Efficacy and safety of budesonide administered by pressurized metered-dose inhaler in children with asthma.

PubMed

Meltzer, Eli O; Pearlman, David S; Eckerwall, Gӧran; Uryniak, Tom; DePietro, Michael; Lampl, Kathy

2015-12-01

Budesonide is approved for delivery using a nebulized solution and dry-powder inhaler, but its use through a pressurized metered-dose inhaler (pMDI) in pediatric patients with asthma has not been determined. To examine the efficacy and safety of 160 μg twice daily of budesonide through a pMDI vs placebo in children 6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids. A 6-week, international, multicenter, double-blinded, parallel-group, phase 2 study randomized 304 pediatric patients (mean age, 9 years; 21.7% <8 years) 1:1 to 160 μg (80 μg × 2 inhalations) twice daily of budesonide through a pMDI or placebo after a 7- to 21-day run-in period. The primary efficacy end point was change from baseline in morning peak expiratory flow (PEF); safety end points included adverse events, vital signs, and discontinuations. Budesonide treatment significantly improved morning PEF vs placebo; mean treatment effect (budesonide vs placebo) was 13.6 L/min (P < .0001). Budesonide also showed significant improvements vs placebo for forced expiratory volume in 1 second, evening PEF, forced expiratory flow at 25% to 75% of pulmonary volume, reliever medication use, nighttime awakenings, awakenings with reliever use, and percentage of patients with at least 15- and at least 30-L/min increase in morning PEF from baseline. The numbers of patients experiencing adverse events and discontinuations were smaller in the budesonide than in the placebo group. No serious adverse events were reported. Budesonide at 160 μg twice daily through a pMDI was generally well tolerated and significantly improved lung function, symptoms, rescue medication use, and nighttime awakenings vs placebo in children 6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids. Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Evaluation of proficiency in using different inhaler devices among intern doctors.

PubMed

Kshatriya, Ravish M; Khara, Nimit V; Paliwal, Rajiv P; Patel, Satish N

2016-01-01

Doctors may have deficiencies in the ability to use different inhalers, which in turn, can result in improper technique by the patients and poorly controlled asthma and chronic obstructive pulmonary disease (COPD). To evaluate intern doctors' proficiency in using various inhaler devices. Seventy interns were evaluated for their proficiency in using pressurized metered dose inhaler (pMDI), pMDI with spacer, rotahaler, turbuhaler, and nebulizer. A structured assessment sheet was scored for identification and preparation of device, administration, coordination, and skill of explanation on a scale of 0-5. Common errors such as failure to shake pMDI before use, inability to identify the empty device, inadequate breath holding, and failure to advise gargles after use were recorded. pMDI and pMDI with spacer were identified correctly by 89% and 79% of interns. Over 90% could identify rotahaler and nebulizer whereas only 9% could identify turbuhaler. 79% and 60% could prepare pMDI and pMDI with spacer appropriately. Nebulizer preparation was performed correctly by 79% and almost all interns could not prepare turbuhaler. Only one intern administered turbuhaler correctly. About half of the participants knew the correct co-ordination for pMDI and pMDI with spacer. Two interns showed proper co-ordination in using turbuhaler. None could provide correct explanation for turbuhaler usage; whereas 76% and 70% did it for nebulizer and rotahaler, respectively. Only 43% of interns remembered to shake pMDI before use. Proficiency in using different inhaler devices amongst interns is poor. It is essential to provide adequate training for inhaler devices usage to medical graduates for proper management of asthma and COPD patients by those future primary care physicians and specialists.

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

Improved delivery of ipratropium bromide/fenoterol from Respimat Soft Mist Inhaler in patients with COPD.

PubMed

Kilfeather, S A; Ponitz, H H; Beck, E; Schmidt, P; Lee, A; Bowen, I; Hesse, Ch

2004-05-01

We performed a multicentre, randomised, double-blind (within-device), placebo- and active-controlled, parallel-group study to compare the efficacy and safety of ipratropium bromide plus fenoterol hydrobromide (IB/FEN; Berodual) delivered via the novel, propellant-free Respimat Soft Mist Inhaler (SMI) and from a chlorofluorocarbon (CFC)-metered-dose inhaler (MDI) in moderate-to-severe chronic obstructive pulmonary disease (COPD) patients. After 2-weeks' run-in (CFC-MDI [IB 20 microg/FEN 50 microg per actuation] two actuations q.i.d. [MDI 40/100]), 892 patients were randomised to Respimat SMI containing IB 10 microg/FEN 25 microg (Respimat SMI 10/25), IB 20 microg/FEN 50 microg (Respimat SMI 20/50) or placebo (one actuation q.i.d.), or a CFC-MDI containing IB 20 microg/FEN 50 microg (MDI 40/100) or placebo (two actuations q.i.d.) for 12 weeks. Analysis of the primary endpoint (change in forced expiratory volume in 1 s [FEV1] in the first 60 min after dosing [area under the curve; AUC0-1h]) on day 85 showed that the efficacy of Respimat SMI 20/50 (but not Respimat SMI 10/25) was not inferior to that of MDI 40/100. The safety profile of Respimat SMI was comparable to CFC-MDI. Switching from MDI 40/100 to Respimat SMI was well tolerated. Respimat SMI enables a 50% reduction of the nominal inhaled dose of IB/FEN in COPD patients while offering similar therapeutic efficacy and safety to the CFC-MDI.

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.

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

[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.

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

A randomised open-label cross-over study of inhaler errors, preference and time to achieve correct inhaler use in patients with COPD or asthma: comparison of ELLIPTA with other inhaler devices.

PubMed

van der Palen, Job; Thomas, Mike; Chrystyn, Henry; Sharma, Raj K; van der Valk, Paul Dlpm; Goosens, Martijn; Wilkinson, Tom; Stonham, Carol; Chauhan, Anoop J; Imber, Varsha; Zhu, Chang-Qing; Svedsater, Henrik; Barnes, Neil C

2016-11-24

Errors in the use of different inhalers were investigated in patients naive to the devices under investigation in a multicentre, single-visit, randomised, open-label, cross-over study. Patients with chronic obstructive pulmonary disease (COPD) or asthma were assigned to ELLIPTA vs DISKUS (Accuhaler), metered-dose inhaler (MDI) or Turbuhaler. Patients with COPD were also assigned to ELLIPTA vs Handihaler or Breezhaler. Patients demonstrated inhaler use after reading the patient information leaflet (PIL). A trained investigator assessed critical errors (i.e., those likely to result in the inhalation of significantly reduced, minimal or no medication). If the patient made errors, the investigator demonstrated the correct use of the inhaler, and the patient demonstrated inhaler use again. Fewer COPD patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS, 9/171 (5%) vs 75/171 (44%); MDI, 10/80 (13%) vs 48/80 (60%); Turbuhaler, 8/100 (8%) vs 44/100 (44%); Handihaler, 17/118 (14%) vs 57/118 (48%); Breezhaler, 13/98 (13%) vs 45/98 (46%; all P<0.001). Most patients (57-70%) made no errors using ELLIPTA and did not require investigator instruction. Instruction was required for DISKUS (65%), MDI (85%), Turbuhaler (71%), Handihaler (62%) and Breezhaler (56%). Fewer asthma patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS (3/70 (4%) vs 9/70 (13%), P=0.221); MDI (2/32 (6%) vs 8/32 (25%), P=0.074) and significantly fewer vs Turbuhaler (3/60 (5%) vs 20/60 (33%), P<0.001). More asthma and COPD patients preferred ELLIPTA over the other devices (all P⩽0.002). Significantly, fewer COPD patients using ELLIPTA made critical errors after reading the PIL vs other inhalers. More asthma and COPD patients preferred ELLIPTA over comparator inhalers.

A randomised open-label cross-over study of inhaler errors, preference and time to achieve correct inhaler use in patients with COPD or asthma: comparison of ELLIPTA with other inhaler devices

PubMed Central

van der Palen, Job; Thomas, Mike; Chrystyn, Henry; Sharma, Raj K; van der Valk, Paul DLPM; Goosens, Martijn; Wilkinson, Tom; Stonham, Carol; Chauhan, Anoop J; Imber, Varsha; Zhu, Chang-Qing; Svedsater, Henrik; Barnes, Neil C

2016-01-01

Errors in the use of different inhalers were investigated in patients naive to the devices under investigation in a multicentre, single-visit, randomised, open-label, cross-over study. Patients with chronic obstructive pulmonary disease (COPD) or asthma were assigned to ELLIPTA vs DISKUS (Accuhaler), metered-dose inhaler (MDI) or Turbuhaler. Patients with COPD were also assigned to ELLIPTA vs Handihaler or Breezhaler. Patients demonstrated inhaler use after reading the patient information leaflet (PIL). A trained investigator assessed critical errors (i.e., those likely to result in the inhalation of significantly reduced, minimal or no medication). If the patient made errors, the investigator demonstrated the correct use of the inhaler, and the patient demonstrated inhaler use again. Fewer COPD patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS, 9/171 (5%) vs 75/171 (44%); MDI, 10/80 (13%) vs 48/80 (60%); Turbuhaler, 8/100 (8%) vs 44/100 (44%); Handihaler, 17/118 (14%) vs 57/118 (48%); Breezhaler, 13/98 (13%) vs 45/98 (46%; all P<0.001). Most patients (57–70%) made no errors using ELLIPTA and did not require investigator instruction. Instruction was required for DISKUS (65%), MDI (85%), Turbuhaler (71%), Handihaler (62%) and Breezhaler (56%). Fewer asthma patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS (3/70 (4%) vs 9/70 (13%), P=0.221); MDI (2/32 (6%) vs 8/32 (25%), P=0.074) and significantly fewer vs Turbuhaler (3/60 (5%) vs 20/60 (33%), P<0.001). More asthma and COPD patients preferred ELLIPTA over the other devices (all P⩽0.002). Significantly, fewer COPD patients using ELLIPTA made critical errors after reading the PIL vs other inhalers. More asthma and COPD patients preferred ELLIPTA over comparator inhalers. PMID:27883002

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.

Sildenafil citrate monohydrate-cyclodextrin nanosuspension complexes for use in metered-dose inhalers.

PubMed

Sawatdee, Somchai; Phetmung, Hirihattaya; Srichana, Teerapol

2013-10-15

Sildenafil is a selective phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction and pulmonary hypertension. Sildenafil citrate monohydrate was complexed with α-, hydroxypropyl-β- and γ-cyclodextrin (α-CD, HP-β-CD and γ-CD, respectively) to enhance its water solubility. The complexes of sildenafil citrate monohydrate with all types of CDs were characterized by phase solubility diagrams, (1)H and (13)C NMR, and dielectric constants. Sildenafil citrate monohydrate complexed with CDs was developed as nanosuspensions for use in a pressurized metered-dose inhaler (pMDI). Sildenafil citrate monohydrate pMDI formulations were prepared by a bottom-up process using dried ethanol as a solvent and HFA-134a as an antisolvent and propellant in order to form nanosuspensions. A 3×3 factorial design was applied for the contents of the dried ethanol and HFA-134a propellant. The phase solubility profiles of the sildenafil and cyclodextrins were described as AL type with a mole ratio 1:1. The piperazine moiety of sildenafil formed an inclusion in the cavity of the CDs. The particle diameters of the sildenafil citrate monohydrate suspensions in pMDIs were all within a nanosuspension size range. An assay of the sildenafil content showed that the formation of complexes with CDs was close to 100%. In the case of the formulations with CDs, the emitted doses varied within 97.4±10.8%, the fine particle fractions (FPFs) were in a range of 45-81%, the fine particle dose (FPD) was 12.6±2.0 μg and the mass median aerodynamic diameters (MMADs) were 1.86±0.41 μm. In contrast, the formulations without CDs produced a low emitted dose of sildenafil (<60%). Therefore, only sildenafil citrate monohydrate pMDI formulations containing CDs were suitable for use as aerosols. Copyright © 2013 Elsevier B.V. All rights reserved.

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

Impact of droplet evaporation rate on resulting in vitro performance parameters of pressurized metered dose inhalers.

PubMed

Sheth, Poonam; Grimes, Matthew R; Stein, Stephen W; Myrdal, Paul B

2017-08-07

Pressurized metered dose inhalers (pMDIs) are widely used for the treatment of pulmonary diseases. The overall efficiency of pMDI drug delivery may be defined by in vitro parameters such as the amount of drug that deposits on the model throat and the proportion of the emitted dose that has particles that are sufficiently small to deposit in the lung (i.e., fine particle fraction, FPF). The study presented examines product performance of ten solution pMDI formulations containing a variety of cosolvents with diverse chemical characteristics by cascade impaction with three inlets (USP induction port, Alberta Idealized Throat, and a large volume chamber). Through the data generated in support of this study, it was demonstrated that throat deposition, cascade impactor deposition, FPF, and mass median aerodynamic diameter of solution pMDIs depend on the concentration and vapor pressure of the cosolvent, and the selection of model throat. Theoretical droplet lifetimes were calculated for each formulation using a discrete two-stage evaporation process model and it was determined that the droplet lifetime is highly correlated to throat deposition and FPF indicating that evaporation kinetics significantly influences pMDI drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

High-Speed Laser Image Analysis of Plume Angles for Pressurised Metered Dose Inhalers: The Effect of Nozzle Geometry.

PubMed

Chen, Yang; Young, Paul M; Murphy, Seamus; Fletcher, David F; Long, Edward; Lewis, David; Church, Tanya; Traini, Daniela

2017-04-01

The aim of this study is to investigate aerosol plume geometries of pressurised metered dose inhalers (pMDIs) using a high-speed laser image system with different actuator nozzle materials and designs. Actuators made from aluminium, PET and PTFE were manufactured with four different nozzle designs: cone, flat, curved cone and curved flat. Plume angles and spans generated using the designed actuator nozzles with four solution-based pMDI formulations were imaged using Oxford Lasers EnVision system and analysed using EnVision Patternate software. Reduced plume angles for all actuator materials and nozzle designs were observed with pMDI formulations containing drug with high co-solvent concentration (ethanol) due to the reduced vapour pressure. Significantly higher plume angles were observed with the PTFE flat nozzle across all formulations, which could be a result of the nozzle geometry and material's hydrophobicity. The plume geometry of pMDI aerosols can be influenced by the vapour pressure of the formulation, nozzle geometries and actuator material physiochemical properties.

Nurses' knowledge of inhaler technique in the inpatient hospital setting.

PubMed

De Tratto, Katie; Gomez, Christy; Ryan, Catherine J; Bracken, Nina; Steffen, Alana; Corbridge, Susan J

2014-01-01

High rates of inhaler misuse in patients with chronic obstructive pulmonary disease and asthma contribute to hospital readmissions and increased healthcare cost. The purpose of this study was to examine inpatient staff nurses' self-perception of their knowledge of proper inhaler technique compared with demonstrated technique and frequency of providing patients with inhaler technique teaching during hospitalization and at discharge. A prospective, descriptive study. A 495-bed urban academic medical center in the Midwest United States. A convenience sample of 100 nurses working on inpatient medical units. Participants completed a 5-item, 4-point Likert-scale survey evaluating self-perception of inhaler technique knowledge, frequency of providing patient education, and responsibility for providing education. Participants demonstrated inhaler technique to the investigators using both a metered dose inhaler (MDI) and Diskus device inhaler, and performance was measured via a validated checklist. Overall misuse rates were high for both MDI and Diskus devices. There was poor correlation between perceived ability and investigator-measured performance of inhaler technique. Frequency of education during hospitalization and at discharge was related to measured level of performance for the Diskus device but not for the MDI. Nurses are a key component of patient education in the hospital; however, nursing staff lack adequate knowledge of inhaler technique. Identifying gaps in nursing knowledge regarding proper inhaler technique and patient education about proper inhaler technique is important to design interventions that may positively impact patient outcomes. Interventions could include one-on-one education, Web-based education, unit-based education, or hospital-wide competency-based education. All should include return demonstration of appropriate technique.

A Cost Analysis of Salbutamol Administration by Metered-Dose Inhalers with Spacers versus Nebulization for Patients with Wheeze in the Pediatric Emergency Department: Evidence from Observational Data in Nova Scotia.

PubMed

Spin, Paul; Sketris, Ingrid; Hill-Taylor, Barbara; Ward, Courtney; Hurley, Katrina F

2017-01-01

Despite evidence demonstrating the advantages of metered-dose inhalers with spacers (MDI-s), nebulization (NEB) remains the primary method of asthma treatment in some pediatric emergency departments (PEDs). There is a perception that delivering salbutamol by MDI-s is more costly than by NEB. This research evaluates the relative costs of MDI-s and NEB using local, hospital-specific, patient-level data. Regression models estimated associations between the salbutamol inhalation method and costs, length of stay (LOS) in the PED and hospital, and the probability of admission. Our population was a random sample of 822 patients presenting with wheeze to the PED in 2008/2009. Control variables included age, sex, triage acuity, time of PED visit, other medications, and vitals. Costs were calculated using the prices and quantities of medical resources used per treatment. Probabilistic sensitivity analysis was used. Treatment with MDI-s versus NEB was associated with an absolute decrease in hospitalization of 4.4% (p<0.05) and a 25-hour (p<0.001) reduction in average inpatient stay, after controlling for triage acuity and patient characteristics. This resulted in savings of $24/patient in the PED and $180/patient overall (p<0.001). Inpatient care accounted for more than 90% of total patient costs. Our results suggest economic gains associated with MDI-s for salbutamol inhalation in PEDs. Sensitivity analyses show that this conclusion is not affected by changes in model parameters that may differ by jurisdiction. Since most facilities already collect the data used for this study, our methods could be adopted for a cross-jurisdictional account of the cost effectiveness of MDI-s.

Aerosol deposition in the human lung following administration from a microprocessor controlled pressurised metered dose inhaler.

PubMed Central

Farr, S. J.; Rowe, A. M.; Rubsamen, R.; Taylor, G.

1995-01-01

BACKGROUND--Gamma scintigraphy was employed to assess the deposition of aerosols emitted from a pressurised metered dose inhaler (MDI) contained in a microprocessor controlled device (SmartMist), a system which analyses an inspiratory flow profile and automatically actuates the MDI when predefined conditions of flow rate and cumulative inspired volume coincide. METHODS--Micronised salbutamol particles contained in a commercial MDI (Ventolin) were labelled with 99m-technetium using a method validated by the determination of (1) aerosol size characteristics of the drug and radiotracer following actuation into an eight stage cascade impactor and (2) shot potencies of these non-volatile components as a function of actuation number. Using nine healthy volunteers in a randomised factorial interaction design the effect of inspiratory flow rate (slow, 30 l/min; medium, 90 l/min; fast, 270 l/min) combined with cumulative inspired volume (early, 300 ml; late, 3000 ml) was determined on total and regional aerosol lung deposition using the technique of gamma scintigraphy. RESULTS--The SmartMist firing at the medium/early setting (medium flow and early in the cumulative inspired volume) resulted in the highest lung deposition at 18.6 (1.42)%. The slow/early setting gave the second highest deposition at 14.1 (2.06)% with the fast/late setting resulting in the lowest (7.6 (1.15)%). Peripheral lung deposition obtained for the medium/early (9.1 (0.9)%) and slow/early (7.5 (1.06)%) settings were equivalent but higher than those obtained with the other treatments. This reflected the lower total lung deposition at these other settings as no difference in regional deposition, expressed as a volume corrected central zone:peripheral zone ratio, was apparent for all modes of inhalation studied. CONCLUSIONS--The SmartMist device allowed reproducible actuation of an MDI at a preprogrammed point during inspiration. The extent of aerosol deposition in the lung is affected by a change in

Asthma management and inhalation techniques among community pharmacists in 2009: a comparison with the 1999 survey.

PubMed

Casset, Anne; Meunier-Spitz, Marion; Rebotier, Pauline; Lefèvre, Hassina; Barth, Christian; Heitz, Christiane; de Blay, Frédéric

2014-11-01

In a 1999 survey, community pharmacists from the Alsace region of France had a reasonably good knowledge of asthma treatment and prevention, but their skill in the use of asthma inhalation devices left room for improvement. Since then, health authorities have encouraged the involvement of community pharmacists in patient care and education in order to improve asthma control. The aim of this study was to assess the change in the knowledge of asthma management and inhaler technique skills of community pharmacists in the same geographic area after a 10-year interval. In 2009, 86 randomly selected community pharmacists from the Alsace region answered a standardized questionnaire about their theoretical knowledge of and practical attitude toward asthma management and inhaled delivery systems, following which their skills in the use of four inhalation devices (pressurized metered-dose inhaler (pMDI) with/without a spacer, breath-actuated pMDI and dry powder inhaler (DPI)) were evaluated. Very few pharmacists were required to manage an acute asthma exacerbation at the pharmacy, but all responded well by administering a short-acting inhaled β2-agonist. Theoretical knowledge of asthma management (criteria of severity of asthma exacerbation, guidelines and drugs triggering asthma exacerbations) was still average. Compared with 1999, they were twice as confident in demonstrating inhaler use, and their skills in using the pMDI, breath-actuated pMDI and DPI had improved significantly (p < 0.001). Since 1999, pharmacists' skill in the use of inhalers has improved, but theoretical knowledge of asthma management is still average, pointing to the importance of continuing pharmaceutical education.

A Tablet-Based Multimedia Education Tool Improves Provider and Subject Knowledge of Inhaler Use Techniques.

PubMed

Mulhall, Aaron M; Zafar, Muhammad A; Record, Samantha; Channell, Herman; Panos, Ralph J

2017-02-01

Although inhaled medications are effective therapies for COPD, many patients and providers use them incorrectly. We recruited providers who prescribe inhalers or teach inhaler technique and assessed their use of metered-dose inhalers (MDIs), various dry powder inhalers (DPIs), and Respimat using predefined checklists. Then they watched tablet-based multimedia educational videos that demonstrated correct inhaler technique by a clinical pharmacist with teach-back from a patient and were re-evaluated. We also recruited patients with COPD and assessed their use of their prescribed inhalers and then retested them after 3-6 months. Baseline and follow-up respiratory symptoms were measured by the COPD Assessment Test. Fifty-eight providers and 50 subjects participated. For all providers, correct inhaler technique (reported as percentage correct steps) increased after the videos: MDI without a spacer (72% vs 97%) MDI with a spacer (72% vs 96%), formoterol DPI (50% vs 94%), mometasone DPI (43% vs 95%), tiotropium DPI (73% vs 99%), and Respimat (32% vs 93%) (before vs after, P < .001 for all comparisons). Subjects also improved their inhaler use technique after viewing the educational videos: MDI without a spacer (69% vs 92%), MDI with a spacer (73% vs 95%), and tiotropium DPI (83% vs 96%) (before vs after, P < .001 for all comparisons). The beneficial effect of this educational intervention declined slightly for subjects but was durably improved after several months. COPD Assessment Test scores did not demonstrate any change in respiratory symptoms. A tablet-based inhaler education tool improved inhaler technique for both providers and subjects. Although this intervention did show durable efficacy for improving inhaler use by patients, it did not reduce their respiratory symptoms. Copyright © 2017 by Daedalus Enterprises.

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.

