by inhalation are used to illustrate the statistical procedures. Statistically significant departures from a monotonic dose response were obtained for time-weighted average labeling indices with an estimated ZED at a formaldehyde dose of 5.4 ppm, with a lower 95% confidence limit of 2.7 ppm. It is concluded that demonstration of a statistically significant bi-phasic dose-response curve, together with estimation of the resulting ZED, could serve as a point-of departure in establishing a reference dose for low-dose risk assessment.

The importance of inhaler devices: the choice of inhaler device may lead to suboptimal adherence in COPD patients.

PubMed

Darbà, Josep; Ramírez, Gabriela; Sicras, Antoni; Francoli, Pablo; Torvinen, Saku; Sánchez-de la Rosa, Rainel

2015-01-01

This study aims to identify factors associated with poor adherence to COPD treatment in patients receiving a fixed-dose combination (FDC) of inhaled corticosteroids and long-acting β2-agonist (ICS/LABA), focusing on the importance of inhaler devices. We conducted a retrospective and multicenter study based on a review of medical registries between 2007 and 2012 of COPD patients (n=1,263) treated with ICS/LABA FDC, whose medical devices were either dry powder inhalers (DPIs) or pressurized metered-dose inhalers (pMDI). Medication adherence included persistence outcomes through 18 months and medication possession ratios. Data on exacerbations, comorbidities, demographic characteristics, and health care resource utilization were also included as confounders of adherence. The analyses revealed that COPD patients whose medication was delivered through a DPI were less likely to have medication adherence compared to patients with pMDI, after adjusting for confounding factors, especially active ingredients. Younger groups of patients were less likely to be adherent compared to the oldest group. Smoker men were less likely to be adherent compared to women and non-smokers. Comorbidities decreased the probability of treatment adherence. Those patients that visited their doctor once a month were more likely to adhere to their medication regimen; however, suboptimal adherence was more likely to occur among those patients who visited more than three times per month their doctor. We also found that worsening of COPD is negatively associated with adherence. According to this study, inhaler devices influence patients' adherence to long-term COPD medication. We also found that DPIs delivering ICS/LABA FDC had a negative impact on adherence. Patients' clinic and socioeconomic characteristics were associated with adherence.

Inhibition of neutral endopeptidase potentiates bronchoconstriction induced by neurokinin A in asthmatic patients.

PubMed

Crimi, N; Palermo, F; Oliveri, R; Polosa, R; Magrì, S; Mistretta, A

1994-02-01

The endogenous tachykinins exhibit a range of properties which may be relevant in the pathophysiology of asthma. Their effects on the airways seem to be modulated by a variety of lung peptidases, including neutral endopeptidase (NEP). In order to evaluate the potential role of endogenous NEP activity in modulating tachykinins-induced bronchoconstriction in man in vivo, six atopic asthmatic patients, with a mean FEV1 value of 3.38 +/- 0.76 l, and a histamine PD20 mean value of 0.024 mg, were studied. The influence of inhaled phosphoramidon (a potent NEP inhibitor) was examined against the NKA-induced bronchospasm in a double-blind, placebo-controlled randomized study. Changes in airway calibre were followed as FEV1 and agonists responsiveness expressed as PD20 and PD15 for histamine and NKA respectively. Patients received nebulized phosphoramidon sodium salt (10(-5) M) or a control solution 10 min prior to the bronchoprovocation test with NKA. No significant difference was noticed between any of the study days and after inhaled phosphoramidon on baseline FEV1 values (3.29 +/- 0.90 l) in comparison with the control solution (3.31 +/- 0.79 l). Inhaled NKA produced a dose-dependent fall in FEV1 values in all the subjects studied with a mean PD15 value of 20.91 x 10(-9) mol. Phosphoramidon administered by inhalation elicited a significant (P < 0.01 vs baseline and control solution) potentiation in the airway responsiveness to inhaled NKA, the NKA PD15 value decreasing to 9.45 x 10(-9) mol. The present study confirms that inhaled NKA induces a dose-related bronchoconstriction in asthmatic patients and demonstrates that inhaled phosphoramidon potentiates NKA-induced bronchoconstriction.

RESPIRATORY RESPONSE AND INTERNAL TISSUE DOSE OF INHALED CHLORINE IN THE RESPIRATORY TRACT OF F344 RATS: SEX AND SPECIES COMPARISONS

EPA Science Inventory

Inhaled Cl₂ causes irritant effects in the respiratory tract. Females of various toxicological studies show more severe effects than males, notably a decrease in survivability observed in rats of a 2-year bioassay (CIIT, 1993; Wolf et al., 1995, Fundam. Appl. Toxic...