In vivo comparison of the relative systemic bioavailability of fluticasone propionate from three anti-static spacers and a metered dose inhaler

PubMed Central

Nair, Arun; Menzies, Daniel; Hopkinson, Pippa; McFarlane, Lesley; Lipworth, Brian J

2009-01-01

AIMS The systemic bioavailability of inhaled fluticasone propionate (FP) depends primarily on lung absorption and can be quantified by measuring suppression of overnight and early morning urinary cortisol/creatinine (OUCC and EMUCC, respectively). The aim of the study was to determine the relative bioavailability of hydrofluoroalkane (HFA) FP to the lungs via anti-static plastic (Zerostat-V and Aerochamber Max), metal (Nebuchamber) anti-static spacers and metered dose inhaler [Flixotide Evohaler (EH) (pMDI)]. METHODS A randomized, double-blind, double-dummy, four-way crossover design was used. Eighteen mild to moderate asthmatics received single doses of placebo/HFA-FP 2 mg via the 280-ml Zerostat-V (ZS); 250-ml Nebuchamber (NC); 197-ml Aerochamber Max (AC); and pMDI (EH). Measurements of OUCC and EMUCC were made at baseline and 10 h after each dose. RESULTS Significant suppression of OUCC and EMUCC occurred from baseline with all three spacers, but not Evohaler (geometric mean fold suppression, 95% confidence interval): ZS, 2.74 (1.75, 4.30), P < 0.001; NC, 3.31 (1.81, 6.06), P < 0.001; AC, 4.98 (3.39, 7.31), P < 0.001; and for EH this was 1.42 (0.92, 2.21), P = 0.169 (equating to a 64, 70, 80 and 30% fall in OUCC via the ZS, NC, AC and EH devices, respectively). There were significant differences between all three spacers vs. EH. When compared with the Evohaler, the Zerostat V resulted in 48% greater suppression (P = 0.009); the Nebuchamber 57% greater suppression (P = 0.001); and the Aerochamber Max 71% greater suppression of OUCC (P < 0.001). CONCLUSION All three antistatic spacers significantly increased the relative systemic bioavailability of HFA-FP compared with the standard pMDI. PMID:19220273

The effect of actuator nozzle designs on the electrostatic charge generated in pressurised metered dose inhaler aerosols.

PubMed

Chen, Yang; Young, Paul M; Fletcher, David F; Chan, Hak Kim; Long, Edward; Lewis, David; Church, Tanya; Traini, Daniela

2015-04-01

To investigate the influence of different actuator nozzle designs on aerosol electrostatic charges and aerosol performances for pressurised metered dose inhalers (pMDIs). Four actuator nozzle designs (flat, curved flat, cone and curved cone) were manufactured using insulating thermoplastics (PET and PTFE) and conducting metal (aluminium) materials. Aerosol electrostatic profiles of solution pMDI formulations containing propellant HFA 134a with different ethanol concentration and/or model drug beclomethasone dipropionate (BDP) were studied using a modified electrical low-pressure impactor (ELPI) for all actuator designs and materials. The mass of the deposited drug was analysed using high performance liquid chromatography (HPLC). Both curved nozzle designs for insulating PET and PTFE actuators significantly influenced aerosol electrostatics and aerosol performance compared with conducting aluminium actuator, where reversed charge polarity and higher throat deposition were observed with pMDI formulation containing BDP. Results are likely due to the changes in plume geometry caused by the curved edge nozzle designs and the bipolar charging nature of insulating materials. This study demonstrated that actuator nozzle designs could significantly influence the electrostatic charges profiles and aerosol drug deposition pattern of pMDI aerosols, especially when using insulating thermoplastic materials where bipolar charging is more dominant.

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.

Deposition and transport of linezolid mediated by a synthetic surfactant Synsurf® within a pressurized metered dose inhaler: a Calu-3 model

PubMed Central

van Rensburg, Lyné; van Zyl, Johann M; Smith, Johan

2018-01-01

Background Previous studies in our laboratory demonstrated that a synthetic peptide containing lung surfactant enhances the permeability of chemical compounds through bronchial epithelium. The purpose of this study was to test two formulations of Synsurf® combined with linezolid as respirable compounds using a pressurized metered dose inhaler (pMDI). Methods Aerosolization efficiency of the surfactant-drug microparticles onto Calu-3 monolayers as an air interface culture was analyzed using a Next Generation Impactor™. Results The delivered particles and drug dose showed a high dependency from the preparation that was aerosolized. Scanning electron microscopy imaging allowed for visualization of the deposited particles, establishing them as liposomal-type structures (diameter 500 nm to 2 μm) with filamentous features. Conclusion The different surfactant drug combinations allow for an evaluation of the significance of the experimental model system, as well as assessment of the formulations providing a possible noninvasive, site-specific, delivery model via pMDI. PMID:29765201

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.

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

MDI with DIY Spacer versus Nebulizer for Bronchodilator Therapy in Children Admitted with Asthmatic Attack.

PubMed

Leelathipkul, Lalit; Tanticharoenwiwat, Pattara; Ithiawatchakul, Jutinan; Prommin, Danu; Sirisalee, Pasu; Junhunee, Parinya; Poachanukoon, Orapan

2016-07-01

Inhaled bronchodilator treatment given via the pressurized metered-dose inhaler (pMDI) with spacer has been recommended for an acute asthma treatment. Unfortunately, most of commercially available spacers are at high cost while a do-it-yourself (DIY) spacer has lower cost as it is made from plastic bottle and siphon pump which are inexpensive and easilyfound materials. This study aims to compare treatment response in nebulizer and DIY spacer used for asthmatic children. A prospective, randomized control study was conducted in children aged 1-15 years old hospitalized for mild to moderate asthmatic attack at Thammasat University Hospital between June 2014 and March 2015. The patients were divided into 2 groups, receiving β2-agonist via nebulization and via pMDI with DIY spacer. Their vital signs and oxygen saturation were monitored and asthma scores were also recorded at admission, 24 hours, 48 hours, and before discharge. The satisfaction of equipment use was evaluated employing questionnaires. 40 childrens were enrolled with male at 72.5% and mean age at 3.1±1.6 years old. There was no significant difference in efficacy of β2-agonist among 2 groups when comparing in consideration of vital signs, oximetry, asthma scores and hospital stay. However, there were significantly different on side effect in which the DIY spacer had less tachycardia and agitation. Satisfaction of parents and healthcare workers were higher in DIY spacer. MDI with DIY spacer was able to be used effectively when compared with nebulization to treat mild to moderate acute exacerbations of asthma in children admitted in hospital.

Factors affecting the stability and performance of ipratropium bromide; fenoterol hydrobromide pressurized-metered dose inhalers.

PubMed

Ninbovorl, Jenjira; Sawatdee, Somchai; Srichana, Teerapol

2013-12-01

The aim of the study was to investigate the factors affecting the stability and performance of ipratropium bromide and fenoterol hydrobromide in a pressurized-metered dose inhaler (pMDI). A factorial design was applied to investigate the effects of three parameters (propellant, water, and ethanol) on the performance of 27 designed formulations of a solution-based pMDI. The formulations that contained a hydrofluoroalkane (HFA) propellant lower than 72% v/v and an ethanol concentration higher than 27% v/v remained as clear solutions. Nine formulations that contained the HFA propellant higher than 74% v/v precipitated. The results indicated that it was not only the HFA propellant content of the formulations that was related to the formulation instability but also ethanol content. Only six formulations from the 18 formulations, that did not precipitate, produced drug contents that were within the acceptable range (80-120%). These six formulations generated aerosols with mass median aerodynamic diameters (MMAD) of approximately 2 μm with a fine particle fraction (FPF; particle size, <6.4 μm) between 45% and 52%. The MMAD and FPF did not change significantly after 6 months of storage (P > 0.05).

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

PubMed

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

2001-12-01

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

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.

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 ...

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 ...

Insights into Spray Development from Metered-Dose Inhalers Through Quantitative X-ray Radiography

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

Mason-Smith, Nicholas; Duke, Daniel J.; Kastengren, Alan L.

Typical methods to study pMDI sprays employ particle sizing or visible light diagnostics, which suffer in regions of high spray density. X-ray techniques can be applied to pharmaceutical sprays to obtain information unattainable by conventional particle sizing and light-based techniques. We present a technique for obtaining quantitative measurements of spray density in pMDI sprays. A monochromatic focused X-ray beam was used to perform quantitative radiography measurements in the near-nozzle region and plume of HFA-propelled sprays. Measurements were obtained with a temporal resolution of 0.184 ms and spatial resolution of 5 mu m. Steady flow conditions were reached after around 30more » ms for the formulations examined with the spray device used. Spray evolution was affected by the inclusion of ethanol in the formulation and unaffected by the inclusion of 0.1% drug by weight. Estimation of the nozzle exit density showed that vapour is likely to dominate the flow leaving the inhaler nozzle during steady flow. Quantitative measurements in pMDI sprays allow the determination of nozzle exit conditions that are difficult to obtain experimentally by other means. Measurements of these nozzle exit conditions can improve understanding of the atomization mechanisms responsible for pMDI spray droplet and particle formation.« less

Tuning Aerosol Particle Size Distribution of Metered Dose Inhalers Using Cosolvents and Surfactants

PubMed Central

Saleem, Imran Y.; Smyth, Hugh D. C.

2013-01-01

Objectives. The purpose of these studies was to understand the influence of cosolvent and surfactant contributions to particle size distributions emitted from solution metered dose inhalers (pMDIs) based on the propellant HFA 227. Methods. Two sets of formulations were prepared: (a) pMDIs-HFA 227 containing cosolvent (5–15% w/w ethanol) with constant surfactant (pluronic) concentration and (b) pMDIs-HFA 227 containing surfactant (0–5.45% w/w pluronic) with constant cosolvent concentration. Particle size distributions emitted from these pMDIs were analyzed using aerodynamic characterization (inertial impaction) and laser diffraction methods. Results. Both cosolvent and surfactant concentrations were positively correlated with median particle sizes; that is, drug particle size increased with increasing ethanol and pluronic concentrations. However, evaluation of particle size distributions showed that cosolvent caused reduction in the fine particle mode magnitude while the surfactant caused a shift in the mode position. These findings highlight the different mechanisms by which these components influence droplet formation and demonstrate the ability to utilize the different effects in formulations of pMDI-HFA 227 for independently modulating particle sizes in the respirable region. Conclusion. Potentially, the formulation design window generated using these excipients in combination could be used to match the particle size output of reformulated products to preexisting pMDI products. PMID:23984381

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.

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.

Validation of scores of use of inhalation devices: valoration of errors *

PubMed Central

Zambelli-Simões, Letícia; Martins, Maria Cleusa; Possari, Juliana Carneiro da Cunha; Carvalho, Greice Borges; Coelho, Ana Carla Carvalho; Cipriano, Sonia Lucena; de Carvalho-Pinto, Regina Maria; Cukier, Alberto; Stelmach, Rafael

2015-01-01

Abstract Objective: To validate two scores quantifying the ability of patients to use metered dose inhalers (MDIs) or dry powder inhalers (DPIs); to identify the most common errors made during their use; and to identify the patients in need of an educational program for the use of these devices. Methods: This study was conducted in three phases: validation of the reliability of the inhaler technique scores; validation of the contents of the two scores using a convenience sample; and testing for criterion validation and discriminant validation of these instruments in patients who met the inclusion criteria. Results: The convenience sample comprised 16 patients. Interobserver disagreement was found in 19% and 25% of the DPI and MDI scores, respectively. After expert analysis on the subject, the scores were modified and were applied in 72 patients. The most relevant difficulty encountered during the use of both types of devices was the maintenance of total lung capacity after a deep inhalation. The degree of correlation of the scores by observer was 0.97 (p < 0.0001). There was good interobserver agreement in the classification of patients as able/not able to use a DPI (50%/50% and 52%/58%; p < 0.01) and an MDI (49%/51% and 54%/46%; p < 0.05). Conclusions: The validated scores allow the identification and correction of inhaler technique errors during consultations and, as a result, improvement in the management of inhalation devices. PMID:26398751

The use of a quartz crystal microbalance as an analytical tool to monitor particle/surface and particle/particle interactions under dry ambient and pressurized conditions: a study using common inhaler components.

PubMed

Turner, N W; Bloxham, M; Piletsky, S A; Whitcombe, M J; Chianella, I

2016-12-19

Metered dose inhalers (MDI) and multidose powder inhalers (MPDI) are commonly used for the treatment of chronic obstructive pulmonary diseases and asthma. Currently, analytical tools to monitor particle/particle and particle/surface interaction within MDI and MPDI at the macro-scale do not exist. A simple tool capable of measuring such interactions would ultimately enable quality control of MDI and MDPI, producing remarkable benefits for the pharmaceutical industry and the users of inhalers. In this paper, we have investigated whether a quartz crystal microbalance (QCM) could become such a tool. A QCM was used to measure particle/particle and particle/surface interactions on the macroscale, by additions of small amounts of MDPI components, in the powder form into a gas stream. The subsequent interactions with materials on the surface of the QCM sensor were analyzed. Following this, the sensor was used to measure fluticasone propionate, a typical MDI active ingredient, in a pressurized gas system to assess its interactions with different surfaces under conditions mimicking the manufacturing process. In both types of experiments the QCM was capable of discriminating interactions of different components and surfaces. The results have demonstrated that the QCM is a suitable platform for monitoring macro-scale interactions and could possibly become a tool for quality control of inhalers.

Extra-fine particle inhaled corticosteroids, pharma-cokinetics and systemic activity in children with asthma.

PubMed

Wolthers, Ole D

2016-02-01

During recent years, extra-fine particle inhaled corticosteroids with a median aerodynamic diameter ≤2 μm have been introduced in the treatment of asthma. The aim of this paper was to review pharmacokinetics and systemic activity of extra-fine particle hydroalkane pressurized metered dose inhaled (pMDI) ciclesonide and beclomethasone dipropionate in children. A literature review was performed. Systemic bioavailability of oral and pulmonary deposition of extra-fine ciclesonide and beclomethasone dipropionate was 52% and 82%, the half-life in serum 3.2 and 1.5 h and first-pass hepatic metabolism >99% and 60%, respectively. Secondary analyses of urine cortisol/creatinine excretion found no effects of ciclesonide pMDI between 40 and 320 μg/day or of beclomethasone dipropionate pMDI between 80 and 400 μg/day. Ciclesonide pMDI 40, 80 and 160 μg/day caused no effects on short-term lower leg growth rate as assessed by knemometry. Ciclesonide 320 μg/day was associated with a numerically short-term growth suppression equivalent to 30% which was similar to 25% and 36% suppression caused by beclomethasone dipropionate HFA and CFC 200 μg/day, respectively. Consistent with the differences in key pharmacokinetic features, beclomethasone dipropionate is associated with a systemic activity detected by knemometry at a lower dose than ciclesonide. Whether that correlates with a clinically important difference remains to be explored. Assessments of systemic activity of beclomethasone dipropionate <200 μg/day and of ciclesonide >180 μg/day as well as head-to-head comparisons are warranted. Preferably, such studies should apply the sensitive method of knemometry. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Evaluating the technique of using inhalation device in COPD and bronchial asthma patients.

PubMed

Arora, Piyush; Kumar, Lokender; Vohra, Vikram; Sarin, Rohit; Jaiswal, Anand; Puri, M M; Rathee, Deepti; Chakraborty, Pitambar

2014-07-01

In asthma management, poor handling of inhalation devices and wrong inhalation technique are associated with decreased medication delivery and poor disease control. The key to overcome the drawbacks in inhalation technique is to make patients familiar with issues related to correct use and performance of these medical devices. The objective of this study was to evaluate and analyse technique of use of the inhalation device used by patients of COPD and Bronchial Asthma. A total of 300 cases of BA or COPD patients using different types of inhalation devices were included in this observational study. Data were captured using a proforma and were analysed using SPSS version 15.0. Out of total 300 enrolled patients, 247 (82.3%) made at least one error. Maximum errors observed in subjects using MDI (94.3%), followed by DPI (82.3%), MDI with Spacer (78%) while Nebulizer users (70%) made least number of errors (p = 0.005). Illiterate patients showed 95.2% error while post-graduate and professionals showed 33.3%. This difference was statistically significant (p < 0.001). Self-educated patients committed 100% error, while those trained by a doctor made 56.3% error. Majority of patients using inhalation devices made errors while using the device. Proper education to patients on correct usage may not only improve control of the symptoms of the disease but might also allow dose reduction in long term. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of workers' exposure to methylene diphenyl diisocyanate (MDI) in an automobile manufacturing company, Iran.

PubMed

Kakooei, Hossein; Shahtaheri, Seyed Jamaleddin; Karbasi, Hossein-Ali

2006-01-01

Evaluation of personal inhalation exposure to methylene diphenyl diisocyanate (MDI) among 39 employees, working in the window fixation and window glue processes in an automobile manufacturing company was performed. This study was conducted for both case and control groups. After sampling and sample preparation processes, MDI was determined with a UV-VIS spectrophotometer at 590 nm; the lung function was assessed with a digital spirometer, too. The average concentration of MDI in the window fixation, and window glue workplaces were 34.53 and 27.37 micro g/m3, respectively, which was lower than the threshold limit value (TLV) recommended by the American Conference of Governmental Industrial Hygienists (ACGIH) (51 micro g/m3). Respiratory symptoms in the exposed group were significantly different compared to the unexposed group (p < .05). Lung capacities in the case group were lower than in the control group (p < .05). Therefore, MDI can be easily measured making it possible to evaluate the adverse effects caused by occupational exposure.

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.

The influence of initial atomized droplet size on residual particle size from pressurized metered dose inhalers.

PubMed

Sheth, Poonam; Stein, Stephen W; Myrdal, Paul B

2013-10-15

Pressurized metered dose inhalers (pMDIs) are widely used for the treatment of diseases of the lung, including asthma and chronic obstructive pulmonary disease. The mass median aerodynamic diameter of the residual particles (MMADR) delivered from a pMDI plays a key role in determining the amount and location of drug deposition in the lung and thereby the efficacy of the inhaler. The mass median diameter of the initial droplets (MMDI), upon atomization of a formulation, is a significant factor influencing the final particle size. The purpose of this study was to evaluate the extent that MMDI and initial droplet geometric standard deviation (GSD) influence the residual aerodynamic particle size distribution (APSDR) of solution and suspension formulations. From 48 solution pMDI configurations with varying ethanol concentrations, valve sizes and actuator orifice diameters, it was experimentally found that the effective MMDI ranged from 7.8 to 13.3 μm. Subsequently, computational methods were utilized to determine the influence of MMDI on MMADR, by modulating the MMDI for solution and suspension pMDIs. For solution HFA-134a formulations of 0.5% drug in 10% ethanol, varying the MMDI from 7.5 to 13.5 μm increased the MMADR from 1.4 to 2.5 μm. For a suspension formulation with a representative particle size distribution of micronized drug (MMAD=2.5 μm, GSD=1.8), the same increase in MMDI resulted in an increase in the MMADR from 2.7 to only 3.3 μm. Hence, the same increase in MMDI resulted in a 79% increase in MMADR for the solution formulation compared to only a 22% increase for the suspension formulation. Similar trends were obtained for a range of drug concentrations and input micronized drug sizes. Thus, APSDR is more sensitive to changes in MMDI for solution formulations than suspension formulations; however, there are situations in which hypothetically small micronized drug in suspension (e.g. 500 nm MMAD) could resemble trends observed for solution formulations

Effect of budesonide/formoterol pressurized metered-dose inhaler on exacerbations versus formoterol in chronic obstructive pulmonary disease: The 6-month, randomized RISE (Revealing the Impact of Symbicort in reducing Exacerbations in COPD) study.

PubMed

Ferguson, Gary T; Tashkin, Donald P; Skärby, Tor; Jorup, Carin; Sandin, Kristina; Greenwood, Michael; Pemberton, Kristine; Trudo, Frank

2017-11-01

Prevention of exacerbations is a primary goal for chronic obstructive pulmonary disease (COPD) therapy. This randomized, double-blind, double-dummy, parallel-group, multicenter study evaluated the effect of budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus formoterol dry powder inhaler (DPI) on reducing COPD exacerbations. 1219 patients aged ≥40 years with moderate-to-very-severe COPD (per lung function) and a history of ≥1 COPD exacerbation received budesonide/formoterol pMDI 320/9 μg twice daily (BID) during a 4-week run-in. Patients were then randomized 1:1 to receive budesonide/formoterol pMDI 320/9 μg BID (n = 606) or formoterol DPI 9 μg BID (n = 613) for 26 weeks. Exacerbations were identified using predefined criteria for symptom worsening and treatment with systemic corticosteroids and/or antibiotics and/or hospitalization. The primary endpoint was annual rate of exacerbations. Budesonide/formoterol pMDI resulted in a 24% reduction in annual rate of exacerbations (0.85 vs 1.12; rate ratio: 0.76 [95% CI: 0.62, 0.92]; P = 0.006), and a significant risk reduction for time to first exacerbation (hazard ratio: 0.78 [95% CI: 0.64, 0.96]; P = 0.016) versus formoterol DPI. The most commonly reported adverse events (AEs; ≥3%) in budesonide/formoterol and formoterol groups were COPD (4.5% vs 8.6%) and nasopharyngitis (5.0% vs 5.2%). Pneumonia AEs were reported in 0.5% and 1.0% of budesonide/formoterol-treated and formoterol-treated patients, respectively. Budesonide/formoterol pMDI is an effective treatment option for reducing exacerbation rates in COPD patients with moderate-to-very-severe airflow limitation and history of exacerbations. No increase in pneumonia was observed with budesonide/formoterol; safety data were consistent with its established profile. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Towards the bioequivalence of pressurised metered dose inhalers 1: design and characterisation of aerodynamically equivalent beclomethasone dipropionate inhalers with and without glycerol as a non-volatile excipient.

PubMed

Lewis, D A; Young, P M; Buttini, F; Church, T; Colombo, P; Forbes, B; Haghi, M; Johnson, R; O'Shea, H; Salama, R; Traini, D

2014-01-01

A series of semi-empirical equations were utilised to design two solution based pressurised metered dose inhaler (pMDI) formulations, with equivalent aerosol performance but different physicochemical properties. Both inhaler formulations contained the drug, beclomethasone dipropionate (BDP), a volatile mixture of ethanol co-solvent and propellant (hydrofluoroalkane-HFA). However, one formulation was designed such that the emitted aerosol particles contained BDP and glycerol, a common inhalation particle modifying excipient, in a 1:1 mass ratio. By modifying the formulation parameters, including actuator orifice, HFA and metering volumes, it was possible to produce two formulations (glycerol-free and glycerol-containing) which had identical mass median aerodynamic diameters (2.4μm±0.1 and 2.5μm±0.2), fine particle dose (⩽5μm; 66μg±6 and 68μg±2) and fine particle fractions (28%±2% and 30%±1%), respectively. These observations demonstrate that it is possible to engineer formulations that generate aerosol particles with very different compositions to have similar emitted dose and in vitro deposition profiles, thus making them equivalent in terms of aerosol performance. Analysis of the physicochemical properties of each formulation identified significant differences in terms of morphology, thermal properties and drug dissolution of emitted particles. The particles produced from both formulations were amorphous; however, the formulation containing glycerol generated particles with a porous structure, while the glycerol-free formulation generated particles with a primarily spherical morphology. Furthermore, the glycerol-containing particles had a significantly lower dissolution rate (7.8%±2.1%, over 180min) compared to the glycerol-free particles (58.0%±2.9%, over 60min) when measured using a Franz diffusion cell. It is hypothesised that the presence of glycerol in the emitted aerosol particles altered solubility and drug transport, which may have

Isocyanate and total inhalable particulate air measurements in the European wood panel industry.

PubMed

Vangronsveld, E; Berckmans, S; Verbinnen, K; Van Leeuw, C; Bormans, C

2010-11-01

It is well known that the use of MDI (methylene diphenyldiisocyanate) as an alternative for formaldehyde-based resins is seen as a responsible option to reduce formaldehyde emissions for CWP (Composite Wood Products) in buildings. However, there are concerns raised regarding the exposure risk of workers. The purpose of this article is to provide the reader with factual information to demonstrate that the use of MDI compared to other agents used in CWP production processes does not pose increased inhalation exposure risks for workers. Personal and area air measurements were carried out at nine Composite Wood Panel plants throughout Europe to assess potential inhalation exposures to MDI and wood dust as Total Inhalable Particulates (TIP). In total, 446 pairs of samples were collected for MDI and TIP of which 283 pairs were personal samples and the remaining 163 pairs were area samples collected at key locations along the production line. This data together with published formaldehyde exposure data has been used to evaluate the exposure safety margin opposite what are considered relevant occupational exposure limits. The methods used for sampling and analysing MDI and TIP are based on internationally accepted methods, i.e. MDHS 25/3 (or ISO 16702) for MDI, and MDHS 14/3 for TIP. The job functions with an increased exposure profile for TIP were the cleaners, drying operators and quality control staff, and for MDI, the cleaners and quality control staff. The areas with an increased exposure profile for TIP are the conveyor area from OSB blender to former area and the OSB press infeed, and for MDI the OSB weigh belt and OSB former bin area. The exposure safety margin opposite the selected exposure limits can be ranked as MDI>TIP>formaldehyde (high margin of safety to low margin of safety), indicating that the use of MDI also reduces the exposure risks to workers during production of CWP compared to formaldehyde. By reducing the airborne TIP concentrations, a respiratory

Prediction and assessment of flammability hazards associated with metered-dose inhalers containing flammable propellants.

PubMed

Dalby, R N

1992-05-01

Several potential replacements for chlorofluorocarbons (CFCs) in metered-dose inhalers (MDIs) are flammable. The flammability hazard associated with their use was assessed using a range of MDIs containing 0-100% (w/w) n-butane (flammable) in HFC-134a (non-flammable) fitted with either 25-, 63-, or 100-microliters metering valves or continuous valves. In flame projection tests each MDI was fired horizontally into a flame, and the ignited flume length emitted from the MDI was measured. Flame projections of greater than or equal to 60 cm were produced by all formulations fitted with continuous valves which contained greater than or equal to 40% (w/w) n-butane in HFC-134a. Using metering valves the maximum flame projection obtained was 30 cm. This was observed with a formulation containing 90% (w/w) n-butane in HFC-134a and a 100-microliters valve. For a particular formulation, smaller metering valves produced shorter flame projections. Because many MDIs are used in conjunction with extension devices, the likelihood of accidental propellant vapor ignition was determined in Nebuhaler and Inspirease reservoirs and a Breathancer spacer. Ignition was predictable based on propellant composition, metered volume, number of actuations, and spacer capacity. Calculated n-butane concentrations in excess of the lower flammability limit [LFL; 1.9% (v/v)] but below the upper flammability limit [UFL; 8.5% (v/v)] were usually predictive of flammability following ignition by a glowing nichrome wire mounted inside the extension device. No ignition was predicted or observed following one or two 25-microliters actuations of 100% n-butane into large volume Nebuhaler (750 ml) or Inspirease (660 ml) devices.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of inhaler techniques employed by patients with respiratory diseases in southern Brazil: a population-based study*

PubMed Central

de Oliveira, Paula Duarte; Menezes, Ana Maria Baptista; Bertoldi, Andréa Dâmaso; Wehrmeister, Fernando César; Macedo, Silvia Elaine Cardozo

2014-01-01

OBJECTIVE: To identify incorrect inhaler techniques employed by patients with respiratory diseases in southern Brazil and to profile the individuals who make such errors. METHODS: This was a population-based, cross-sectional study involving subjects ≥ 10 years of age using metered dose inhalers (MDIs) or dry powder inhalers (DPIs) in 1,722 households in the city of Pelotas, Brazil. RESULTS: We included 110 subjects, who collectively used 94 MDIs and 49 DPIs. The most common errors in the use of MDIs and DPIs were not exhaling prior to inhalation (66% and 47%, respectively), not performing a breath-hold after inhalation (29% and 25%), and not shaking the MDI prior to use (21%). Individuals ≥ 60 years of age more often made such errors. Among the demonstrations of the use of MDIs and DPIs, at least one error was made in 72% and 51%, respectively. Overall, there were errors made in all steps in 11% of the demonstrations, whereas there were no errors made in 13%.Among the individuals who made at least one error, the proportion of those with a low level of education was significantly greater than was that of those with a higher level of education, for MDIs (85% vs. 60%; p = 0.018) and for DPIs (81% vs. 35%; p = 0.010). CONCLUSIONS: In this sample, the most common errors in the use of inhalers were not exhaling prior to inhalation, not performing a breath-hold after inhalation, and not shaking the MDI prior to use. Special attention should be given to education regarding inhaler techniques for patients of lower socioeconomic status and with less formal education, as well as for those of advanced age, because those populations are at a greater risk of committing errors in their use of inhalers. PMID:25410839

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.

Incidence of oral thrush in patients with COPD prescribed inhaled corticosteroids: Effect of drug, dose, and device.

PubMed

Dekhuijzen, P N Richard; Batsiou, Maria; Bjermer, Leif; Bosnic-Anticevich, Sinthia; Chrystyn, Henry; Papi, Alberto; Rodríguez-Roisin, Roberto; Fletcher, Monica; Wood, Lucy; Cifra, Alessandra; Soriano, Joan B; Price, David B

2016-11-01

Little information is available on real-life occurrence of oral thrush in COPD patients treated with ICS. We investigated oral thrush incidence in COPD patients prescribed FDC ICS/LABA therapies and assessed whether it is modulated by the ICS type, dose, and delivery device. We conducted a historical, observational, matched cohort study (one baseline year before and one outcome year after initiation of therapy) using data from the UK Optimum Patient Care Research Database. We assessed oral thrush incidence in patients initiating long-acting bronchodilators or FDC ICS/LABA therapy. We then compared different combination therapies (budesonide/formoterol fumarate dihydrate [BUD/FOR] and fluticasone propionate/salmeterol xinafoate [FP/SAL]) and devices (DPI and pMDI). Patients prescribed FDC ICS/LABA had significantly greater odds of experiencing oral thrush than those prescribed long-acting bronchodilators alone (adjusted OR 2.18 [95% CI 1.84-2.59]). Significantly fewer patients prescribed BUD/FOR DPI developed oral thrush compared with FP/SAL DPI (OR 0.77 [0.63-0.94]) when allowing for differences in prescribed doses between the drugs. A significantly smaller proportion of patients developed oral thrush in the FP/SAL pMDI arm than in the FP/SAL DPI arm (OR 0.67 [0.55-0.82]). Additionally, in the FP/SAL cohort (both DPI and pMDI), increased risk of oral thrush was significantly associated with high ICS daily dose (OR 1.97 [1.22-3.17] vs low daily dose). ICS use increases oral thrush incidence in COPD and this effect is dose-dependent for FP/SAL therapies. Of the therapies assessed, FP/SAL pMDI and BUD/FOR DPI may be more protective against oral thrush. Copyright © 2016 Elsevier Ltd. All rights reserved.

Reverse water-in-fluorocarbon emulsions for use in pressurized metered-dose inhalers containing hydrofluoroalkane propellants.

PubMed

Butz, N; Porté, C; Courrier, H; Krafft, M P; Vandamme, Th F

2002-05-15

Pulmonary administration of drugs has demonstrated numerous advantages in the treatment of pulmonary diseases due to direct targeting to the respiratory tract. It enables avoiding the first pass effect, reduces the amount of drugs administered, targets drugs to specific sites and reduces their side effects. Reverse water-in-fluorocarbon (FC) emulsions are potential drug delivery systems for pulmonary administration using pressurized metered-dose inhalers (pMDI). The external phase of these emulsions consists of perfluorooctyl bromide (PFOB, perflubron), whereas their internal phase contains the drugs solubilized or dispersed in water. These emulsions are stabilized by a perfluoroalkylated dimorpholinophosphate (F8H11DMP), i.e. a fluorinated surfactant. This study demonstrates the possibility of delivering a reverse fluorocarbon emulsion via the pulmonary route using a CFC-free pMDI. Two hydrofluoroalkanes (HFAs) (Solkane(R) 134a and Solkane(R) 227) were used as propellants, and various solution (or emulsion)/propellant ratios (1/3, 1/2, 2/3, 1/1, 3/2, 3/1 v/v) were investigated. The insolubility of water (with or without the fluorinated surfactant F8H11DMP) in both HFA 227 and HFA 134a was demonstrated. PFOB and the reverse emulsion were totally soluble or dispersible in all proportions in both propellants. This study demonstrated also that the reverse FC emulsion can be successfully used to deliver caffeine in a homogeneous and reproducible way. The mean diameter of the emulsion water droplets in the pressured canister was investigated immediately after packaging and after 1 week of storage at room temperature. Best results were obtained with emulsion/propellant ratios comprised between 2/3 and 3/2, and with HFA 227 as propellant.

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.

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

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

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

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.

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

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

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

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

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

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.

[Persistence to treatment by type of inhaler device in patients with asthma and chronic obstructive pulmonary disease].

PubMed

Sicras, A; Ferrer, V; Collar, J M; Navarro, R; Sáez, M

To assess the initial treatment persistence with inhaled corticosteroids and long-acting beta-2 adrenergic bronchodilators (ICS/LABA) depending on the inhaler device used (pMDI or DPI), for the treatment of asthma and COPD. An multicenter observational study. Subjects in initial treatment with ICS/LABA during 2007-2011 were included, and a follow-up period of 3 years. 2 groups of study (asthma, COPD) and 2 subgroups were prepared according to the device type inhaler (pMDI or DPI). The main measurements were: sociodemographic, comorbidity, adherence (rate possession medication -RPM-), persistence, drugs, exacerbation rates, resources use, and their costs (direct and indirect costs). Multivariate methods were used for the variables correction, with significance level of P<.05. The study included 2,082 asthma patients (pMDI: N = 566, 27.2%; DPI = 1,516, 72.8%). Patients with MDI devices showed a higher degree of persistence (32.5 vs. 27.8%; P=.037), treatment adherence (RPM: 83.1 vs. 80.5%; P<.001), fewer exacerbations (17.7 vs. 24.9%; P=.001) and lower health care costs (2,583 vs. 2,938 EUR; P = 0.042). 1,418 patients with COPD also were analyzed (pMDI: N = 524, 41.9%; DPI: N = 824, 58.1%) were analyzed. Patients with MDI devices also showed a higher degree of persistence (31.5 vs. 24.8%; P=.005), treatment adherence (RPM: 83.3 vs. 80.1%; P= .001), less exacerbations (40.1 vs. 48.2%; P=.002) and lower health care costs (3,922 vs. 4,588 EUR; P=.021). pMDI devices (as ICS/LABA initial treatment) are associated with higher treatment persistence either in asthma or COPD, with lower exacerbation rates, and use of health resources and cost. Copyright © 2016 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

Real-Life Outcomes for Patients with Asthma Prescribed Spacers for Use with Either Extrafine- or Fine-Particle Inhaled Corticosteroids.

PubMed

Guilbert, Theresa W; Colice, Gene; Grigg, Jonathan; van Aalderen, Wim; Martin, Richard J; Israel, Elliot; Postma, Dirkje S; Roche, Nicolas; Phipatanakul, Wanda; Hillyer, Elizabeth V; Evans, Jennifer M; Dolovich, Myrna B; Price, David B

Spacers are often used with pressurized metered-dose inhalers (pMDIs) to eliminate the need for coordinating inhalation with actuation. To investigate the real-life effectiveness of spacers prescribed for use with either extrafine- or fine-particle inhaled corticosteroids (ICSs). This historical matched cohort study examined anonymous medical record data over 2 years (1-year baseline, 1-year outcome) for patients with asthma aged 12 to 80 years initiating ICSs by pMDI with or without prescribed spacer. We compared outcomes for spacer versus no-spacer arms, matched for key baseline and asthma-related characteristics, within 2 ICS cohorts: (1) extrafine-particle ICS (beclomethasone) and (2) fine-particle ICS (fluticasone). Effectiveness end points were compared using conditional regression methods. Matched spacer and no-spacer arms of the extrafine-particle ICS cohort each included 2090 patients (69% females; median age, 46-47 years) and the 2 arms of the fine-particle ICS cohort each included 444 patients (67% females; median age, 45 years). With extrafine-particle ICS, we observed no significant difference between spacer and no-spacer arms in severe exacerbation rate (primary end point): adjusted rate ratio, 1.01 (95% CI, 0.83-1.23). With fine-particle ICS, the severe exacerbation rate ratio with spacers was 0.77 (0.47-1.25). Oropharyngeal candidiasis incidence was low and similar in spacer and no-spacer arms for both ICS cohorts. We found no evidence that prescribed spacer devices are associated with improved asthma outcomes for extrafine- or fine-particle ICS administered by pMDI. These findings challenge long-standing assumptions that spacers should improve pMDI effectiveness and indicate the need for pragmatic trials of spacers in clinical practice. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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.

Effect of Pressurized Metered Dose Inhaler Spray Characteristics and Particle Size Distribution on Drug Delivery Efficiency.

PubMed

Yousefi, Morteza; Inthavong, Kiao; Tu, Jiyuan

2017-10-01

A key issue in pulmonary drug delivery is improvement of the delivery device for effective and targeted treatment. Pressurized metered dose inhalers (pMDIs) are the most popular aerosol therapy device for treating lung diseases. This article studies the effect of spray characteristics: injection velocity, spray cone angle, particle size distribution (PSD), and its mass median aerodynamic diameter (MMAD) on drug delivery. An idealized oral airway geometry, extending from mouth to the main bronchus, was connected to a pMDI device. Inhalation flow rates of 15, 30, and 60 L/min were used and drug particle tracking was a one-way coupled Lagrangian model. The results showed that most particles deposited in the pharynx, where the airway has a reduced cross-sectional area. Particle deposition generally decreased with initial spray velocity and with increased spray cone angle for 30 and 60 L/min flow rates. However, for 15 L/min flow rate, the deposition increased slightly with an increase in the spray velocity and cone angle. The effect of spray cone angle was more significant than the initial spray velocity on particle deposition. When the MMAD of a PSD was reduced, the deposition efficiency also reduces, suggesting greater rates of particle entry into the lung. The deposition rate showed negligible change when the MMAD was more than 8 μm. Spray injection angle and velocity change the drug delivery efficacy; however, the efficiency shows more sensitivity to the injection angle. The 30 L/min airflow rate delivers spray particles to the lung more efficiently than 15 and 60 L/min airflow rate, and reducing MMAD can help increase drug delivery to the lung.

Clinical outcome associated with the use of different inhalation method with and without humidification in asthmatic mechanically ventilated patients.

PubMed

Moustafa, Islam O F; ElHansy, Muhammad H E; Al Hallag, Moataz; Fink, James B; Dailey, Patricia; Rabea, Hoda; Abdelrahim, Mohamed E A

2017-08-01

Inhaled-medication delivered during mechanical-ventilation is affected by type of aerosol-generator and humidity-condition. Despite many in-vitro studies related to aerosol-delivery to mechanically-ventilated patients, little has been reported on clinical effects of these variables. The aim of this study was to determine effect of humidification and type of aerosol-generator on clinical status of mechanically ventilated asthmatics. 72 (36 females) asthmatic subjects receiving invasive mechanical ventilation were enrolled and assigned randomly to 6 treatment groups of 12 (6 females) subjects each received, as possible, all inhaled medication using their assigned aerosol generator and humidity condition during delivery. Aerosol-generators were placed immediately after humidifier within inspiratory limb of mechanical ventilation circuit. First group used vibrating-mesh-nebulizer (Aerogen Solo; VMN) with humidification; Second used VMN without humidification; Third used metered-dose-inhaler with AeroChamber Vent (MDI-AV) with humidification; Forth used MDI-AV without humidification; Fifth used Oxycare jet-nebulizer (JN) with humidification; Sixth used JN without humidification. Measured parameters included clinical-parameters reflected patient response (CP) and endpoint parameters e.g. length-of-stay in the intensive-care-unit (ICU-days) and mechanical-ventilation days (MV-days). There was no significant difference between studied subjects in the 6 groups in baseline of CP. VMN resulted in trend to shorter ICU-days (∼1.42days) compared to MDI-AV (p = 0.39) and relatively but not significantly shorter ICU-days (∼0.75days) compared JN. Aerosol-delivery with or without humidification did not have any significant effect on any of parameters studied with very light insignificant tendency of delivery at humid condition to decrease MV-days and ICU-days. No significant effect was found of changing humidity during aerosol-delivery to ventilated-patient. VMN to deliver

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

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...

Methylene Diphenyl Diisocyanate (monomeric MDI) and polymeric MDI (PMDI)

Integrated Risk Information System (IRIS)

TOXICOLOGICAL REVIEW of METHYLENE DIPHENYL DIISOCYANATE ( MDI ) ( CAS No . 101 - 68 - 8 and 9016 - 87 - 9 ) In Support of Summary Information on the Integrated Risk Information System ( IRIS ) February 1998 U.S . ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , DC TABLE OF CONTENTS TOXICOLOGICAL REV

MDI Exposure for Spray-On Truck Bed Lining.

PubMed

Lofgren, Don J; Walley, Terry L; Peters, Phillip M; Weis, Marty L

2003-10-01

Worker exposure to MDI (methylenediphenyl isocyanate) in the sprayed-on truck bed lining industry was assessed by examining Washington State OSHA inspection files and industrial insurance records. The industry uses MDI to form a protective urethane coating on pick-up truck beds. The lining is applied by a worker using a handheld spray gun with application equipment at temperatures and pressures specified by the urethane supplier. Inspections with MDI sampling were initially identified by searching the agency's laboratory database and were further screened for the targeted process. Data for 13 employers was found and extracted from the inspection records. All were small companies with only 1 to 2 workers exposed to MDI; 10 of the 13 employers had started the bed lining service within the last 4 years. The process was found in truck bed lining specialty shops as well as in other truck-related businesses. Six different urethane products were used with reported MDI monomer concentrations of up to 75 percent along with varying concentrations of MDI pre-polymers and other reactants and solvents. Sampling for MDI by inspectors found 7 worksites with worker exposure in excess of the state and OSHA ceiling limit of 0.200 mg/M(3). Deficiencies in respirator programs and engineering controls for MDI were cited. A review of the industrial insurance records found a total of five MDI-related claims at 4 inspected worksites, two for new-onset asthma. It was concluded that workers in the urethane sprayed-on truck bed lining industry are at an increased risk of developing illnesses associated with isocyanate exposure. Interventions are needed to further assess the hazard as well as motivate and assist franchisers, distributors, and retailers to implement effective engineering controls and respiratory protection programs in this nationally emerging small employer industry.

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

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.

Exposure to 4,4'-methylenediphenyl diisocyanate (MDI) during moulding of rigid polyurethane foam: determination of airborne MDI and urinary 4,4'-methylenedianiline (MDA).

PubMed

Kääriä, K; Hirvonen, A; Norppa, H; Piirilä, P; Vainio, H; Rosenberg, C

2001-04-01

Occupational exposure to 4,4'-methylenediphenyl diisocyanate (MDI) was measured during moulding of rigid polyurethane foam. The aim of the study was to find out whether an MDI-derived urinary amine metabolite could be detected in the urine of workers exposed to apparently low levels of MDI. Airborne MDI was sampled on 1-(2-methoxyphenyl)-piperazine (2MP)-impregnated glass fibre filters and determined by high-performance liquid chromatography (HPLC) using ultraviolet (UV) and electrochemical (EC) detection. The limit of detection of MDI was 3 ng ml-1 for a 20 microliters injection. The precision of sample preparation, expressed as relative standard deviation (RSD), was 1.3% with UV detection and 2.1% with EC detection at a concentration of 70 ng MDI ml-1 (n = 6). The 2MP-MDI derivative was stable at +4 degrees C up to eight weeks. The accuracy of the method was validated in an international quality control programme. Workers (n = 57) from three different factories participated in the study. Urinary 4,4'-methylenedianiline (MDA) metabolite was determined after acid hydrolysis as heptafluorobutyric anhydride derivatives by gas chromatography-mass spectrometry using chemical ionisation and monitoring negative ions. The limit of detection in urine was 0.2 nmol l-1. The precision of six analyses for a urine sample spiked to a concentration of 1 nmol l-1 was 29% (RSD). The MDI concentrations were below the limit of detection in most (64%) of the air samples collected in the worker's breathing zone. Still, detectable amounts of MDA were found in 97% of the urine samples. Monitoring of urinary MDA appears to be an appropriate method of assessing MDI exposure in work environments with low or undetectable MDI concentrations in the workplace air.

MDI: integrity index of cytoskeletal fibers observed by AFM

NASA Astrophysics Data System (ADS)

Manghi, Massimo; Bruni, Luca; Croci, Simonetta

2016-06-01

The Modified Directional Index (MDI) is a form factor of the angular spectrum computed from the 2D Fourier transform of an image marking the prevalence of rectilinear features throughout the picture. We study some properties of the index and we apply it to AFM images of cell cytoskeleton regions featuring patterns of rectilinear nearly parallel actin filaments as in the case of microfilaments grouped in bundles. The analysis of AFM images through MDI calculation quantifies the fiber directionality changes which could be related to fiber damages. This parameter is applied to the images of Hs 578Bst cell line, non-tumoral and not immortalized human epithelial cell line, irradiated with X-rays at doses equivalent to typical radiotherapy treatment fractions. In the reported samples, we could conclude that the damages are mainly born to the membrane and not to the cytoskeleton. It could be interesting to test the parameter also using other kinds of chemical or physical agents.

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.

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.

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.

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.

Tracked Active Region Patches for MDI and HMI

NASA Astrophysics Data System (ADS)

Turmon, Michael; Hoeksema, J. Todd; Bobra, Monica

2014-06-01

We describe tracked active-region patch data products that have been developed for HMI (HMI Active Region Patches, or HARPs) and for MDI (MDI Tracked Active Region Patches, or MDI TARPs). Both data products consist of tracked magnetic features on the scale of solar active regions. The now-released HARP data product covers 2010-present (>2000 regions to date). Like the HARPs, the MDI TARP data set is a catalog of active regions (ARs), indexed by a region ID number, analogous to a NOAA AR number, and time. The TARPs contain 6170 regions spanning 72000 images taken over 1996-2010, and will be availablein the MDI resident archive (RA).MDI TARPs are computed based on the 96-minute synoptic magnetograms and intensitygrams. As with the related HARP data product, the approximate threshold for significance is 100G. Use of both image types together allows faculae and sunspots to be separated out as sub-classes of activity, in addition to identifying the overall active region that they are in. After being identified in single images, the magnetically-active patches are grouped and tracked from image to image. Merges among growing active regions, as well as faint active regions hovering at the threshold of detection, are handled automatically. Regions are tracked from their inception until they decay within view, or transit off the visible disk. For each active region and for each time, a bitmap image is stored containing the precise outline of the active region. Also, metadata such as areas and integrated fluxes are stored for each AR and for each time. Because there is a cross-calibration between the HMI and MDI magnetograms (Liu et al. 2012), it is straightforward to use the same classification and tracking rules for the HMI HARPs and the MDI TARPs. We show results demonstrating region correspondence, region boundary agreement, and agreement of flux metadata using the approximately 140 regions in the May 2010-October 2010 time period. We envision several uses for these data

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.

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.

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

PubMed

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

2016-10-17

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

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;�

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

Discriminating Ability of Abbreviated Impactor Measurement Approach (AIM) to Detect Changes in Mass Median Aerodynamic Diameter (MMAD) of an Albuterol/Salbutamol pMDI Aerosol.

PubMed

David Christopher, J; Patel, Rajni B; Mitchell, Jolyon P; Tougas, Terrence P; Goodey, Adrian P; Quiroz, Jorge; Andersson, Patrik U; Lyapustina, Svetlana

2017-11-01

This article reports on results from a two-lab, multiple impactor experiment evaluating the abbreviated impactor measurement (AIM) concept, conducted by the Cascade Impaction Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of this experiment was to expand understanding of the performance of an AIM-type apparatus based on the Andersen eight-stage non-viable cascade impactor (ACI) for the assessment of inhalation aerosols and sprays, compared with the full-resolution version of that impactor described in the pharmacopeial compendia. The experiment was conducted at two centers with a representative commercially available pressurized metered dose inhaler (pMDI) containing albuterol (salbutamol) as active pharmaceutical ingredient (API). Metrics of interest were total mass (TM) emitted from the inhaler, impactor-sized mass (ISM), as well as the ratio of large particle mass (LPM) to small particle mass (SPM). ISM and the LPM/SPM ratio together comprise the efficient data analysis (EDA) metrics. The results of the comparison demonstrated that in this study, the AIM approach had adequate discrimination to detect changes in the mass median aerodynamic diameter (MMAD) of the ACI-sampled aerodynamic particle size distribution (APSD), and therefore could be employed for routine product quality control (QC). As with any test method considered for inclusion in a regulatory filing, the transition from an ACI (used in development) to an appropriate AIM/EDA methodology (used in QC) should be evaluated and supported by data on a product-by-product basis.

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.

Power spectra comparison between GOLF and spatially masked MDI velocity signals

NASA Astrophysics Data System (ADS)

Henney, C. J.; Ulrich, R. K.; Bertello, L.; Bogart, R. S.; Bush, R. I.; Scherrer, P. H.; Cortés, T. Roca; Turck-Chièze, S.

1999-08-01

The Global Oscillations at Low Frequency (GOLF) and the Michelson Doppler Imager (MDI) instruments aboard the Solar and Heliospheric Observatory (SOHO) give an excellent opportunity to search for solar low frequency oscillation modes previously undetected from ground based experiments. Presented here is a comparison of the velocity power spectra between the two instruments. In addition, this paper outlines work towards creating a GOLF-simulated signal utilizing MDI velocity images. The simulation of the GOLF signal is achieved by integrating spatially weighted masks with MDI full-disk Doppler images. The GOLF-simulated signal and a selection of additional spatially masked MDI velocity signals are compared with the observed GOLF signal for a 759 day period from May 25, 1996 through June 22, 1998. Ultimately, a cross-analysis process between GOLF and MDI signals could lead to an enhancement of our ability to detect low frequency solar oscillations. For low degree (l<= 3) and low frequency acoustic modes, the signal-to-background ratio between GOLF and the spatially masked MDI velocity data is compared here.

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

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.

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.

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.

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.

Development of the Muscle Dysmorphia Inventory (MDI).

PubMed

Rhea, D J; Lantz, C D; Cornelius, A E

2004-12-01

The development of the 6-factor, 27-item Muscle Dysmorphia Inventory (MDI) was based on Lantz et al. proposed model of characteristics associated with Muscle Dysmorphia. quantitative procedures including item-to-total correlations, exploratory and confirmatory factor analyses, and structure equation modeling confirmed the construct validity of the scale. Convergent validity was also tested. bodybuilding and powerlifting competition venues, weight training facilities, and university athletic venues. the 1(st) study consisted of 77 experienced male free weight lifters. The 2(nd) study consisted of 156 male non-competitive bodybuilders and weight lifters and 168 elite level powerlifters and bodybuilders. The 3(rd) study consisted of 151 male and female bodybuilders and weight lifters. each participant completed demographic information, the MDI, Drive for Thinness subscale of the Eating Disorder Inventory, and the Training Dependency subscale of the Bodybuilding Dependence Scale. Reliability estimates (Cronbach's a) ranged from 0.72 to 0.94. Factor loadings in all 3 studies supported the 6-factor structure (size/symmetry, supplement use, exercise dependence, pharmacological use, dietary behavior, and physique protection). Much of the scale validation was focused on construct validity, however, correlations with the MDI's subscales and the Training Dependency subscale of the Bodybuilding Dependence Scale and the Drive for Thinness subscale of the Eating Disorder Inventory provided evidence of convergent validity also. From these preliminary results, the MDI appears to contribute to the identification of a newly formed disorder by offering a multi-dimensional measure of factors related to Muscle Dysmorphia.

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

40 CFR 721.10298 - MDI terminated polyester polyurethane polymer (generic).

Code of Federal Regulations, 2014 CFR

2014-07-01

... polymer (generic). 721.10298 Section 721.10298 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.10298 MDI terminated polyester polyurethane polymer (generic). (a... generically as MDI terminated polyester polyurethane polymer (P-11-662) is subject to reporting under this...

40 CFR 721.10298 - MDI terminated polyester polyurethane polymer (generic).

Code of Federal Regulations, 2013 CFR

2013-07-01

... polymer (generic). 721.10298 Section 721.10298 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.10298 MDI terminated polyester polyurethane polymer (generic). (a... generically as MDI terminated polyester polyurethane polymer (P-11-662) is subject to reporting under this...

40 CFR 721.10298 - MDI terminated polyester polyurethane polymer (generic).

Code of Federal Regulations, 2012 CFR

2012-07-01

... polymer (generic). 721.10298 Section 721.10298 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.10298 MDI terminated polyester polyurethane polymer (generic). (a... generically as MDI terminated polyester polyurethane polymer (P-11-662) is subject to reporting under this...

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.

Studies on the bronchodilator, tremorogenic, cardiovascular and hypokalaemic effects of fenoterol dry powder in asthma.

PubMed Central

Bauer, K G; Kaik, B; Sertl, K; Kaik, G A

1993-01-01

1. The airway and tremor response and cardiovascular and hypokalaemic effects of single and cumulative doses of fenoterol given by dry powder capsules (DPC) and by metered dose inhaler (MDI) were studied in asthmatics in two randomized, crossover trials. 2. Single doses of fenoterol DPC and MDI (0.2 mg, 0.4 mg), investigated in 24 subjects, produced similar, dose-dependent increases in FEV1. Fenoterol DPC caused less tremor response and less hypokalaemic effects than fenoterol MDI. 3. Cumulative doses of fenoterol DPC and MDI (0.2, 0.6, 1.4, 3.0, 6.2 mg), investigated in 12 subjects, produced a comparable bronchodilatation (mean maximum increase in FEV1 was 0.53 +/- 0.06/0.52 +/- 0.081 for DPC/MDI) and a similar, dose-dependent rise in heart rate (35 +/- 3.81/41 +/- 2.25 beats min(-1)). The rise in tremor and the fall in plasma potassium were smaller after DPC than after MDI. The mean maximum changes were 51.58 +/- 6.41/95.83 +/- 6.75 cm s(-2) for tremor and -0.68 +/- 0.09/-0.96 +/- 0.10 mmol l(-1) for potassium. 4. Our findings may result from a difference in the pharmacokinetics of the dry powder and the aerosol formulation, particularly differences in distribution and absorption. 5. In conclusion, fenoterol DPC used in low therapeutic doses (0.2,0.4 mg), is preferable to the MDI. Fenoterol DPC used as rescue medication in high cumulative doses, do not suggest a greater safety margin than the MDI and the same restrictions should be considered for the fenoterol dry powder formulation as suggested for the MDI. PMID:12959305

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

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...

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...

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

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

Measurements of airborne methylene diphenyl diisocyanate (MDI) concentration in the U.S. workplace.

PubMed

Booth, Karroll; Cummings, Barbara; Karoly, William J; Mullins, Sharon; Robert, William P; Spence, Mark; Lichtenberg, Fran W; Banta, J

2009-04-01

This article summarizes a large body of industry air sampling data (8134 samples) in which airborne MDI concentrations were measured in a wide variety of manufacturing processes that use either polymeric MDI (PMDI) or monomeric (pure) MDI. Data were collected during the period 1984 through 1999. A total of 606 surveys were conducted for 251 companies at 317 facilities. The database includes 3583 personal (breathing zone) samples and 4551 area samples. Data demonstrate that workplace airborne MDI concentrations are extremely low in a majority of the manufacturing operations. Most (74.6%) of the airborne MDI concentrations measured in the personal samples were nondetectable, i.e., below the limits of quantification (LOQs). A variety of validated industrial hygiene sampling/analytical methods were used for data collection; most are modifications of OSHA Method 47. The LOQs for these methods ranged from 0.1-0.5 microg/sample. The very low vapor pressures of both monomeric MDI and PMDI largely explain the low airborne concentrations found in most operations. However, processes or applications in which the chemical is sprayed or heated may result in higher airborne concentrations and higher exposure potentials if appropriate control measures are not implemented. Data presented in this article will be a useful reference for employers in helping them to manage their health and safety program as it relates to respiratory protection during MDI/PMDI applications.

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.

The mitochondrial outer membrane protein MDI promotes local protein synthesis and mtDNA replication.

PubMed

Zhang, Yi; Chen, Yong; Gucek, Marjan; Xu, Hong

2016-05-17

Early embryonic development features rapid nuclear DNA replication cycles, but lacks mtDNA replication. To meet the high-energy demands of embryogenesis, mature oocytes are furnished with vast amounts of mitochondria and mtDNA However, the cellular machinery driving massive mtDNA replication in ovaries remains unknown. Here, we describe a Drosophila AKAP protein, MDI that recruits a translation stimulator, La-related protein (Larp), to the mitochondrial outer membrane in ovaries. The MDI-Larp complex promotes the synthesis of a subset of nuclear-encoded mitochondrial proteins by cytosolic ribosomes on the mitochondrial surface. MDI-Larp's targets include mtDNA replication factors, mitochondrial ribosomal proteins, and electron-transport chain subunits. Lack of MDI abolishes mtDNA replication in ovaries, which leads to mtDNA deficiency in mature eggs. Targeting Larp to the mitochondrial outer membrane independently of MDI restores local protein synthesis and rescues the phenotypes of mdi mutant flies. Our work suggests that a selective translational boost by the MDI-Larp complex on the outer mitochondrial membrane might be essential for mtDNA replication and mitochondrial biogenesis during oogenesis. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

TPP-dendrimer nanocarriers for siRNA delivery to the pulmonary epithelium and their dry powder and metered-dose inhaler formulations.

PubMed

Bielski, Elizabeth; Zhong, Qian; Mirza, Hamad; Brown, Matthew; Molla, Ashura; Carvajal, Teresa; da Rocha, Sandro R P

2017-07-15

The regulation of genes utilizing the RNA interference (RNAi) mechanism via the delivery of synthetic siRNA has great potential in the treatment of a variety of lung diseases. However, the delivery of siRNA to the lungs is challenging due to the poor bioavailability of siRNA when delivered intraveneously, and difficulty in formulating and maintaining the activity of free siRNA when delivered directly to the lungs using inhalation devices. The use of non-viral vectors such as cationic dendrimers can help enhance the stability of siRNA and its delivery to the cell cytosol. Therefore, in this work, we investigate the ability of a triphenylphosphonium (TPP) modified generation 4 poly(amidoamine) (PAMAM) dendrimer (G4NH 2 -TPP) to enhance the in vitro transfection efficiency of siRNA in a model of the pulmonary epithelium and their aerosol formulations in pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). Complexes of siRNA and G4NH 2 -TPP were prepared with varying TPP densities and increasing N/P ratios. The complexation efficiency was modulated by the presence of the TPP on the dendrimer surface, allowing for a looser complexation compared to unmodified dendrimer as determined by gel electrophoresis and polyanion competition assay. An increase in TPP density and N/P ratio led to an increase in the in vitro gene knockdown of stably green fluorescent protein (eGFP) expressing lung alveolar epithelial (A549) cells. G4NH 2 -12TPP dendriplexes (G4NH 2 PAMAM dendrimers containing 12 TPP molecules on the surface complexed with siRNA) at N/P ratio 30 showed the highest in vitro gene knockdown efficiency. To assess the potential of TPP-dendriplexes for pulmonary use, we also developed micron particle technologies for both pMDIs and DPIs and determined their aerosol characteristics utilizing an Andersen Cascade Impactor (ACI). Mannitol microparticles encapsulating 12TPP-dendriplexes were shown to be effective in producing aerosols suitable for deep lung

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.

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...

Age-specific inhalation radiation dose commitment factors for selected radionuclides

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

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

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

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

Influences of the Ratio of Polyol and MDI on the Acoustic Parameters of Polyurethane

NASA Astrophysics Data System (ADS)

Wang, Yonghua; Liu, Zheming; Wu, Haiquan; Zhang, Chengchun; Yu, Huadong; Ren, Luquan; Ichchou, Mohamed

2018-05-01

In this paper, the influence of different ratio of polyol and MDI on the absorption coefficient and acoustic parameters of polyurethane was studied. Ratio of 100:40 and 100:45 show the best sound absorption performance, and the change trend of transmission loss and sound absorption coefficient are opposite. The flow resistance increased with the increasing of the ratio of polyol and MDI, the greater the flow resistance, the worse the high frequency sound absorption property of the polyurethane. When the ratio of polyol and MDI keep 100:45, the minimum porosity of sample, the polyurethane porosity increase with the ratio of polyol and MDI increase.

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.

Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry

EPA Pesticide Factsheets

EPA's methodology for estimation of inhalation reference concentrations (RfCs) as benchmark estimates of the quantitative dose-response assessment of chronic noncancer toxicity for individual inhaled chemicals.

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 ...

From dust to dose: Effects of forest disturbance on increased inhalation exposure.

PubMed

Whicker, Jeffrey J; Pinder, John E; Breshears, David D; Eberhart, Craig F

2006-09-15

Ecosystem disturbances that remove vegetation and disturb surface soils are major causes of excessive soil erosion and can result in accelerated transport of soils contaminated with hazardous materials. Accelerated wind erosion in disturbed lands that are contaminated is of particular concern because of potential increased inhalation exposure, yet measurements regarding these relationships are lacking. The importance of this was highlighted when, in May of 2000, the Cerro Grande fire burned over roughly 30% of Los Alamos National Laboratory (LANL), mostly in ponderosa pine (Pinus ponderosa) forest, and through areas with soils containing contaminants, particularly excess depleted and natural uranium. Additionally, post-fire thinning was performed in burned and unburned forests on about 25% of LANL land. The first goal of this study was to assess the potential for increased inhalation dose from uranium contaminated soils via wind-driven resuspension of soil following the Cerro Grande Fire and subsequent forest thinning. This was done through analysis of post-disturbance measurements of uranium air concentrations and their relationships with wind velocity and seasonal vegetation cover. We found a 14% average increase in uranium air concentrations at LANL perimeter locations after the fire, and the greatest air concentrations occurred during the months of April-June when wind velocities are highest, no snow cover, and low vegetation cover. The second goal was to develop a methodology to assess the relative contribution of each disturbance type towards increasing public and worker exposure to these resuspended soils. Measurements of wind-driven dust flux in severely burned, moderately burned, thinned, and unburned/unthinned forest areas were used to assess horizontal dust flux (HDF) in these areas. Using empirically derived relationships between measurements of HDF and respirible dust, coupled with onsite uranium soil concentrations, we estimate relative increases in

Methylene Diphenyl Diisocyanate (MDI) And Related Compounds

EPA Pesticide Factsheets

This document addresses the use of methylene diphenyl diisocyanate (MDI) and related compounds (See Appendix 1) in products that may result in consumer and general population exposures, particularly in or around buildings, including homes and schools.

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

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.

Effects of Known Determinants on Methylene Bisphenyl Isocyanate (MDI) Concentration During Spray-On Truck Bed-Lining Processes.

PubMed

Schaal, Nicholas C; Brazile, William J; Finnie, Katie L; Tiger, James P

2017-08-01

Occupational exposure to methylene bisphenyl isocyanate (MDI) presents serious worker health concerns as it may lead to short- and long-term health effects such as asthma, airway irritation, hypersensitivity pneumonitis, and irritation of skin and mucous membranes. While studies of worker isocyanate exposures during vehicle painting activities are widespread, few studies have investigated the spray-on truck bed-liner (STBL) industry. The purpose of this study was to determine the effectiveness of several ventilation system variables and process characteristics in controlling MDI concentrations in the STBL industry. A total of 47 personal air samples were collected for MDI during 18 site visits at nine STBL companies in Colorado and Wyoming. Ventilation system and process characteristics that were assessed included: ventilation system face velocity, airflow, air changes per minute (AC/M), capture velocity, percent of MDI in bed-liner product, application temperature, application pressure, paint booth temperature, paint booth relative humidity, paint booth volume, and quantity of bed-liner product applied. Pearson correlation revealed percentage of MDI in bed-liner product (r = 0.557, n = 14, P < 0.05) and process temperature (r = 0.677, n = 14, P < 0.05) had high positive correlation with MDI concentration. Ventilation system face velocity (r = -0.578, n = 14, P < 0.05) and AC/M (r = -0.657, n = 14, P < 0.05) had high negative correlation with MDI concentration while airflow (r = -0.475, n = 14, P < 0.05) and capture velocity (r = -0.415, n = 14, P = 0.07) had moderate negative correlation with MDI concentration. Multiple linear regression revealed process temperature and capture velocity made a statistically significant and unique contribution in estimating MDI concentration (F (2, 11) = 10.99, P < 0.05) with an adjusted R2 of 0.61, explaining 61% of the variability in MDI concentration. This investigation contributed to an understudied STBL industry by targeting

Can patients with asthma feel inhaler therapy working right away? Two clinical trials testing the effect of timing of assessment on patient perception.

PubMed

Leidy, Nancy Kline; Gutierrez, Benjamin; Lampl, Kathy; Uryniak, Tom; O'Brien, Christopher D

2009-12-01

Feeling a maintenance therapy work right away may provide positive reinforcement and may offer one way to improve adherence in patients with asthma. Precise measurement is required to accurately compare the presence of this effect across clinical trial treatment groups. Two randomized, controlled studies tested whether timing of assessment (daily vs weekly, study 1; and predose vs postdose, study 2) influenced patients' reports of whether they can feel a medication working right away (perception), and their satisfaction with this perception (satisfaction). These 2-week US-based multicenter double-blind, parallel-group studies included patients > or = 18 years of age with mild to moderate persistent asthma. In each, patients were randomized to one of two drugs with different onset profiles: budesonide/formoterol pressurized metered-dose inhaler (pMDI) 80/4.5 microg x 2 inhalations (160/9 microg) twice daily or budesonide pMDI 80 microg x 2 inhalations (160 microg) twice daily. Patients were further randomized to complete previously validated perception and satisfaction questions in a cross-over fashion, either daily and weekly (N = 123) or predose and postdose (N = 134). Patient surveys also assessed perceptions of the onset of effect of medication and their value of these perceptions. No significant differences were observed in patients' reports of perception, either daily versus weekly or predose versus postdose. A statistically significant difference in satisfaction was found in study 1 only, favoring weekly recall (p < 0.05), with sensitivity analysis showing no difference by treatment group (p = 0.162). Across both studies, most patients (87%) who perceived their inhaler working right away (136 of 157 patients) identified positive airway sensations. Most patients reported that feeling their medication work right away is reassuring and would help them manage their asthma. Assessment timing has no effect on patient response to the perception of feeling a

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, ...

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.

MDI 301, a nonirritating retinoid, improves abrasion wound healing in damaged/atrophic skin

PubMed Central

Warner, Roscoe L.; Bhagavathula, Narasimharao; Nerusu, Kamalakar; Hanosh, Andrew; McClintock, Shannon D.; Naik, Madhav K.; Johnson, Kent J.; Ginsburg, Isaac; Varani, James

2010-01-01

MDI 301 is a picolinic acid-substituted ester of 9-cis retinoic acid. It has been shown in the past that MDI 301 increases epidermal thickness, decreases matrix metalloproteinase (MMP) activity, and increases procollagen synthesis in organ-cultured human skin. Unlike all-trans retinoic acid (RA), MDI 301 does not induce expression of proinflammatory cytokines or induce expression of leukocyte adhesion molecules in human skin. In the present study we examined topical MDI 301 treatment for ability to improve the structure and function of skin in three models of skin damage in rodents and for ability to improve abrasion wound healing in these models. MDI 301 was applied daily to the skin of rats treated with the potent corticosteroid, clobetasol propionate, to the skin of diabetic rats (8 weeks posttreatment with streptozotocin) and to the skin of aged (14–16-month-old) rats. In all three models, subsequently induced abrasion wounds healed more rapidly in the retinoid-treated animals than in vehicle-treated controls. Immediately after complete wound closure, tissue from the wound site (as well as from a control site) was put into organ culture and maintained for 3 days. At the end of the incubation period, culture fluids were assessed for soluble type I collagen and for MMPs-2 and -9. In all three models, the level of type I collagen was increased and MMP levels were decreased by MDI 301. In all three models, skin irritation during the retinoid-treatment phase was virtually nonexistent. PMID:18211583

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...

The nature of the MDI/wood bond

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

Marcinko, J.J.; Phanopoulos, C.; Newman, W.H.

1995-12-01

Polymeric diphenylmethane diisocyanate (pMDI) binders have been used in the wood composite industry for 20 years. Almost one half of the oriented strand board (OSB) manufactures in North America are taking advantage of its processing speed and superior board performance. MDI`s current use in Strandboard, MDF (medium density fiber board), LVL (laminated veneer lumber), Plywood, and Particleboard is wide spread. A fundamental understanding of the role of MIDI as a binder in these complex composites is essential for further processing optimization. Experimental data is presented which investigates the nature of the chemical bonding in wood composites. Solid state nuclear magneticmore » resonance (NMR) data is combined with data from thermal analysis and fluorescence microscopy to investigate the chemistry, penetration, and morphology of the isocyanate/wood interphase. Structure property relationships are developed and related to composite performance. The study contrasts isocyanate and phenol formaldehyde binder systems.« less

Design and Development of a Salbutamol Intake Detector for Low Respiratory Treatment

NASA Astrophysics Data System (ADS)

Vui Hin, Tsen; Ilyani Ramli, Nur

2017-08-01

This paper proposed a new salbutamol intake detector design using asthma spacer and gas sensor. The device enable real time monitoring of propellant level inhaled by the infant which will decrease the recovery time of the asthma attack. Microcontroller Arduino UNO is program to control the input and output of the system. MQ6 gas sensor detecting the propellant Hydrofluoroalkane from the metered dose inhaler (MDI) canister and demonstrated the level of propellant inhaled on the LCD in real time. MQ6 gas sensor suitable used to detect concentration of propellant inside the asthma spacer due to it is low sensitive to natural gas where include the carbon dioxide exhaled by the infant. Besides this, MQ6 gas sensor also highly sensitive to propane and the preview aerosol inventor mentioned propane as propellant which used for MDI to push the salbutamol out from MDI canister. Therefore, MQ6 gas sensor is suitable to detect propellant inside asthma spacer. The output voltage of MQ6 in initial state where no propellant inside asthma spacer is between 0.55V and 0.65V. Furthermore, when the MDI canister is been pressed, the concentration of propellant is increased and the output voltage of MQ6 gas sensor also increased in ranged between 1.1V and 1.2V.

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

The in vitro and in vivo investigation of a novel small chamber dry powder inhalation delivery system for preclinical dosing to rats.

PubMed

Sellers, Shari; Horodnik, Walter; House, Aileen; Wylie, Jennifer; Mauser, Peter; Donovan, Brent

2015-01-01

This research describes a novel "minitower" dry powder delivery system for nose-only delivery of dry powder aerosols to spontaneously breathing rats. The minitower system forces pressurized air through pre-filled capsules to deliver aerosolized drug to four nose ports; three of which house spontaneously breathing rats, with the fourth used as a control. Within each port are vent filters which capture drug that was not inhaled for further quantitation. These vent filters along with a novel control system referred to as the "artificial rat lung", allow for the theoretical amount of drug delivered and subsequently inhaled by each rat to be calculated. In vitro and in vivo studies have demonstrated this system's ability to deliver aerosolized drug to rats. The in vitro study showed that ∼30% of the starting dose reached the 4 ports and was available for inhalation. During in-vivo studies, rats inhaled ∼34% of the delivered dose. Of the estimated inhaled dose, 12-18% was detectable in the various tissue samples, with over 30% of the recovered dose found in the rat's lungs. Results show that this system is capable of reproducibly delivering drug to the lungs of spontaneously breathing rats. Advantages over current delivery methods include being amenable to the administration of multiple doses and using less (milligram) amount of starting material. In addition, this technique avoids anesthesia which is typically required for instillation or insufflation, and thus has the potential as an efficient and noninvasive aerosol delivery method for preclinical drug development.

Reliability of the MDi Psoriasis® Application to Aid Therapeutic Decision-Making in Psoriasis.

PubMed

Moreno-Ramírez, D; Herrerías-Esteban, J M; Ojeda-Vila, T; Carrascosa, J M; Carretero, G; de la Cueva, P; Ferrándiz, C; Galán, M; Rivera, R; Rodríguez-Fernández, L; Ruiz-Villaverde, R; Ferrándiz, L

2017-09-01

Therapeutic decisions in psoriasis are influenced by disease factors (e.g., severity or location), comorbidity, and demographic and clinical features. We aimed to assess the reliability of a mobile telephone application (MDi-Psoriasis) designed to help the dermatologist make decisions on how to treat patients with moderate to severe psoriasis. We analyzed interobserver agreement between the advice given by an expert panel and the recommendations of the MDi-Psoriasis application in 10 complex cases of moderate to severe psoriasis. The experts were asked their opinion on which treatments were most appropriate, possible, or inappropriate. Data from the same 10 cases were entered into the MDi-Psoriasis application. Agreement was analyzed in 3 ways: paired interobserver concordance (Cohen's κ), multiple interobserver concordance (Fleiss's κ), and percent agreement between recommendations. The mean percent agreement between the total of 1210 observations was 51.3% (95% CI, 48.5-54.1%). Cohen's κ statistic was 0.29 and Fleiss's κ was 0.28. Mean agreement between pairs of human observers only, excluding the MDi-Psoriasis recommendations, was 50.5% (95% CI, 47.6-53.5%). Paired agreement between the recommendations of the MDi-Psoriasis tool and the majority opinion of the expert panel (Cohen's κ) was 0.44 (68.2% agreement). The MDi-Psoriasis tool can generate recommendations that are comparable to those of experts in psoriasis. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Inhaled corticosteroids in ventilated preterm neonates: a non-randomized dose-ranging study.

PubMed

Raghuram, Kamini; Dunn, Michael; Jangaard, Krista; Reilly, Maureen; Asztalos, Elizabeth; Kelly, Edmond; Vincer, Michael; Shah, Vibhuti

2018-05-07

Inhaled corticosteroids (ICS) offer targeted treatment for bronchopulmonary dysplasia (BPD) with minimal systemic effects compared to systemic steroids. However, dosing of ICS in the management of infants at high-risk of developing BPD is not well established. The objective of this study was to determine an effective dose of ICS for the treatment of ventilator-dependent infants to facilitate extubation or reduce fractional inspired oxygen concentration. Forty-one infants born at < 32 weeks gestational age (GA) or < 1250 g who were ventilator-dependent at 10-28 days postnatal age were included. A non-randomized dose-ranging trial was performed using aerosolized inhaled beclomethasone with hydrofluoralkane propellant (HFA-BDP). Four dosing groups (200, 400, 600 and 800 μg twice daily for 1 week) with 11, 11, 10 and 9 infants in each group, respectively, were studied. The primary outcome was therapeutic efficacy (successful extubation or reduction in FiO 2 of > 75% from baseline) in ≥60% of infants in the group. Oxygen requirements, complications and long-term neurodevelopmental outcomes were also assessed. The median age at enrollment was 22 (10-28) postnatal days. The primary outcome, therapeutic efficacy as defined above, was not achieved in any group. However, there was a significant reduction in post-treatment FiO 2 at a dose of 800 μg bid. No obvious trends were seen in long-term neurodevelopmental outcomes. Therapeutic efficacy was not achieved with all studied doses of ICS. A significant reduction in oxygen requirements was noted in ventilator-dependent preterm infants at 10-28 days of age when given 800 μg of HFA-BDP bid. Larger randomized trials of ICS are required to determine efficacy for the management of infants at high-risk for development of BPD. This clinical trial was registered retrospectively on clinicaltrials.gov. The registration number is NCT03503994 .

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

Metropolitan MDI workshop wisdom : project organization and outreach

DOT National Transportation Integrated Search

1999-03-01

In autumn of 1996 former Secretary of Transportation Federico Pena announced that New York, New Jersey, Connecticut, San Antonio, Phoenix and Seattle were chosen to participate in the Metropolitan Model Deployment Initiative (MDI) program. The progra...

Identification of factors involved in medication compliance: incorrect inhaler technique of asthma treatment leads to poor compliance

PubMed Central

Darbà, Josep; Ramírez, Gabriela; Sicras, Antoni; García-Bujalance, Laura; Torvinen, Saku; Sánchez-de la Rosa, Rainel

2016-01-01

Objective To identify the impact of delivery device of inhaled corticosteroids and long-acting β2-agonist (ICS/LABA) on asthma medication compliance, and investigate other factors associated with compliance. Materials and methods We conducted a retrospective and multicenter study based on a review of medical registries of asthmatic patients treated with ICS/LABA combinations (n=2,213) whose medical devices were either dry powder inhalers (DPIs, such as Accuhaler®, Turbuhaler®, and NEXThaler®) or pressurized metered-dose inhalers (pMDI). Medication compliance included persistence outcomes through 18 months and medication possession ratios. Data on potential confounders of treatment compliance such as asthma exacerbations, comorbidities, demographic characteristics, and health care resource utilization were also explored. Results The probability of asthma medication compliance in case of DPIs was lower compared to pMDIs, which suggests that inhaler devices influence inhalation therapies. There were additional confounding factors that were considered as explanatory variables of compliance. A worse measure of airflow obstruction (forced expiration volume in 1 second), comorbidities and general practitioner (GP) consultations more than once per month decreased the probability of compliance. Within comorbidities, alcoholism was positively associated with compliance. Patients of 29–39, 40–50, and 51–61 age groups or suffering from more than two exacerbations during the study period were more likely to comply with their medication regime. The effects of DPIs toward compliance varied with the different DPIs. For instance, Accuhaler® had a greater negative effect on compliance compared to Turbuhaler® and Nexthaler® in cases of patients who suffered exacerbations. We found that GP consultations reduced the probability of medication compliance for patients treated with formoterol/budesonide combination. For retired patients, visiting the GP increased the

A new penetration test method: protection efficiency of glove and clothing materials against diphenylmethane diisocyanate (MDI).

PubMed

Henriks-Eckerman, Maj-Len; Mäkelä, Erja

2015-03-01

Reported cases of allergic contact dermatitis caused by methylenediphenyl diisocyanate (MDI) have increased and thereby increased the need for adequate skin protection. Current standardized permeation and penetration test methods give information about efficacy of protective materials against individual components of the polyurethane systems. They do not give information of what kind of clothing materials workers should wear against splashes when handling mixed MDI-polyurethane formulations, which contain MDI, its oligomers, and polyols. The aim of this study was to develop and validate a sensitive penetration test method that can be used to select clothing that is protective enough against uncured splashes of MDI-polyurethane, still easy to use, and also, to find affordable glove materials that provide adequate protection during a short contact. The penetration of MDI through eight representative glove or clothing materials was studied with the developed test procedure. One MDI hardener and two polymeric MDI (PMDI)-polyol formulations representing different curing times were used as test substances. The materials tested included work clothing (woven) fabric, arm shields (nonwoven fabric), old T-shirt, winter gloves, and gloves of nitrile rubber, leather, vinyl (PVC), and natural rubber. A drop (50 µl) of test substance was added to the outer surface of the glove/clothing material, which had Tape Fixomull attached to the inner surface as a collection medium. After penetration times of 5 or 20min, the collecting material was removed and immediately immersed into acetonitrile containing 1-(2-methoxyphenyl)-piperazine for derivatization. The formed urea derivatives of 2,4'-MDI and 4,4'-MDI were analysed using liquid chromatography with mass spectrometric and UV detection. The precision of the test method was good for the material with high penetration (work clothing fabric) of MDI, as the relative standard deviation (RSD) was 14 and 20%. For the arm shield with a low

[Duration of bronchodilator effect of inhaled Salmeterol (dry powder x metered dose inhaler) in children with acute asthma attack].

PubMed

Solé, D; Rizzo, M C; Porto, I M; Gomez, I D; Sano, F; Figueiredo, M A; Naspitz, C K

1996-01-01

Patients during a mild to moderate acute attack of asthma (FEV1: 50 - 80% of predicted) were treated with Salmeterol MDI - 50mcg or Rotadisk - 50mcg or Salbutamol (MDI -200mcg). The children were followed by Spirometry, measuring FEV1 (basal) and after treatment: at 30 minutes, 60 minutes and thereafter every 60 minutes until 780 minutes, if the patients maintained the FEV1 above 80% of the predicted value and/or an increment of 20% in the VEF1 basal value. The Salmeterol group showed a significant bronchodilation at 60 minutes which was maintained in half of the patients up to 9 hours. This was not observed in the Salbutamol group: the peak bronchodilatation was observed at 30 minutes and the bronchodilation effect was observed in half of the patients up to 6 hours. There were no significant differences between both presentations of Salmeterol. This drug allowed a prolonged bronchodilator effect and is, according to the several consensus on management of asthma, an adequate option in the treatment of moderate to severe asthma.

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

TARPs: Tracked Active Region Patches from SoHO/MDI

NASA Astrophysics Data System (ADS)

Turmon, M.; Hoeksema, J. T.; Bobra, M.

2013-12-01

We describe progress toward creating a retrospective MDI data product consisting of tracked magnetic features on the scale of solar active regions, abbreviated TARPs (Tracked Active Region Patches). The TARPs are being developed as a backward-looking extension (covering approximately 3500 regions spanning 1996-2010) to the HARP (HMI Active Region Patch) data product that has already been released for HMI (2010-present). Like the HARPs, the MDI TARP data set is designed to be a catalog of active regions (ARs), indexed by a region ID number, analogous to a NOAA AR number, and time. TARPs from MDI are computed based on the 96-minute synoptic magnetograms and pseudo-continuum intensitygrams. As with the related HARP data product, the approximate threshold for significance is 100G. Use of both image types together allows faculae and sunspots to be separated out as sub-classes of activity, in addition to identifying the overall active region that the faculae/sunspots are part of. After being identified in single images, the magnetically-active patches are grouped and tracked from image to image. Merges among growing active regions, as well as faint active regions hovering at the threshold of detection, are handled automatically. Regions are tracked from their inception until they decay within view, or transit off the visible disk. The final data product is indexed by a nominal AR number and time. For each active region and for each time, a bitmap image is stored containing the precise outline of the active region. Additionaly, metadata such as areas and integrated fluxes are stored for each AR and for each time. Because there is a calibration between the HMI and MDI magnetograms (Liu, Hoeksema et al. 2012), it is straightforward to use the same classification and tracking rules for the HARPs (from HMI) and the MDI TARPs. We anticipate that this will allow a consistent catalog spanning both instruments. We envision several uses for the TARP data product, which will be

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.

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.

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...

40 CFR 721.2540 - Diphenylmethane diisocyanate (MDI) modified.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) TOXIC SUBSTANCES CONTROL ACT SIGNIFICANT NEW USES OF CHEMICAL SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.2540 Diphenylmethane diisocyanate (MDI) modified. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as a...

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.

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

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.

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

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

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

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.

Biological monitoring of workers exposed to 4,4'-methylenediphenyl diisocyanate (MDI) in 19 French polyurethane industries.

PubMed

Robert, A; Ducos, P; Francin, J M; Marsan, P

2007-04-01

To study the range of urinary levels of 4,4'-methylenedianiline (MDA), a metabolite of methylenediphenyl diisocyanate (MDI), across factories in the polyurethane industries and to evaluate the validity of this biomarker to assess MDI occupational exposure. Workers exposed to MDI, as well as non-occupationally exposed subjects, were studied and pre- and post-shift urine samples were collected from 169 workers of 19 French factories and 120 controls. Details on work activities and practices were collected by a questionnaire and workers were classified into three job categories. The identification and quantification of the total urinary MDA were performed by high-performance liquid chromatography with electrochemical detection (HPLC/EC). For all the factories, MDA was detectable in 73% of the post-shift urine samples. These post-shift values, in the range of <0.10 (detection limit)-23.60 microg/l, were significantly higher than those of the pre-shift samples. Urinary MDA levels in the control group were in the range of < 0.10-0.80 microg/l. The degree of automation of the mixing operation (polyols and MDI) appears as a determinant in the extent of exposure levels. The highest amounts of MDA in urine were found in the spraying or hot processes. The excretion levels of the workers directly exposed to the hardener containing the MDI monomer were significantly higher than those of the other workers. In addition, skin exposure to MDI monomer or to polyurethane resin during the curing step were always associated with significant MDA levels in urine. Total MDA in post-shift urine samples is a reliable biomarker to assess occupational exposure to MDI in various industrial applications and to help factories to improve their manufacturing processes and working practices. A biological guiding value not exceeding 7 microg/l (5 microg/g creatinine) could be proposed in France.

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

Critical analysis of common canister programs: a review of cross-functional considerations and health system economics.

PubMed

Larson, Trent; Gudavalli, Ravindra; Prater, Dean; Sutton, Scott

2015-04-01

Respiratory inhalers constitute a large percentage of hospital pharmacy expenditures. Metered-dose inhaler (MDI) canisters usually contain enough medication to last 2 to 4 weeks, while the average hospital stay for acute hospitalizations of respiratory illnesses is only 4-5 days. Hospital pharmacies are often unable to operationalize relabeling of inhalers at discharge to meet regulatory requirements. This dilemma produces drug wastage. The common canister (CC) approach is a method some hospitals implemented in an effort to minimize the costs associated with this issue. The CC program uses a shared inhaler, an individual one-way valve holding chamber, and a cleaning protocol. This approach has been the subject of considerable controversy. Proponents of the CC approach reported considerable cost savings to their institutions. Opponents of the CC approach are not convinced the benefits outweigh even a minimal risk of cross-contamination since adherence to protocols for hand washing and disinfection of the MDI device cannot be guaranteed to be 100% (pathogens from contaminated devices can enter the respiratory tract through inhalation). Other cost containment strategies, such as unit dose nebulizers, may be useful to realize similar reductions in pharmacy drug costs while minimizing the risks of nosocomial infections and their associated medical costs. The CC strategy may be appropriate for some hospital pharmacies that face budget constraints, but a full evaluation of the risks, benefits, and potential costs should guide those who make hospital policy decisions.

Ozone Inhalation Leads to a Dose-Dependent Increase of Cytogenetic Damage in Human Lymphocytes

PubMed Central

Holland, Nina; Davé, Veronica; Venkat, Subha; Wong, Hofer; Donde, Aneesh; Balmes, John R; Arjomandi, Mehrdad

2014-01-01

Ozone is an important constituent of ambient air pollution and represents a major public health concern. Oxidative injury due to ozone inhalation causes the generation of reactive oxygen species and can be genotoxic. To determine whether ozone exposure causes genetic damage in peripheral blood lymphocytes, we employed a well-validated cytokinesis-block micronucleus Cytome assay. Frequencies of micronuclei (MN) and nucleoplasmic bridges (NB) were used as indicators of cytogenetic damage. Samples were obtained from 22 non-smoking healthy subjects immediately before and 24-hr after controlled 4-hr exposures to filtered air, 100 ppb, and 200 ppb ozone while exercising in a repeated-measure study design. Inhalation of ozone at different exposure levels was associated with a significant dose-dependent increase in MN frequency (P < 0.0001) and in the number of cells with more than 1 MN per cell (P < 0.0005). Inhalation of ozone also caused an increase in the number of apoptotic cells (P = 0.002). Airway neutrophilia was associated with an increase in MN frequency (P = 0.033) independent of the direct effects of ozone exposure (P < 0.0001). We also observed significant increases in both MN and NB frequencies after exercise in filtered air, suggesting that physical activity is also an important inducer of oxidative stress. These results corroborate our previous findings that cytogenetic damage is associated with ozone exposure, and show that damage is dose-dependent. Further study of ozone-induced cytogenetic damage in airway epithelial cells could provide evidence for the role of oxidative injury in lung carcinogenesis, and help to address the potential public health implications of exposures to oxidant environments. PMID:25451016

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...

The History of Therapeutic Aerosols: A Chronological Review.

PubMed

Stein, Stephen W; Thiel, Charles G

2017-02-01

In 1956, Riker Laboratories, Inc., (now 3 M Drug Delivery Systems) introduced the first pressurized metered dose inhaler (MDI). In many respects, the introduction of the MDI marked the beginning of the modern pharmaceutical aerosol industry. The MDI was the first truly portable and convenient inhaler that effectively delivered drug to the lung and quickly gained widespread acceptance. Since 1956, the pharmaceutical aerosol industry has experienced dramatic growth. The signing of the Montreal Protocol in 1987 led to a surge in innovation that resulted in the diversification of inhaler technologies with significantly enhanced delivery efficiency, including modern MDIs, dry powder inhalers, and nebulizer systems. The innovative inhalers and drugs discovered by the pharmaceutical aerosol industry, particularly since 1956, have improved the quality of life of literally hundreds of millions of people. Yet, the delivery of therapeutic aerosols has a surprisingly rich history dating back more than 3500 years to ancient Egypt. The delivery of atropine and related compounds has been a crucial inhalation therapy throughout this period and the delivery of associated structural analogs remains an important therapy today. Over the centuries, discoveries from many cultures have advanced the delivery of therapeutic aerosols. For thousands of years, therapeutic aerosols were prepared by the patient or a physician with direct oversight of the patient using custom-made delivery systems. However, starting with the Industrial Revolution, advancements in manufacturing resulted in the bulk production of therapeutic aerosol delivery systems produced by people completely disconnected from contact with the patient. This trend continued and accelerated in the 20th century with the mass commercialization of modern pharmaceutical inhaler products. In this article, we will provide a summary of therapeutic aerosol delivery from ancient times to the present along with a look to the future. We

The History of Therapeutic Aerosols: A Chronological Review

PubMed Central

Thiel, Charles G.

2017-01-01

Abstract In 1956, Riker Laboratories, Inc., (now 3 M Drug Delivery Systems) introduced the first pressurized metered dose inhaler (MDI). In many respects, the introduction of the MDI marked the beginning of the modern pharmaceutical aerosol industry. The MDI was the first truly portable and convenient inhaler that effectively delivered drug to the lung and quickly gained widespread acceptance. Since 1956, the pharmaceutical aerosol industry has experienced dramatic growth. The signing of the Montreal Protocol in 1987 led to a surge in innovation that resulted in the diversification of inhaler technologies with significantly enhanced delivery efficiency, including modern MDIs, dry powder inhalers, and nebulizer systems. The innovative inhalers and drugs discovered by the pharmaceutical aerosol industry, particularly since 1956, have improved the quality of life of literally hundreds of millions of people. Yet, the delivery of therapeutic aerosols has a surprisingly rich history dating back more than 3500 years to ancient Egypt. The delivery of atropine and related compounds has been a crucial inhalation therapy throughout this period and the delivery of associated structural analogs remains an important therapy today. Over the centuries, discoveries from many cultures have advanced the delivery of therapeutic aerosols. For thousands of years, therapeutic aerosols were prepared by the patient or a physician with direct oversight of the patient using custom-made delivery systems. However, starting with the Industrial Revolution, advancements in manufacturing resulted in the bulk production of therapeutic aerosol delivery systems produced by people completely disconnected from contact with the patient. This trend continued and accelerated in the 20th century with the mass commercialization of modern pharmaceutical inhaler products. In this article, we will provide a summary of therapeutic aerosol delivery from ancient times to the present along with a look to the

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

Advanced technologies and devices for inhalational anesthetic drug dosing.

PubMed

Meyer, J-U; Kullik, G; Wruck, N; Kück, K; Manigel, J

2008-01-01

Technological advances in micromechanics, optical sensing, and computing have led to innovative and reliable concepts of precise dosing and sensing of modern volatile anesthetics. Mixing of saturated desflurane flow with fresh gas flow (FGF) requires differential pressure sensing between the two circuits for precise delivery. The medical gas xenon is administered most economically in a closed circuit breathing system. Sensing of xenon in the breathing system is achieved with miniaturized and unique gas detector systems. Innovative sensing principles such as thermal conductivity and sound velocity are applied. The combination of direct injection of volatile anesthetics and low-flow in a closed circuit system requires simultaneous sensing of the inhaled and exhaled gas concentrations. When anesthetic conserving devices are used for sedation with volatile anesthetics, regular gas concentration monitoring is advised. High minimal alveolar concentration (MAC) of some anesthetics and low-flow conditions bear the risk of hypoxic gas delivery. Oxygen sensing based on paramagnetic thermal transduction has become the choice when long lifetime and one-time calibration are required. Compact design of beam splitters, infrared filters, and detectors have led to multiple spectra detector systems that fit in thimble-sized housings. Response times of less than 500 ms allow systems to distinguish inhaled from exhaled gas concentrations. The compact gas detector systems are a prerequisite to provide "quantitative anesthesia" in closed circuit feedback-controlled breathing systems. Advanced anesthesia devices in closed circuit mode employ multiple feedback systems. Multiple feedbacks include controls of volume, concentrations of anesthetics, and concentration of oxygen with a corresponding safety system. In the ideal case, the feedback system delivers precisely what the patient is consuming. In this chapter, we introduce advanced technologies and device concepts for delivering

Airway symptoms and lung function in pipelayers exposed to thermal degradation products from MDI-based polyurethane.

PubMed Central

Jakobsson, K; Kronholm-Diab, K; Rylander, L; Hagmar, L

1997-01-01

OBJECTIVES: To study the prevalence of symptoms from the eyes and the upper and lower respiratory tract, lung function, and immunological sensitisation towards isocyanates in pipelayers exposed to thermal degradation products from methylene diphenyl diisocyanate (MDI)-based polyurethane (PUR). MATERIAL AND METHODS: 50 presently active and 113 formerly active pipelayers were examined. Also, 65 unexposed workers were investigated for comparison. The one year prevalence of symptoms and smoking history (questionnaire data), lung function (vital capacity (VC) and forced expiratory volume in one second (FEV1), and atopy (positive skin prick tests towards standard allergens) were assessed among pipelayers and controls. For the pipelayers, the presence of work related symptoms and estimates of isocyanate and welding exposure were obtained from an interview. Skin prick tests towards specific isocyanate antigens and determinations of IgE-MDI and IgG-MDI in serum were also performed. RESULTS: The prevalence of episodes (more than once a month) of irritative eye symptoms, congestion of the nose, and soreness or dryness in the throat was much higher among the PUR pipelayers than among the controls. Most of the pipelayers with symptoms reported that these had started and occurred in relation to the PUR welding tasks. Presently active pipelayers with recent high PUR exposure showed a significant reduction of FEV1 compared with the controls. The estimated reduction, adjusted for smoking, was -0.3 l (P = 0.04). There was no confounding effect of ordinary welding. None of the pipelayers showed positive skin prick reactions against the specific isocyanate antigens used, or positive IgE-MDI, and only two had increased IgG-MDI. CONCLUSIONS: The findings indicate that exposure to thermal degradation products from MDI-based polyurethane has adverse effects on the mucous membranes and airways. PMID:9470895

Financial effect of converting ipratropium-albuterol therapy from inhalers to nebulizer treatments at an academic health system.

PubMed

Loborec, Steven M; Johnson, Shawn E; Keating, Ellen A

2016-02-01

The results of a study to assess the financial impact of an automatic formulary substitution of ipratropium-albuterol nebulization solution for ipratropium-albuterol metered-dose inhalers (MDIs) at an academic health system are reported. The study was conducted at a 1242-bed urban academic health system. Data were collected regarding all respiratory medication administrations during a three-month period before the MDI-to-nebulizer substitution (October-December 2012) and the same period of 2013 (after the substitution was implemented). Purchasing data were compared between the two time periods to measure the impact of the formulary substitution on pharmacy department costs, and documented administrations were assessed to evaluate associated changes in respiratory therapist (RT) workload. With 100% prescriber compliance with the formulary substitution, the number of MDI administrations of ipratropium-albuterol declined from 13,667 in October-December 2012 to zero in the same period of 2013. The substitution required expenditures for equipment (vibrating mesh nebulizer technology and patient-specific kits) and RT personnel (one additional RT was hired), but those added costs were substantially outweighed by cost savings resulting from a substantial reduction in overall respiratory drug spending. An automatic substitution of ipratropium-albuterol nebulization solution for MDIs resulted in a three-month savings of $99,359 in drug cost and an extrapolated full-year savings of $397,436. When additional costs associated with the substitution were taken into account, there was an overall savings of $146,806 during the implementation year and a projected savings of $257,936 for each following year. Copyright © 2016 by the American Society of Health-System Pharmacists, 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.

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, ...

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

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.

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

Human Dose-Response Data for Francisella tularensis and a Dose- and Time-Dependent Mathematical Model of Early-Phase Fever Associated with Tularemia After Inhalation Exposure.

PubMed

McClellan, Gene; Coleman, Margaret; Crary, David; Thurman, Alec; Thran, Brandolyn

2018-04-25

Military health risk assessors, medical planners, operational planners, and defense system developers require knowledge of human responses to doses of biothreat agents to support force health protection and chemical, biological, radiological, nuclear (CBRN) defense missions. This article reviews extensive data from 118 human volunteers administered aerosols of the bacterial agent Francisella tularensis, strain Schu S4, which causes tularemia. The data set includes incidence of early-phase febrile illness following administration of well-characterized inhaled doses of F. tularensis. Supplemental data on human body temperature profiles over time available from de-identified case reports is also presented. A unified, logically consistent model of early-phase febrile illness is described as a lognormal dose-response function for febrile illness linked with a stochastic time profile of fever. Three parameters are estimated from the human data to describe the time profile: incubation period or onset time for fever; rise time of fever; and near-maximum body temperature. Inhaled dose-dependence and variability are characterized for each of the three parameters. These parameters enable a stochastic model for the response of an exposed population through incorporation of individual-by-individual variability by drawing random samples from the statistical distributions of these three parameters for each individual. This model provides risk assessors and medical decisionmakers reliable representations of the predicted health impacts of early-phase febrile illness for as long as one week after aerosol exposures of human populations to F. tularensis. © 2018 Society for Risk Analysis.

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

When Intensive Insulin Therapy (MDI) Fails in Patients With Type 2 Diabetes: Switching to GLP-1 Receptor Agonist Versus Insulin Pump.

PubMed

Cohen, Ohad; Filetti, Sebastiano; Castañeda, Javier; Maranghi, Marianna; Glandt, Mariela

2016-08-01

Treatment with insulin, alone or with oral or injectable hypoglycemic agents, is becoming increasingly common in patients with type 2 diabetes. However, approximately 40% of patients fail to reach their glycemic targets with the initially prescribed regimen and require intensification of insulin therapy, which increases the risks of weight gain and hypoglycemia. Many of these patients eventually reach a state in which further increases in the insulin dosage fail to improve glycemic control while increasing the risks of weight gain and hypoglycemia. The recently completed OpT2mise clinical trial showed that continuous subcutaneous insulin infusion (CSII) is more effective in reducing glycated hemoglobin (HbA1c) than intensification of multiple daily injection (MDI) insulin therapy in patients with type 2 diabetes who do not respond to intensive insulin therapy. CSII therapy may also be useful in patients who do not reach glycemic targets despite multidrug therapy with basal-bolus insulin and other agents, including glucagon-like peptide (GLP)-1 receptor agonists; current guidelines offer no recommendations for the treatment of such patients. Importantly, insulin and GLP-1 receptor agonists have complementary effects on glycemia and, hence, can be used either sequentially or in combination in the initial management of diabetes. Patients who have not previously failed GLP-1 receptor agonist therapy may show reduction in weight and insulin dose, in addition to moderate improvement in HbA1c, when GLP-1 receptor agonist therapy is added to MDI regimens. In subjects with long-standing type 2 diabetes who do not respond to intensive insulin therapies, switching from MDI to CSII and/or the addition of GLP-1 receptor agonists to MDI have the potential to improve glycemic control without increasing the risk of adverse events. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for

Particle interactions of fluticasone propionate and salmeterol xinafoate detected with single particle aerosol mass spectrometry (SPAMS).

PubMed

Jetzer, Martin W; Morrical, Bradley D; Fergenson, David P; Imanidis, Georgios

2017-10-30

Particle co-associations between the active pharmaceutical ingredients fluticasone propionate and salmeterol xinafoate were examined in dry powder inhaled (DPI) and metered dose inhaled (MDI) combination products. Single Particle Aerosol Mass Spectrometry was used to investigate the particle interactions in Advair Diskus ® (500/50 mcg) and Seretide ® (125/25 mcg). A simple rules tree was used to identify each compound, either alone or co-associated at the level of the individual particle, using unique marker peaks in the mass spectra for the identification of each drug. High levels of drug particle co-association (fluticasone-salmeterol) were observed in the aerosols emitted from Advair Diskus ® and Seretide ® . The majority of the detected salmeterol particles were found to be in co-association with fluticasone in both tested devices. Another significant finding was that rather coarse fluticasone particles (in DPI) and fine salmeterol particles (both MDI and DPI) were forming the particle co-associations. Copyright © 2017 Elsevier B.V. All rights reserved.

Modelling and mitigating dose to firefighters from inhalation of radionuclides in wildland fire smoke

DOE PAGES

Viner, Brian J.; Jannik, Tim; Stone, Daniel; ...

2015-06-12

Firefighters responding to wildland fires where surface litter and vegetation contain radiological contamination will receive a radiological dose by inhaling resuspended radioactive material in the smoke. This may increase their lifetime risk of contracting certain types of cancer. Using published data, we modelled hypothetical radionuclide emissions, dispersion and dose for 70th and 97th percentile environmental conditions and for average and high fuel loads at the Savannah River Site. We predicted downwind concentration and potential dose to firefighters for radionuclides of interest ( 137Cs, 238Pu, 90Sr and 210Po). Predicted concentrations exceeded dose guidelines in the base case scenario emissions of 1.0more » × 10 7 Bq ha –1 for 238Pu at 70th percentile environmental conditions and average fuel load levels for both 4- and 14-h shifts. Under 97th percentile environmental conditions and high fuel loads, dose guidelines were exceeded for several reported cases for 90Sr, 238Pu and 210Po. Potential for exceeding dose guidelines was mitigated by including plume rise (>2 m s –1) or moving a small distance from the fire owing to large concentration gradients near the edge of the fire. As a result, our approach can quickly estimate potential dose from airborne radionuclides in wildland fire and assist decision-making to reduce firefighter exposure.« less

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...

Time-Distance Helioseismology with the MDI Instrument: Initial Results

NASA Technical Reports Server (NTRS)

Duvall, T. L., Jr.; Kosovichev, A. G.; Scherrer, P. H.; Bogart, R. S.; Bush, R. I.; DeForest, C.; Hoeksema, J. T.; Schou, J.; Saba, J. L. R.; Tarbell, T. D.;

Comparison of acoustic travel-time measurements of solar meridional circulation from SDO/HMI and SOHO/MDI

NASA Astrophysics Data System (ADS)

Liang, Zhi-Chao; Birch, Aaron C.; Duvall, Thomas L., Jr.; Gizon, Laurent; Schou, Jesper

2017-05-01

Context. Time-distance helioseismology is one of the primary tools for studying the solar meridional circulation, especially in the lower convection zone. However, travel-time measurements of the subsurface meridional flow suffer from a variety of systematic errors, such as a center-to-limb variation and an offset due to the position angle (P-angle) uncertainty of solar images. It has been suggested that the center-to-limb variation can be removed by subtracting east-west from south-north travel-time measurements. This ad hoc method for the removal of the center-to-limb effect has been adopted widely but not tested for travel distances corresponding to the lower convection zone. Aims: We explore the effects of two major sources of the systematic errors, the P-angle error arising from the instrumental misalignment and the center-to-limb variation, on the acoustic travel-time measurements in the south-north direction. Methods: We apply the time-distance technique to contemporaneous medium-degree Dopplergrams produced by SOHO/MDI and SDO/HMI to obtain the travel-time difference caused by meridional circulation throughout the solar convection zone. The P-angle offset in MDI images is measured by cross-correlating MDI and HMI images. The travel-time measurements in the south-north and east-west directions are averaged over the same observation period (May 2010 to Apr. 2011) for the two data sets and then compared to examine the consistency of MDI and HMI travel times after applying the above-mentioned corrections. Results: The offsets in the south-north travel-time difference from MDI data induced by the P-angle error gradually diminish with increasing travel distance. However, these offsets become noisy for travel distances corresponding to waves that reach the base of the convection zone. This suggests that a careful treatment of the P-angle problem is required when studying a deep meridional flow. After correcting the P-angle and the removal of the center

Systemic effects of H2S inhalation at human equivalent dose of pathologic halitosis on rats.

PubMed

Yalçın Yeler, Defne; Aydin, Murat; Gül, Mehmet; Hocaoğlu, Turgay; Özdemir, Hakan; Koraltan, Melike

2017-10-01

Halitosis is composed by hundreds of toxic gases. It is still not clear whether halitosis gases self-inhaled by halitosis patients cause side effects. The aim of the study was to investigate the effect of H 2 S inhalation at a low concentration (human equivalent dose of pathologic halitosis) on rats. The threshold level of pathologic halitosis perceived by humans at 250 ppb of H 2 S was converted to rat equivalent concentration (4.15 ppm). In the experimental group, 8 rats were exposed to H 2 S via continuous inhalation but not the control rats. After 50 days, blood parameters were measured and tissue samples were obtained from the brain, kidney and liver and examined histopathologically to determine any systemic effect. While aspartate transaminase, creatine kinase-MB and lactate dehydrogenase levels were found to be significantly elevated, carbondioxide and alkaline phosphatase were decreased in experimental rats. Other blood parameters were not changed significantly. Experimental rats lost weight and became anxious. Histopathological examination showed mononuclear inflammatory cell invasion in the portal areas, nuclear glycogen vacuoles in the parenchymal area, single-cell necrosis in a few foci, clear expansion in the central hepatic vein and sinusoids, hyperplasia in Kupffer cells and potential fibrous tissue expansion in the portal areas in the experimental rats. However, no considerable histologic damage was observed in the brain and kidney specimens. It can be concluded that H 2 S inhalation equivalent to pathologic halitosis producing level in humans may lead to systemic effects, particularly heart or liver damage in rats.

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

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.

Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids.

PubMed

Bateman, Eric D; Guerreros, Alfredo G; Brockhaus, Florian; Holzhauer, Björn; Pethe, Abhijit; Kay, Richard A; Townley, Robert G

2017-08-01

Dose-related efficacy and safety of fevipiprant (QAW039), an oral DP 2 (CRTh2) receptor antagonist, was assessed in patients with allergic asthma uncontrolled by low-dose inhaled corticosteroids (ICS).Adult patients were randomised to 12 weeks' treatment with once-daily (1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d ) or twice-daily (2, 25, 75 or 150 mg b.i.d ) fevipiprant (n=782), montelukast 10 mg q.d (n=139) or placebo (n=137). All patients received inhaled budesonide 200 μg b.i.d Fevipiprant produced a statistically significant improvement in the primary end-point of change in pre-dose forced expiratory volume in 1 s at week 12 (p=0.0035) with a maximum model-averaged difference to placebo of 0.112 L. The most favourable pairwise comparisons to placebo were for the fevipiprant 150 mg q.d and 75 mg b.i.d groups, with no clinically meaningful differences between q.d and b.i.d Montelukast also demonstrated a significant improvement in this end-point. No impact on other efficacy end-points was observed. Adverse events were generally mild/moderate in severity, and were evenly distributed across doses and treatments.Fevipiprant appears to be efficacious and well-tolerated in this patient population, with an optimum total daily dose of 150 mg. Further investigations into the clinical role of fevipiprant in suitably designed phase III clinical trials are warranted. Copyright ©ERS 2017.

Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids

PubMed Central

Guerreros, Alfredo G.; Brockhaus, Florian; Pethe, Abhijit; Kay, Richard A.; Townley, Robert G.

2017-01-01

Dose-related efficacy and safety of fevipiprant (QAW039), an oral DP2 (CRTh2) receptor antagonist, was assessed in patients with allergic asthma uncontrolled by low-dose inhaled corticosteroids (ICS). Adult patients were randomised to 12 weeks' treatment with once-daily (1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d.) or twice-daily (2, 25, 75 or 150 mg b.i.d.) fevipiprant (n=782), montelukast 10 mg q.d. (n=139) or placebo (n=137). All patients received inhaled budesonide 200 μg b.i.d. Fevipiprant produced a statistically significant improvement in the primary end-point of change in pre-dose forced expiratory volume in 1 s at week 12 (p=0.0035) with a maximum model-averaged difference to placebo of 0.112 L. The most favourable pairwise comparisons to placebo were for the fevipiprant 150 mg q.d. and 75 mg b.i.d. groups, with no clinically meaningful differences between q.d. and b.i.d. Montelukast also demonstrated a significant improvement in this end-point. No impact on other efficacy end-points was observed. Adverse events were generally mild/moderate in severity, and were evenly distributed across doses and treatments. Fevipiprant appears to be efficacious and well-tolerated in this patient population, with an optimum total daily dose of 150 mg. Further investigations into the clinical role of fevipiprant in suitably designed phase III clinical trials are warranted. PMID:28838980

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.

Simultaneous Determination of Formoterol Fumarate and Budesonide Epimers in Metered Dose Inhaler Using Ion-Pair Chromatography.

PubMed

Salem, Y A; Shaldam, M A; El-Sherbiny, D T; El-Wasseef, D R; El-Ashry, S M

2017-11-01

A simple, accurate and valid ion-pairing chromatographic method was developed for the simultaneous determination of formoterol fumarate (FF) and budesonide (BUD) epimers in metered dose inhaler. The separation was performed on C-18 column using mobile phase consisting of acetonitrile:0.05 M sodium acetate buffer (40:60% v/v) containing 0.03% sodium dodecyl sulfate adjusted to pH 3.1 using increasing volumes of either TEA or orthophosphoric acid isocratically eluted at 1.0 mL/min. Quantitation was achieved with UV detection at 214 nm. The retention times were 3.22, 6.41 and 6.91 min for formoterol fumarate, budesonide epimers B and A, respectively. The linearity range was 0.05-5.0 μg/mL for formoterol fumarate and 0.5-50.0 μg/mL for budesonide. The method was validated for, linearity; lower limit of quantification, lower limit of detection accuracy and precision. The proposed method is rapid (7 min), reproducible (RSD < 2.0%) and achieves satisfactory resolution between FF and BUD B (resolution factor = 12.07). The mean recoveries of the analytes in metered dose inhaler (99.97 and 99.83% for FF and BUD, respectively) were satisfactory. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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.

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

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

INHALATION EXPOSURE-RESPONSE METHODOLOGY

EPA Science Inventory

The Inhalation Exposure-Response Analysis Methodology Document is expected to provide guidance on the development of the basic toxicological foundations for deriving reference values for human health effects, focusing on the hazard identification and dose-response aspects of the ...

Synthesis of Polyurethanes Membranes from Rubber Seed Oil and Methylene Diphenyl Diisocyanates (MDI)

NASA Astrophysics Data System (ADS)

Marlina; Nurman, S.; Saleha, S.; Fitriani; Thanthawi, I.

2017-03-01

Rubber seed oil and methylene diphenyl diisocyanates (MDI) based polyurethane membrane has been prepared in this study. The main objective of this research is manufacture of polyurethane membranes from avocado seed oil, as a filter of this membrane use as a filter of metals from water such as mercury (Hg). In this study, the polyurethane membrane had been synthesized by varying compositions of rubber seed oil and MDI, with ratios of 10:0.2; 10:0.4; 10:0.6; 10:0.8; 10:1.0; 10:1.2; 10:1.4; 10:1.6; 10:1.8 and 10:2.0 (v/w) at 80°C and 170°C as polymerization and curing temperatures, respectively. Optimum polyurethane membrane was obtained at rubber seed oil: MDI 10: 0.8 v/w, it was dry, non-sticky, smooth and blackish brown. The membrane flux was 5,8307 L / m2.h.bar and rejection factor was 35,3015 %. The results of characterization indicated the formation of urethane bonds (NH at 3480 cm-1, C=O at 1620 cm-1, CN at 1374 cm-1, -OC-NH- at 1096 cm-1 and no -NCO at 2270 cm-1), the value of Tg was 55°C. The polyurethane membrane which treated at the optimum treatment conditions were used to the filter of metals from water such as mercury (Hg).

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

Effect of drug load and plate coating on the particle size distribution of a commercial albuterol metered dose inhaler (MDI) determined using the Andersen and Marple-Miller cascade impactors.

PubMed

Nasr, M M; Ross, D L; Miller, N C

1997-10-01

The purpose of this study is to investigate the effect of drug load, the coating of impactor stages, and the design of cascade impactors on albuterol MDIs particle size distribution measurements. The results of the investigation will be used to explain the "loading effect" recently reported. Particle size distribution parameters of a commercial albuterol MDI were measured using both Andersen (AI) and Marple-Miller (MMI) Cascade Impactors, where plates were either left uncoated or coated with silicone or glycerin. A previously validated HPLC-EC method was used for the assay of albuterol collected by the impactor and in single spray content determinations. Coating impactor collection plates had an impact on measured MMAD and GSD values for single puff measurements but very little or no effect for the multi puff measurements. Due to particle bounce, the percent of albuterol fine particles deposited in the filter and impactor finer stages (< 1.10 microns in AI and < 1.25 microns in MMI) in uncoated single puff experiments was much higher in comparison to either coated single puff or multi-puff (coated and uncoated) measurements. Evaluation of drug load and plate coating are necessary to determine whether observed particle size distributions are representative of the generated aerosol or are the result of particle bounce and reentrainment. In order to minimize particle bounce, especially for single puff determinations, it may be useful to apply a thin layer of a sticky coating agent to the surfaces of impactor plates.

Pharmacometrics-based dose selection of levofloxacin as a treatment for postexposure inhalational anthrax in children.

PubMed

Li, Fang; Nandy, Partha; Chien, Shuchean; Noel, Gary J; Tornoe, Christoffer W

2010-01-01

Levofloxacin was recently (May 2008) approved by the U.S. Food and Drug Administration as a treatment for children following inhalational exposure to anthrax. Given that no clinical trials to assess the efficacy of a chosen dose was conducted, the basis for the dose recommendation was based upon pharmacometric analyses. The objective of this paper is to describe the basis of the chosen pediatric dose recommended for the label. Pharmacokinetic (PK) data from 90 pediatric patients receiving 7 mg/kg of body weight levofloxacin and two studies of 47 healthy adults receiving 500 and 750 mg/kg levofloxacin were used for the pharmacometric analyses. Body weight was found to be a significant covariate for levofloxacin clearance and the volume of distribution. Consistently with developmental physiology, clearance also was found to be reduced in pediatric patients under 2 years of age due to immature renal function. Different dosing regimens were simulated to match adult exposure (area under the concentration-time curve from 0 to 24 h at steady state, maximum concentration of drug in serum at steady state, and minimum concentration of drug in serum at steady state) following the approved adult dose of 500 mg once a day. The recommended dose of 8 mg/kg twice a day was found to match the exposure of the dose approved for adults in a manner that permitted confidence that this dose in children would achieve efficacy comparable to that of adults.

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

Internal dosimetry of inhaled iodine-131.

PubMed

Kiani Nasab, Mitra; Rafat Motavalli, Laleh; Miri Hakimabad, Hashem

2018-01-01

In this paper, the dose assessment for the iodine inhalation exposure in 19 aerosol sizes and three gas/vapor forms at three levels of thyroid uptake, was performed. Two different modes of work (light vs. heavy) and breathing (nose vs. mouth) for aerosol inhalation were investigated. In order to calculate the cumulated activities per unit of inhaled activity, a combined model which included the latest models of both human respiratory and alimentary tract was developed. The S values for 131 I were computed based on the ICRP adult male and female reference voxel phantoms by the Monte Carlo method. Then, the committed equivalent and committed effective dose coefficients were obtained (The data are available at http://www.um.ac.ir/∼mirihakim). In general, for the nonzero thyroid uptakes, the maximum cumulated activity was found in the thyroid. When the thyroid is blocked, however, the maximum depends on the work and breathing mode and radioisotope form. Overall, the maximum CED coefficient was evaluated for the inhalation of elemental iodine at thyroid uptake of ∼27% (2.8 × 10 -8 Sv/Bq). As for the particle inhalation per se, mouth breathing of 0.6 nm and 0.2 μm AMTD particles showed to have the maximum (2.8 × 10 -8 Sv/Bq) and minimum (6.4 × 10 -9 Sv/Bq) CED coefficients, respectively. Compared to the reference CED coefficients, the authors found an increase of about 58% for inhalation of the aerosols with AMAD of 1 μm and 70% for 5 μm. Copyright © 2017 Elsevier Ltd. All rights reserved.

ADRB2 Polymorphisms and Budesonide/Formoterol Responses in COPD

PubMed Central

Meyers, Deborah A.; Bailey, William C.; Sims, Anne-Marie; Bujac, Sarah R.; Goldman, Mitch; Martin, Ubaldo J.

2012-01-01

Background: Effects of β2-adrenergic receptor gene (ADRB2) polymorphism on therapeutic responses to long-acting β2-adrenergic agonists have not been evaluated in long-term COPD trials. We aimed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD. Methods: Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I (NCT00206167) or the 6-month trial II (NCT00206154) were randomly assigned to bid budesonide/formoterol pressurized metered-dose inhaler (pMDI) 320/9 μg or 160/9 μg, budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg (trial II), budesonide pMDI 320 μg (trial II), formoterol dry powder inhaler 9 μg, or placebo. The effect of Gly16Arg on predose FEV1 and 1-h postdose FEV1, exacerbations, diary variables, and adverse events were analyzed. Results: No significant interaction between genotype and treatment response was observed for predose (P ≥ .197) or postdose FEV1 (P ≥ .125) in either pharmacogenetic study (n = 2,866). The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups (both studies). Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment. Conclusion: Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD. Trial registry: ClinicalTrials.gov; Nos.: NCT00206167, NCT00206154; URL: clinicaltrials.gov. PMID:22383665

Multiplexed direct genomic selection (MDiGS): a pooled BAC capture approach for highly accurate CNV and SNP/INDEL detection.

PubMed

Alvarado, David M; Yang, Ping; Druley, Todd E; Lovett, Michael; Gurnett, Christina A

2014-06-01

Despite declining sequencing costs, few methods are available for cost-effective single-nucleotide polymorphism (SNP), insertion/deletion (INDEL) and copy number variation (CNV) discovery in a single assay. Commercially available methods require a high investment to a specific region and are only cost-effective for large samples. Here, we introduce a novel, flexible approach for multiplexed targeted sequencing and CNV analysis of large genomic regions called multiplexed direct genomic selection (MDiGS). MDiGS combines biotinylated bacterial artificial chromosome (BAC) capture and multiplexed pooled capture for SNP/INDEL and CNV detection of 96 multiplexed samples on a single MiSeq run. MDiGS is advantageous over other methods for CNV detection because pooled sample capture and hybridization to large contiguous BAC baits reduces sample and probe hybridization variability inherent in other methods. We performed MDiGS capture for three chromosomal regions consisting of ∼ 550 kb of coding and non-coding sequence with DNA from 253 patients with congenital lower limb disorders. PITX1 nonsense and HOXC11 S191F missense mutations were identified that segregate in clubfoot families. Using a novel pooled-capture reference strategy, we identified recurrent chromosome chr17q23.1q23.2 duplications and small HOXC 5' cluster deletions (51 kb and 12 kb). Given the current interest in coding and non-coding variants in human disease, MDiGS fulfills a niche for comprehensive and low-cost evaluation of CNVs, coding, and non-coding variants across candidate regions of interest. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

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.

Inhalation and Ingestion Intakes with Associated Dose Estimates for Level II and Level III Personnel Using Capstone Study Data

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

Szrom, Fran; Falo, Gerald A.; Lodde, Gordon M.

2009-03-01

Depleted uranium (DU) intake rates and subsequent dose rates were estimated for personnel entering armored combat vehicles perforated with DU penetrators (level II and level III personnel) using data generated during the Capstone Depleted Uranium (DU) Aerosol Study. Inhalation intake rates and associated dose rates were estimated from cascade impactors worn by sample recovery personnel and from cascade impactors that served as area monitors. Ingestion intake rates and associated dose rates were estimated from cotton gloves worn by sample recovery personnel and from wipe test samples from the interior of vehicles perforated with large caliber DU munitions. The mean DUmore » inhalation intake rate for level II personnel ranged from 0.447 mg h-1 based on breathing zone monitor data (in and around a perforated vehicle) to 14.5 mg h-1 based on area monitor data (in a perforated vehicle). The mean DU ingestion intake rate for level II ranged from 4.8 mg h-1 to 38.9 mg h-1 based on the wipe test data including surface to glove transfer factors derived from the Capstone data. Based on glove contamination data, the mean DU ingestion intake rates for level II and level III personnel were 10.6 mg h-1 was and 1.78 mg h-1, respectively. Effective dose rates and peak kidney uranium concentration rates were calculated based on the intake rates. The peak kidney uranium concentration rate cannot be multiplied by the total exposure duration when multiple intakes occur because uranium will clear from the kidney between the exposures.« less

Computationally efficient analysis of particle transport and deposition in a human whole-lung-airway model. Part II: Dry powder inhaler application.

PubMed

Kolanjiyil, Arun V; Kleinstreuer, Clement; Sadikot, Ruxana T

2017-05-01

Pulmonary drug delivery is becoming a favored route for administering drugs to treat both lung and systemic diseases. Examples of lung diseases include asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD) as well as respiratory distress syndrome (ARDS) and pulmonary fibrosis. Special respiratory drugs are administered to the lungs, using an appropriate inhaler device. Next to the pressurized metered-dose inhaler (pMDI), the dry powder inhaler (DPI) is a frequently used device because of the good drug stability and a minimal need for patient coordination. Specific DPI-designs and operations greatly affect drug-aerosol formation and hence local lung deposition. Simulating the fluid-particle dynamics after use of a DPI allows for the assessment of drug-aerosol deposition and can also assist in improving the device configuration and operation. In Part I of this study a first-generation whole lung-airway model (WLAM) was introduced and discussed to analyze particle transport and deposition in a human respiratory tract model. In the present Part II the drug-aerosols are assumed to be injected into the lung airways from a DPI mouth-piece, forming the mouth-inlet. The total as well as regional particle depositions in the WLAM, as inhaled from a DPI, were successfully compared with experimental data sets reported in the open literature. The validated modeling methodology was then employed to study the delivery of curcumin aerosols into lung airways using a commercial DPI. Curcumin has been implicated to possess high therapeutic potential as an antioxidant, anti-inflammatory and anti-cancer agent. However, efficacy of curcumin treatment is limited because of the low bioavailability of curcumin when ingested. Hence, alternative drug administration techniques, e.g., using inhalable curcumin-aerosols, are under investigation. Based on the present results, it can be concluded that use of a DPI leads to low lung deposition efficiencies because large amounts of

Evaluating the length of stay and value of time in a pediatric emergency department with two models by comparing two different albuterol delivery systems.

PubMed

Staggs, Lauren; Peek, Meagan; Southard, Gary; Gracely, Ed; Baxendale, Sidney; Cross, Keith P; Kim, In K

2012-01-01

Asthma is one of the most common childhood illnesses and accounts for a substantial amount of pediatric emergency department visits. Historically, acute exacerbations are treated with a beta agonist via nebulizer therapy (NEB). However, with the advent of the spacer, the medication can be delivered via a metered dose inhaler (MDI+S) with the same efficacy for mild-to-moderate asthma exacerbations. To date, no study has been done to evaluate emergency department (ED) length of stay (LOS) and opportunity cost between nebulized vs MDI+S. The objective of this study was to compare ED LOS and associated opportunity cost among children who present with a mild asthma exacerbation according to the delivery mode of albuterol: MDI+S vs NEB. A structured, retrospective cross-sectional study was conducted. Medical records were reviewed from children aged 1-18 years treated at an urban pediatric ED from July 2007 to June 2008 with a discharge diagnosis International Classification of Disease-9 of asthma. Length of stay was defined: time from initial triage until the time of the guardian signature on the discharge instructions. An operational definition was used to define a mild asthma exacerbation; those patients requiring only one standard weight based albuterol treatment. Emergency department throughput time points, demographic data, treatment course, and delivery method of albuterol were recorded. Three hundred and four patients were analyzed: 94 in the MDI+S group and 209 in the NEB group. Mean age in years for the MDI+S group was 9.57 vs 5.07 for the NEB group (p<0.001). The percentage of patients that received oral corticosteroids was 39.4% in the MDI+S group vs 61.7% in the NEB group (p<0.001). There was no difference between groups in: race, insurance status, gender, or chest radiographs. The mean ED LOS for patients in the MDI+S group was 170 minutes compared to 205 minutes in the NEB group. On average, there was a 25.1 minute time savings per patient in ED treatment

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.

Evaluation of the cure kinetics of the wood/pMDI bondline

Treesearch

David P. Harper; Michael P. Wolcott; Timothy G. Rials

2001-01-01

Micro-dielectric analysis (µDEA) and differentia1 scanning calorimetry (DSC) were used to monitor cure of polymeric diphenyl-methane diisocyanate (pMDI) resin with wood strands in a saturated steam environment. A first-order autocatalyzed kinetic model was employed to determine kinetic parameters. The kinetics were found to follow an Arrhenius relation. A single ramp...

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

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.

Carcinogenesis From Inhaled (PuO2)-Pu-239 in Beagles: Evidence for Radiation Homeostasis at Low Doses?

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

Fisher, Darrell R.; Weller, Richard E.

From the early 1970s to the late 1980s, Pacific Northwest National Laboratory conducted life-span studies in beagle dogs on the biological effects of inhaled plutonium (239PuO2, 238PuO2, and 239Pu[NO3]4) to help predict risks associated with accidental intakes in workers. Years later, the purpose of the present follow-up study is to reassess the dose-response relationship for lung cancer induction in the 239PuO2 dogs compared to controls, with particular focus on the dose-response at low lung doses. A 239PuO2 aerosol (2.3 μm AMAD, 1.9 μm GSD) was administered to six groups of 20 young (18-month old) beagle dogs (10 males and 10more » females) by inhalation at six different activity levels, as previously described in Laboratory reports. Control dogs were sham-exposed. In dose level 1, initial pulmonary lung depositions were 130 ± 48 Bq (3.5 ± 1.3 nCi), corresponding to 1 Bq g-1 lung tissue (0.029 ± 0.001 nCi g-1. Groups 2 through 6 received initial lung depositions (mean values) of 760, 2724, 10345, 37900, and 200000 Bq (22, 79, 300, 1100, and 5800 nCi) 239PuO2, respectively. For each dog, the absorbed dose to lungs was calculated from the initial lung burden and the final lung burden at time of death and lung mass, assuming a single, long-term retention function. Insoluble plutonium oxide exhibited long retention times in the lungs. Increased dose-dependent mortality due to lung cancer (bronchiolar-alveolar carcinoma, adenocarcinoma, epidermoid carcinoma) and radiation pneumonitis (highest exposures group) was observed in dogs exposed to 239PuO2. Calculated lung doses ranged from a few cGy in early-sacrificed dogs to 7764 cGy in dogs that experienced early deaths from radiation pneumonitis. Data were regrouped by lifetime lung dose and plotted as a function of lung tumor incidence. Lung tumor incidence in controls and zero-dose exposed dogs was 18% (5/28). However, no lung tumors were observed in 16 dogs with the lowest lung doses (8 to 22 cGy, mean 14.4 �

Chronic inhalation of carbon monoxide: effects on the respiratory and cardiovascular system at doses corresponding to tobacco smoking.

PubMed

Sørhaug, Sveinung; Steinshamn, Sigurd; Nilsen, Odd G; Waldum, Helge L

2006-12-07

Carbon monoxide (CO) is a dangerous poison in high concentrations, but the long-term effects of low doses of CO, as in the gaseous component of tobacco smoke, are not well known. The aims of our study were to evaluate the long-term effects of inhaled CO on the respiratory and cardiovascular system at doses corresponding to tobacco smoking and its effect on tumourigenesis and pulmonary neuroendocrine (NE) cells. Female Wistar rats were exposed to either CO (200 ppm) for 20 h/day (n=51) or air (n=26) for 72 weeks. Carboxyhaemoglobin was 14.7+/-0.3% in CO exposed animals and 0.3+/-0.1% in controls. In the lungs, no signs of pathology similar to that associated with cigarette smoking were observed, and no differences in number of pulmonary NE cells were observed between the groups. Chronic CO inhalation induced a 20% weight increase of the right ventricle (p=0.001) and a 14% weight increase of the left ventricle and interventricular septum (p<0.001). Histological examination of the myocardium did not reveal any signs of scarring. In the aorta and femoral artery, no signs of atherosclerosis were observed in CO exposed rats. No exposure related carcinogenic effects were observed. Spontaneous tumours were identified in 29% of CO exposed animals and in 28% of the controls. Our results suggest that low dose CO exposure is probably not responsible for the respiratory pathology associated with tobacco smoking. The effects on the cardiovascular system seem to involve myocardial hypertrophy, but not atherogenesis.

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/

Brand and generic use of inhalation medication and frequency of switching in children and adults: A population-based cohort study.

PubMed

Engelkes, Marjolein; van Blijderveen, Jan C; Overbeek, Jetty A; Kuiper, Josephine; Herings, Ron C M; Sturkenboom, Miriam C J M; de Jongste, Johan C; Verhamme, Katia M C; Janssens, Hettie M

2017-11-29

The expiration of patents of brand inhalation medications and the ongoing pressure on healthcare budgets resulted in a growing market for generics. To study the use of brand and generic inhalation medication and the frequency of switching between brand and generic and between devices. In addition, we investigated whether switching affected adherence. From dispensing data from the Dutch PHARMO Database Network a cohort aged ≥ 5 years, using ≥ 1 year of inhalation medication between 2003 and 2012 was selected. Switching was defined as changing from brand to generic or vice versa. In addition, we studied change in aerosol delivery device type (e.g., DPI, pMDI, and nebulizers). Adherence was calculated using the medication possession ratio (MPR). The total cohort comprised 70,053 patients with 1,604,488 dispensations. Per calendar year, 5% switched between brand and generic inhalation medication and 5% switched between devices. Median MPRs over the first 12 months ranged between 33 and 55%. Median MPR over the total period was lower after switch from brand to generic and vice versa for formoterol (44.5 vs. 42.1 and 63.5 vs. 53.8) and beclomethasone (93.8 vs. 59.8 and 81.3 vs. 55.9). Per year, switching between brand and generic inhalation medication was limited to 5% of the patients, switching between device types was observed in 5% as well. Adherence to both generic and brand inhalation medication was low. Effect of switching on adherence was contradictory; depending on time period, medication and type, and direction of switching. Further research on reasons for switching and potential impact on clinical outcomes is warranted.

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.

Developing an in vitro understanding of patient experience with hydrofluoroalkane-metered dose inhalers.

PubMed

Doub, William H; Shah, Vibhakar; Limb, Susan; Guo, Changning; Liu, Xiaofei; Ngo, Diem

2014-11-01

As a result of the Montreal Protocol on Substances that Deplete the Ozone Layer, manufacturers of metered dose inhalers began reformulating their products to use hydrofluoroalkanes (HFAs) as propellants in place of chlorofluorocarbons (CFCs). Although the new products are considered safe and efficacious by the US Food and Drug Administration (FDA), a large number of complaints have been registered via the FDA's Adverse Events Reporting System (FAERS)-more than 7000 as of May 2013. To develop a better understanding of the measurable parameters that may, in part, determine in vitro performance and thus patient compliance, we compared several CFC- and HFA-based products with respect to their aerodynamic performance in response to changes in actuator cleaning interval and interactuation delay interval. Comparison metrics examined in this study were: total drug delivered ex-actuator, fine particle dose (<5 μm), mass median aerodynamic diameter, plume width, plume temperature, plume impaction force, and actuator orifice diameter. Overall, no single metric or test condition distinguishes HFA products from CFC products, but, for individual products tested, there were a combination of metrics that differentiated one from another. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

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.

Contribution of time-activity pattern and microenvironment to black carbon (BC) inhalation exposure and potential internal dose among elementary school children

NASA Astrophysics Data System (ADS)

Jeong, Hyeran; Park, Donguk

2017-09-01

The aims of this study were to quantify the contributions of activities or microenvironments (MEs) to daily total exposure to and potential dose of black carbon (BC). Daily BC exposures (24-h) were monitored using a micro-aethalometer micoAeth AE51 with forty school-aged children living in an urban area in Korea from August 2015 to January 2016. The children's time-activity patterns and the MEs they visited were investigated by means of a time-activity diary (TAD) and follow-up interviews with the children and their parents. Potential inhaled dose was estimated by multiplying the airborne BC concentrations (μg/m3) we monitored for the time the children spent in a particular ME by the inhalation rate (IR, m3/h) for the time-activity performed. The contribution of activities and MEs to overall daily exposure to and potential dose of BC was quantified. Overall mean daily potential dose was equal to 24.1 ± 10.6 μg/day (range: 6.6-46.3 μg/day). The largest contribution to BC exposure and potential dose (51.9% and 41.7% respectively) occurred in the home thanks to the large amount of time spent there. Transportation was where children received the most intense exposure to (14.8%) and potential dose (20.2%) of BC, while it accounted for 7.6% of daily time. School on weekdays during the semester was responsible for 20.3% of exposure and 22.5% of potential dose. Contribution to BC exposure and potential dose was altered by several time-activity parameters, such as type of day (weekdays vs. weekends; school days vs. holidays), season, and gender. Traveling by motor vehicle and subway showed more elevated exposure or potential dose intensity on weekdays or school days, probably influenced by the increased surrounding traffic volumes on these days compared to on weekends or holidays. This study may be used to prioritize targets for minimizing children's exposure to BC and to indicate outcomes of BC control strategies.

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.

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.

Comparison of Time-Distance Local Helioseismology on GONG and MDI Data Sets

NASA Technical Reports Server (NTRS)

Duvall, T. L., Jr.; Zhao, J.; Rajaguru, S. P.; Toner, C. G.; Kosovichev, A. G.; Thompson, M. J.; Hughes, S. J.

2003-01-01

We show first results derived from one rotation of GONG++ and MDI data analyzed independently by different groups with time-distance techniques. We focus on observations obtained during spring 2002 and especially on Carrington rotation 1988 (2002/3/30 - 2002/4/26) and measure flow components and wave speed inhomogeneities over a range of depths for different active regions.

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- ...

Acute and repeated dose inhalation toxicity of para-nitrophenol sodium salt in rats.

PubMed

Smith, L W; Hall, G T; Kennedy, G L

1988-01-01

Para-Nitrophenol Sodium Salt (PNSP) has relatively low acute inhalation toxicity; the 4-hr Approximate Lethal Concentration in rats is greater than 4.7 mg/l. One subacute study was conducted at 0, 0.34 and 2.47 mg PNSP/l for ten 6-hr exposures. Darker urine, proteinuria and elevated creatinine and SGOT were seen after exposure and were still evident after 14 days recovery. Methemoglobinemia also was seen and was reversible at 0.34 mg/l after 14 days. In addition, exposure to 2.47 mg/l caused elevated erythrocytes, hemoglobin and hematocrit. A second subacute study at 0.03 and 0.13 mg PNSP/l showed reversible methemoglobinemia only at 0.13 mg/l. The repeated dose no-observable effect level was 0.03 mg/l. No compound-related pathologic changes were noted in any of the studies.

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

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

Automated bolus advisor control and usability study (ABACUS): does use of an insulin bolus advisor improve glycaemic control in patients failing multiple daily insulin injection (MDI) therapy? [NCT01460446

PubMed Central

2012-01-01

Background People with T1DM and insulin-treated T2DM often do not follow and/or adjust their insulin regimens as needed. Key contributors to treatment non-adherence are fear of hypoglycaemia, difficulty and lack of self-efficacy associated with insulin dose determination. Because manual calculation of insulin boluses is both complex and time consuming, people may rely on empirical estimates, which can result in persistent hypoglycaemia and/or hyperglycaemia. Use of automated bolus advisors (BA) has been shown to help insulin pump users to more accurately meet prandial insulin dosage requirements, improve postprandial glycaemic excursions, and achieve optimal glycaemic control with an increased time within optimal range. Use of a BA containing an early algorithm based on sliding scales for insulin dosing has also been shown to improve HbA1c levels in people treated with multiple daily insulin injections (MDI). We designed a study to determine if use of an automated BA can improve clinical and psychosocial outcomes in people treated with MDI. Methods/design The Automated Bolus Advisor Control and Usability Study (ABACUS) is a 6-month, prospective, randomised, multi-centre, multi-national trial to determine if automated BA use improves glycaemic control as measured by a change in HbA1c in people using MDI with elevated HbA1c levels (#62;7.5%). A total of 226 T1DM and T2DM participants will be recruited. Anticipated attrition of 20% will yield a sample size of 90 participants, which will provide #62;80% power to detect a mean difference of 0.5%, with SD of 0.9%, using a one-sided 5% t-test, with 5% significance level. Other measures of glycaemic control, self-care behaviours and psychosocial issues will also be assessed. Discussion It is critical that healthcare providers utilise available technologies that both facilitate effective glucose management and address concerns about safety and lifestyle. Automated BAs may help people using MDI to manage their diabetes more

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.

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.

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

Lung deposition and systemic bioavailability of different aerosol devices with and without humidification in mechanically ventilated patients.

PubMed

Moustafa, Islam O F; Ali, Mohammed R A-A; Al Hallag, Moataz; Rabea, Hoda; Fink, James B; Dailey, Patricia; Abdelrahim, Mohamed E A

During mechanical ventilation medical aerosol delivery has been reported to be upto two fold greater with dry inhaled gas than with heated humidity. Urine levels at 0.5 h post dose (URSAL0.5%) has been confirmed as an index of lung deposition and 24 h (URSAL24%) as index of systemic absorption. Our aim was to determine the effect of humidification and aerosol device type on drug delivery to ventilated patients using urine levels. In a randomized crossover design, 36 (18female) mechanically ventilated patients were assigned to one of three groups. Groups 1 and 2 received 5000 μg salbutamol using vibrating mesh (VM) and jet nebulizers (JN), respectively, while group 3 received 1600 μg (16 puffs) of salbutamol via metered dose inhaler with AeroChamber Vent (MDI-AV). All devices were placed in the inspiratory limb of ventilator downstream from the humidifier. Each subject received aerosol with and without humidity at >24 h intervals with >12 h washout periods between salbutamol doses. Patients voided urine 15 min before each study dose and urine samples were collected at 0.5 h post dosing and pooled for the next 24 h. The MDI-AV and VM resulted in a higher percentage of urinary salbutamol levels compared to the JN (p < 0.05). Urine levels were similar between humidity and dry conditions. Our findings suggest that in-vitro reports overestimate the impact of dry vs. heated humidified conditions on the delivery of aerosol during invasive mechanical ventilation. Copyright © 2017 Elsevier Inc. All rights reserved.

Challenges of curcumin bioavailability: novel aerosol remedies.

PubMed

Subramani, Parasuraman Aiya; Narala, Venkata R

2013-01-01

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

Intercomparison of SOUP, ASP, LPSP, and MDI magnetograms

NASA Astrophysics Data System (ADS)

Berger, T.; Lites, B.; Martinez-Pillet, V.; Tarbell, T.; Title, A.

2001-05-01

We compare simultaneous magnetograms of a solar active region taken by the Advanced Stokes Polarimeter (ASP) and the Solar Optical Universal Polimeter (SOUP) in 1998. In addition we compare magnetograms taken by the La Palma Stokes Polarimeter (LPSP), the Michelson Doppler Imager (MDI) on SOHO, and the SOUP instrument in 2000. The SOUP instrument on the Swedish Vacuum Solar Telescope (SVST) attains the highest spatial resolution but has the least understood calibration; the ASP on the Dunn Solar Telescope (DST) at Sacramento Peak attains the highest magnetic field precision. The goal of the program is to better quantify the SOUP magnetograms and thereby study magnetic element dynamics in the photosphere with higher precision.

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.

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.

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.

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.

Inhalation dose due to radon, thoron, and progenies in dwellings of a hill station.

PubMed

Sivakumar, R

2017-02-01

The general public spends a major portion of their time in an indoor environment and hence receives a considerable amount of radiation. Knowledge about indoor radiation is important in order to arrive at the actual effective dose received by residents. The indoor radon, thoron, and progeny concentrations observed in the present study were found to vary with seasons of a given year. The highest and lowest indoor average radon, thoron, and progeny levels were observed during winter and summer seasons, respectively. The concentrations of indoor radon, thoron, and progenies were found to vary with the type of houses. The highest 222 Rn, 220 Rn, and progeny concentrations were observed in mud houses and the lowest values were recorded in wooden houses. The indoor 222 Rn concentration correlated well with concentration of its grandparent 238 U in underlying soil with a correlation coefficient of 0.87. The correlation between indoor 220 Rn and 232 Th in the underlying soil was found to be 0.64. The estimated effective doses received by the general public in the present study due to indoor radon and thoron were 1.49 ± 0.49 and 1.30 ± 0.53 mSv/year, respectively. The annual effective doses due to radon and thoron progenies were estimated as 0.76 ± 0.27 and 0.47 ± 0.23 mSv/year, respectively. The contributions from 222 Rn, 220 Rn, and corresponding progenies to the annual effective doses received were 37, 32, 19, and 12%, respectively. The general public living in the study area receives an inhalation dose of 4.02 mSv/year due to indoor radon, thoron, and progenies, which were found to be less than the action limit of ICRP 2009.

Radon and thoron inhalation doses in dwellings with earthen architecture: Comparison of measurement methods.

PubMed

Meisenberg, Oliver; Mishra, Rosaline; Joshi, Manish; Gierl, Stefanie; Rout, Rajeswari; Guo, Lu; Agarwal, Tarun; Kanse, Sandeep; Irlinger, Josef; Sapra, Balvinder K; Tschiersch, Jochen

2017-02-01

The radioactive noble gas radon ( 222 Rn) and its decay products have been considered a health risk in the indoor environment for many years because of their contribution to the radiation dose of the lungs. The radioisotope thoron ( 220 Rn) and its decay products came into focus of being a health risk only recently. The reason for this is its short half-life, so only building material can become a significant source for indoor thoron. In this study, dwellings with earthen architecture were investigated with different independent measurement techniques in order to determine appropriate methods for reliable dose assessment of the dwellers. While for radon dose assessment, radon gas measurement and the assumption of a common indoor equilibrium factor often are sufficient, thoron gas has proven to be an unreliable surrogate for a direct measurement of thoron decay products. Active/time-resolved but also passive/integrating measurements of the total concentration of thoron decay products demonstrated being precise and efficient methods for determining the exposure and inhalation dose from thoron and its decay products. Exhalation rate measurements are a useful method for a rough dose estimate only if the exhalation rate is homogeneous throughout the house. Before the construction of a building in-vitro exhalation rate measurements on the building material can yield information about the exposure that is to be expected. Determining the unattached fraction of radon decay products and even more of thoron decay products leads to only a slightly better precision; this confirms the relative unimportance of the unattached thoron decay products due to their low concentration. The results of this study thereby give advice on the proper measurement method in similar exposure situations. Copyright © 2017 Elsevier B.V. All rights reserved.

IRIS Toxicological Review of Formaldehyde (Inhalation) ...

EPA Pesticide Factsheets

UPDATE EPA is currently revising its Integrated Risk Information System (IRIS) assessment of formaldehyde to address the 2011 NAS peer review recommendations. This assessment addresses both noncancer and cancer human health effects that are relevant to assessing the risks from chronic inhalation exposure to formaldehyde. To facilitate discussion of several scientific issues pertinent to the assessment, EPA convened a state-of-the-science workshop on April 30 and May 1, 2014. This workshop focused on the following three themes: Evidence pertaining to the influence of formaldehyde that is produced endogenously (by the body during normal biological processes) on the toxicity of inhaled formaldehyde, and implications for the health assessment; Mechanistic evidence relevant to formaldehyde inhalation exposure and lymphohematopoietic cancers (leukemia and lymphomas); and Epidemiological research examining the potential association between formaldehyde exposure and lymphohematopoietic cancers (leukemia and lymphomas). June 2010: EPA is conducting an independent expert peer review by the National Academy of Sciences and public comment of the scientific basis supporting the human health hazard and dose-response assessment of Formaldehyde-Inhalation that when finalized will appear on the Integrated Risk Information System (IRIS) database. This draft IRIS health assessment addresses both noncancer and cancer human health effects that may result from chronic inhal

[Deliberate interruptions and changes of dose of inhaled corticosteroids by asthma patients: "a community pharmacy study"].

PubMed

Laforest, L; Van Ganse, É; Devouassoux, G; Chatté, G; Tamberou, C; Belhassen, M; Chamba, G

2015-01-01

Adherence to inhaled corticosteroids (ICS) remains a major issue for asthma management, even among patients receiving a regular prescription from their doctor. The frequency of deliberate interruption of ICS, and of spontaneous changes of dose, were studied in a population of asthma patients recruited in community pharmacies. Asthma patients (aged 18-50) recruited in community pharmacies reported in self-administered questionnaires their spontaneous interruptions and changes of doses of ICS during the past 3 months. The characteristics of patients who interrupted their therapy or who modified the dose were compared with other patients. The studied population included 252 patients (mean age 35 year-old, females: 59%), of whom 62% had inadequately controlled asthma. Among these patients, 25% had interrupted ICS therapy during the past 3 months, while 21% spontaneously changed the dose. The most reported reason for interrupting ICS was the cessation of symptoms (50%). In multivariate analysis, interrupting ICS was mainly associated with inadequate asthma control (OR=3.1, 95% CI 1.5-6.4), while the strongest association with changing ICS doses was the patients' perception of asthma as a concern in their lives (OR=3.2, 95% CI 1.2-8.4). These results underline a poor understanding of the purpose of ICS therapy by patients. They also highlight the need of therapeutic education to improve the management of the disease. Copyright © 2014 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Economics of "essential use exemptions" for metered-dose inhalers under the Montreal Protocol.

PubMed

DeCanio, Stephen J; Norman, Catherine S

2007-10-01

The Montreal Protocol on Substances that Deplete the Ozone Layer has led to rapid reductions in the use of ozone-depleting substances worldwide. However, the Protocol provides for "essential use exemptions" (EUEs) if there are no "technically and economically feasible" alternatives. An application that might qualify as an "essential use" is CFC-powered medical metered-dose inhalers (MDIs) for the treatment of asthma and chronic obstructive pulmonary disease (COPD), and the US and other nations have applied for exemptions in this case. One concern is that exemptions are necessary to ensure access to medications for low-income uninsureds. We examine the consequences of granting or withholding such exemptions, and conclude that government policies and private-sector programs are available that make it economically feasible to phase out chlorofluorocarbons (CFCs) in this application, thereby furthering the global public health objectives of the Montreal Protocol without compromising the treatment of patients who currently receive medication by means of MDIs.

Analysis of Supergranule Sizes and Velocities Using Solar Dynamics Observatory (SDO)/Helioseismic Magnetic Imager (HMI) and Solar and Heliospheric Observatory (SOHO)/Michelson Doppler Imager (MDI) Dopplergrams

NASA Technical Reports Server (NTRS)

Williams, Peter E.; Pesnell, W. Dean; Beck, John G.; Lee, Shannon

2013-01-01

Co-temporal Doppler images from Solar and Heliospheric Observatory (SOHO)/ Michelson Doppler Imager (MDI) and Solar Dynamics Observatory (SDO)/Helioseismic Magnetic Imager (HMI) have been analyzed to extract quantitative information about global properties of the spatial and temporal characteristics of solar supergranulation. Preliminary comparisons show that supergranules appear to be smaller and have stronger horizontal velocity flows within HMI data than was measured with MDI. There appears to be no difference in their evolutionary timescales. Supergranule sizes and velocities were analyzed over a ten-day time period at a 15-minute cadence. While the averages of the time-series retain the aforementioned differences, fluctuations of these parameters first observed in MDI data were seen in both MDI and HMI time-series, exhibiting a strong cross-correlation. This verifies that these fluctuations are not instrumental, but are solar in origin. The observed discrepancies between the averaged values from the two sets of data are a consequence of instrument resolution. The lower spatial resolution of MDI results in larger observed structures with lower velocities than is seen in HMI. While these results offer a further constraint on the physical nature of supergranules, they also provide a level of calibration between the two instruments.

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...

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

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.

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

Comparison between KPVT/SPM and SoHO/MDI magnetograms with an application to solar irradiance reconstructions

NASA Astrophysics Data System (ADS)

Wenzler, T.; Solanki, S. K.; Krivova, N. A.; Fluri, D. M.

2004-12-01

To be able to use both space- and ground-based solar magnetograms and construct long time series of derived parameters it is important to cross-calibrate them so that we can estimate their reliability and combine them. Using two different techniques, we compare magnetograms as well as continuum images recorded by the Spectropolarimeter (SPM) on Kitt Peak and the Michelson Doppler Interferometer (MDI) on board SoHO. We find that the result obtained depends on the method used. The method we favour gives almost identical umbral and penumbral areas and very similar total magnetic fluxes in faculae. The magnetic fluxes in umbrae and penumbrae returned by the two instruments, however, differ considerably. We also demonstrate that SPM data can be employed to reconstruct total solar irradiance variations with almost the same accuracy as recently shown for MDI data.

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.

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.

Airborne concentrations of methylene diphenyl diisocyanate (MDI) in North American wood mills during the manufacturing of oriented strand board (OSB).

PubMed

Karoly, William J; Flatley, John J; Stevenson, Ralph D; Bowers, John D

2004-12-01

Air monitoring data were collected from industrial hygiene surveys over an 8-year period in oriented strand board (OSB) mills. Personal samples were taken to evaluate potential employee exposures to MDI. Area samples were taken to determine the effectiveness of control measures used in the mills to prevent fugitive emissions of wood dust, MDI, and MDI-coated wood dust from the OSB manufacturing process. Personal sampling results (578 samples covering 11 different job categories) ranged from 0.0002-0.524 mg/m3, with a GM = 0.001 and GSD = 3.71. Area sampling results (1657 samples covering 14 stationary locations in the mills) ranged from 0.0002-2.5 mg/m3, with a GM = 0.004 and GSD = 5.52. The statistical range of the data suggests high variability. While exposures to MDI above the established limits (0.051 mg/m3, 8-hour time-weighted average, 0.2 mg/m3, ceiling) can and do occur when engineering controls are not maintained and/or proper work practices and personal protective equipment are not followed/used for certain high exposure potential tasks, the data indicate that over 97% of the personal and 92% of the area sampling results are less than 0.051 mg/m3. Wipe testing was performed to determine the presence of removable, unreacted diisocyanates (NCO functional groups)from various surfaces. Positive results were found in about 13% of the wipe tests on surfaces confined to the blender, forming line, and hopper deck process areas.

Dose-response of an extrafine dry powder inhaler formulation of glycopyrronium bromide: randomized, double-blind, placebo-controlled, dose-ranging study (GlycoNEXT).

PubMed

Beeh, Kai M; Emirova, Aida; Prunier, Hélène; Santoro, Debora; Nandeuil, Marie Anna

2018-01-01

An extrafine formulation of the long-acting muscarinic antagonist, glycopyrronium bromide (GB), has been developed for delivery via the NEXThaler dry powder inhaler (DPI). This study assessed the bronchodilator efficacy and safety of different doses of this formulation in patients with COPD to identify the optimal dose for further development. This was a multicenter, randomized, double-blind, placebo-controlled, incomplete block, three-way crossover study, including three 28-day treatment periods, each separated by a 21-day washout period. Eligible patients had a diagnosis of COPD and post-bronchodilator forced expiratory volume in 1 s (FEV 1 ) 40%-70% predicted. Treatments administered were GB 6.25, 12.5, 25 and 50 μg or matched placebo; all were given twice daily (BID) via DPI, with spirometry assessed on Days 1 and 28 of each treatment period. The primary end point was FEV 1 area under the curve from 0 to 12 h (AUC 0-12 h ) on Day 28. A total of 202 patients were randomized (61% male, mean age 62.6 years), with 178 (88%) completing all the three treatment periods. For the primary end point, all the four GB doses were superior to placebo ( p <0.001) with mean differences (95% CI) of 114 (74, 154), 125 (85, 166), 143 (104, 183) and 187 (147, 228) mL for GB 6.25, 12.5, 25 and 50 μg BID, respectively. All four GB doses were also statistically superior to placebo for all secondary efficacy end points, showing clear dose-response relationships for most of the endpoints. Accordingly, GB 25 μg BID met the criteria for the minimally acceptable dose. Adverse events were reported by 15.5, 16.2, 10.9 and 14.3% of patients receiving GB 6.25, 12.5, 25 and 50 μg BID, respectively, and 14.8% receiving placebo. This study supports the selection of GB 25 μg BID as the minimal effective dose for patients with COPD when delivered with this extrafine DPI formulation.

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.

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...

Temporally and Spatially Resolved x-ray Fluorescence Measurements of in-situ Drug Concentration in Metered-Dose Inhaler Sprays

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

Duke, Daniel J.; Kastengren, Alan L.; Mason-Smith, Nicholas

Drug concentration measurements in MDI sprays are typically performed using particle filtration or laser scattering. These techniques are ineffective in proximity to the nozzle, making it difficult to determine how factors such as nozzle design will affect the precipitation of co-solvent droplets in solution-based MDIs, and the final particle distribution. In optical measurements, scattering from the constituents is difficult to separate. We present a novel technique to directly measure drug distribution. A focused x-ray beam was used to stimulate x-ray fluorescence from the bromine in a solution containing 85% HFA, 15% ethanol co-solvent, and 1 / IPBr. Instantaneous concentration measurementsmore » were obtained with 1 ms temporal resolution and 5 spatial resolution, providing information in a region that is inaccessible to many other diagnostics. The drug remains homogeneously mixed over time, but was found to be higher at the centerline than at the periphery. This may have implications for oropharyngeal deposition in vivo. Measurements in the dynamic, turbulent region of MDIs allow us to understand the physical links between formulation, inspiration, and geometry on final particle size and distribution. This will ultimately lead to a better understanding of how MDI design can be improved to enhance respirable fraction.« less

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

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

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.

Inflammatory subtypes in cough-variant asthma: association with maintenance doses of inhaled corticosteroids.

PubMed

Matsuoka, Hirofumi; Niimi, Akio; Matsumoto, Hisako; Takemura, Masaya; Ueda, Tetsuya; Yamaguchi, Masafumi; Jinnai, Makiko; Inoue, Hideki; Ito, Isao; Chin, Kazuo; Mishima, Michiaki

2010-12-01

Sputum cell-subtype profiles in cough-variant asthma (CVA) are unknown. Ninety-eight inhaled corticosteroid (ICS)-naive CVA patients were classified according to sputum eosinophil (eos)/neutrophil (neu) counts, as reported in subjects with asthma, as eosinophilic (E) (eos ≥ 1.0%, neu < 61%; n = 28), neutrophilic (N) (eos < 1.0%, neu ≥ 61%; n = 31), mixed granulocytic (M) (eos ≥ 1.0%, neu ≥ 61%; n = 12), and paucigranulocytic (P) (eos < 1.0%, neu < 61%; n = 27) subtypes. Patient characteristics; sputum levels of eosinophil cationic protein (ECP), IL-8, and neutrophil elastase (NE); and daily ICS doses required to maintain control during follow-up (6, 12, 18, and 24 months) were compared, retrospectively. Subtype N patients, predominantly women, were marginally older than the other subtypes, but FEV(1), airway responsiveness, and total and specific IgE results did not differ. ECP levels were higher in M and E than in N and P subtypes, being similar between M and E or N and P subtypes. Levels of IL-8 and NE were higher in M than in other subtypes, being similar among the latter. ICS doses were initially similar in all subtypes (800 μg equivalent of beclomethasone) but were higher in M than in N and P subtypes throughout follow-up, with E being intermediate between M and N or P subtypes. ICS doses decreased (halved or quartered) in E, N, and P patients followed for 24 months (P < .0001 for all) but remained unchanged in M subjects. IL-8 and NE levels correlated positively with ECP levels. In addition to eosinophils, neutrophils, which are possibly activated in the presence of eosinophils, may participate in the pathophysiology of CVA.

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

Reducing the radiation dose from inhaled americium-241 using continuously administered DTPA therapy.

PubMed

Guilmette, R A; Muggenburg, B A

1988-02-01

Accelerating the removal of a radionuclide from the body of a contaminated individual is the only available approach to decreasing the radiation dose from such exposures. In this study, continuous infusion of a chelating agent, DTPA, was given to dogs that had inhaled a moderately soluble aerosol, 241 AmO2, not only to accelerate clearance of the radionuclide from the lung but also to prevent its deposition in liver and bone. Treatment was begun with an intravenous injection of CaDTPA 1 h after exposure, and was continued for 64 days after exposure by implanting subcutaneously osmotic pumps containing ZnDTPA at 1 day after exposure. The results showed that the infusion therapy was effective in blocking the translocation of 99.5 per cent of the 241Am that would have been deposited in liver, and 98.3 per cent of the 241Am that would have been deposited in bone. This result was significantly better than the result achieved using repeated intravenous injections of DTPA, the method of treatment in current use for actinide contamination cases.

Development of a High Efficiency Dry Powder Inhaler: Effects of Capsule Chamber Design and Inhaler Surface Modifications

PubMed Central

Behara, Srinivas R.B.; Farkas, Dale R.; Hindle, Michael; Longest, P. Worth

2013-01-01

Purpose The objective of this study was to explore the performance of a high efficiency dry powder inhaler (DPI) intended for excipient enhanced growth (EEG) aerosol delivery based on changes to the capsule orientation and surface modifications of the capsule and device. Methods DPIs were constructed by combining newly designed capsule chambers (CC) with a previously developed three-dimensional (3D) rod array for particle deagglomeration and a previously optimized EEG formulation. The new CCs oriented the capsule perpendicular to the incoming airflow and were analyzed for different air inlets at a constant pressure drop across the device. Modifications to the inhaler and capsule surfaces included use of metal dispersion rods and surface coatings. Aerosolization performance of the new DPIs was evaluated and compared with commercial devices. Results The proposed capsule orientation and motion pattern increased capsule vibrational frequency and reduced the aerosol MMAD compared with commercial/modified DPIs. The use of metal rods in the 3D array further improved inhaler performance. Coating the inhaler and capsule with PTFE significantly increased emitted dose (ED) from the optimized DPI. Conclusions High efficiency performance is achieved for EEG delivery with the optimized DPI device and formulation combination producing an aerosol with MMAD < 1.5 µm, FPF<5µm/ED > 90%, and ED > 80%. PMID:23949304

Safety, Tolerability and Pharmacokinetics of Single Doses of Oxytocin Administered via an Inhaled Route in Healthy Females: Randomized, Single-blind, Phase 1 Study.

PubMed

Fernando, Disala; Siederer, Sarah; Singh, Sunita; Schneider, Ian; Gupta, Ashutosh; Powell, Marcy; Richards, Duncan; McIntosh, Michelle P; Lambert, Peter; Fowles, Susan

2017-08-01

The utility of intramuscular (IM) oxytocin for the prevention of postpartum hemorrhage in resource-poor settings is limited by the requirement for temperature-controlled storage and skilled staff to administer the injection. We evaluated the safety, tolerability and pharmacokinetics (PK) of a heat-stable, inhaled (IH) oxytocin formulation. This phase 1, randomized, single-center, single-blind, dose-escalation, fixed-sequence study (NCT02542813) was conducted in healthy, premenopausal, non-pregnant, non-lactating women aged 18-45years. Subjects initially received IM oxytocin 10 international units (IU) on day 1, IH placebo on day 2, and IH oxytocin 50μg on day 3. Subjects were then randomized 4:1 using validated GSK internal software to IH placebo or ascending doses of IH oxytocin (200, 400, 600μg). PK was assessed by comparing systemic exposure (maximum observed plasma concentration, area under the concentration-time curve, and plasma concentrations at 10 and 30min post dose) for IH versus IM oxytocin. Adverse events (AEs), spirometry, laboratory tests, vital signs, electrocardiograms, physical examinations, and cardiac telemetry were assessed. Subjects were recruited between September 14, 2015 and October 12, 2015. Of the 16 subjects randomized following initial dosing, 15 (IH placebo n=3; IH oxytocin n=12) completed the study. IH (all doses) and IM oxytocin PK profiles were comparable in shape. However, systemic exposure with IH oxytocin 400μg most closely matched IM oxytocin 10IU. Systemic exposure was approximately dose proportional for IH oxytocin. No serious AEs were reported. No clinically significant findings were observed for any safety parameters. These data suggest that similar oxytocin systemic exposure can be achieved with IM and IH administration routes, and no safety concerns were identified with either route. The inhalation route may offer the opportunity to increase access to oxytocin for women giving birth in resource-poor settings. Copyright �

Structure and Rotation of the Solar Interior: Initial Results from the MDI Medium-L Program

NASA Technical Reports Server (NTRS)

Kosovichev, A. G.; Schou, J.; Scherrer, P. H.; Bogart, R. S.; Bush, R. I.; Hoeksema, J. T.; Aloise, J.; Bacon, L.; Burnette, A.; DeForest, C.;

Long-Acting β-Agonist in Combination or Separate Inhaler as Step-Up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids.

PubMed

Turner, Steve; Richardson, Kathryn; Murray, Clare; Thomas, Mike; Hillyer, Elizabeth V; Burden, Anne; Price, David B

Adding a long-acting β 2 -agonist (LABA) to inhaled corticosteroids (ICS) using a fixed-dose combination (FDC) inhaler is the UK guideline recommendation for children aged more than 4 years with uncontrolled asthma. The evidence of benefit of adding an FDC inhaler over a separate LABA inhaler is limited. The objective of this study was to compare the effectiveness of a LABA added as an FDC inhaler, and as a separate inhaler, in children with uncontrolled asthma. Two UK primary care databases were used to create a matched cohort study with a 2-year follow-up period. We included children prescribed their first step-up from ICS monotherapy. Two cohorts were formed for children receiving an add-on LABA as an FDC inhaler, or a separate LABA inhaler. Matching variables and confounders were identified by comparing characteristics during a baseline year of follow-up. Outcomes were examined during the subsequent year. The primary outcome was an adjusted odds ratio for overall asthma control (defined as follows: no asthma-related hospital admission or emergency room visit, prescription for oral corticosteroids or antibiotic with evidence of respiratory consultation, and ≤2 puffs of short-acting β-agonist daily). The final study consisted of 1330 children in each cohort (mean age 9 years; 59% male). In the separate ICS+LABA cohort, the odds of achieving overall asthma control were lower (adjusted odds ratio, 0.77 [95% confidence interval, 0.66-0.91]; P = .001) compared with the FDC cohort. The study demonstrates a small but significant benefit in achieving asthma control from an add-on LABA as an FDC, compared with a separate inhaler and this supports current guideline recommendations. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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.

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 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 Injuries

MedlinePlus

... breathe in toxic substances, such as smoke (from fires), chemicals, particle pollution, and gases. Inhalation injuries can ... of thermal injuries. Over half of deaths from fires are due to inhalation injuries. Symptoms of inhalation ...

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.

Inhalant Use and Inhalant Use Disorders in the United States

PubMed Central

Howard, Matthew O.; Bowen, Scott E.; Garland, Eric L.; Perron, Brian E.; Vaughn, Michael G.

2011-01-01

More than 22 million Americans age 12 and older have used inhalants, and every year more than 750,000 use inhalants for the first time. Despite the substantial prevalence and serious toxicities of inhalant use, it has been termed “the forgotten epidemic.” Inhalant abuse remains the least-studied form of substance abuse, although research on its epidemiology, neurobiology, treatment, and prevention has accelerated in recent years. This review examines current findings in these areas, identifies gaps in the research and clinical literatures pertaining to inhalant use, and discusses future directions for inhalant-related research and practice efforts. PMID:22003419

Inhaled Carbon Nanotubes Reach the Sub-Pleural Tissue in Mice

PubMed Central

Ryman-Rasmussen, Jessica P.; Cesta, Mark F.; Brody, Arnold R.; Shipley-Phillips, Jeanette K.; Everitt, Jeffrey; Tewksbury, Earl W.; Moss, Owen R.; Wong, Brian A.; Dodd, Darol E.; Andersen, Melvin E.; Bonner, James C.

2009-01-01

Summary Carbon nanotubes have fibre-like shape1 and stimulate inflammation at the surface of the peritoneum when injected into the abdominal cavity of mice2, raising concerns that inhaled nanotubes3 may cause pleural fibrosis and/or mesothelioma4. Here we show that multi-walled carbon nanotubes reach the sub-pleura in mice after a single inhalation exposure of 30 mg/m3 for 6 hours. Nanotubes were embedded in the sub-pleural wall and within sub-pleural macrophages. Mononuclear cell aggregates on the pleural surface increased in number and size after 1 day and nanotube-containing macrophages were observed within these foci. Sub-pleural fibrosis increased after 2 and 6 weeks following inhalation. None of these effects were seen in mice that inhaled carbon black nanoparticles or a lower dose of nanotubes (1 mg/m3). This work advances a growing literature on pulmonary toxicology of nanotubes5 and suggests that minimizing inhalation of nanotubes during handling is prudent until further long term assessments are conducted. PMID:19893520

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

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.

Inhaled chemotherapy in lung cancer: future concept of nanomedicine

PubMed Central

Zarogoulidis, Paul; Chatzaki, Ekaterini; Porpodis, Konstantinos; Domvri, Kalliopi; Hohenforst-Schmidt, Wolfgang; Goldberg, Eugene P; Karamanos, Nikos; Zarogoulidis, Konstantinos

2012-01-01

Regional chemotherapy was first used for lung cancer 30 years ago. Since then, new methods of drug delivery and pharmaceuticals have been investigated in vitro, and in animals and humans. An extensive review of drug delivery systems, pharmaceuticals, patient monitoring, methods of enhancing inhaled drug deposition, safety and efficacy, and also additional applications of inhaled chemotherapy and its advantages and disadvantages are presented. Regional chemotherapy to the lung parenchyma for lung cancer is feasible and efficient. Safety depends on the chemotherapy agent delivered to the lungs and is dose-dependent and time-dependent. Further evaluation is needed to provide data regarding early lung cancer stages, and whether regional chemotherapy can be used as neoadjuvant or adjuvant treatment. Finally, inhaled chemotherapy could one day be administered at home with fewer systemic adverse effects. PMID:22619512

Inhaler technique maintenance: gaining an understanding from the patient's perspective.

PubMed

Ovchinikova, Ludmila; Smith, Lorraine; Bosnic-Anticevich, Sinthia

2011-08-01

The aim of this study was to determine the patient-, education-, and device-related factors that predict inhaler technique maintenance. Thirty-one community pharmacists were trained to deliver inhaler technique education to people with asthma. Pharmacists evaluated (based on published checklists), and where appropriate, delivered inhaler technique education to patients (participants) in the community pharmacy at baseline (Visit 1) and 1 month later (Visit 2). Data were collected on participant demographics, asthma history, current asthma control, history of inhaler technique education, and a range of psychosocial aspects of disease management (including adherence to medication, motivation for correct technique, beliefs regarding the importance of maintaining correct technique, and necessity and concern beliefs regarding preventer therapy). Stepwise backward logistic regression was used to identify the predictors of inhaler technique maintenance at 1 month. In total 145 and 127 participants completed Visits 1 and 2, respectively. At baseline, 17% of patients (n = 24) demonstrated correct technique (score 11/11) which increased to 100% (n = 139) after remedial education by pharmacists. At follow-up, 61% (n = 77) of patients demonstrated correct technique. The predictors of inhaler technique maintenance based on the logistic regression model (X(2) (3, N = 125) = 16.22, p = .001) were use of a dry powder inhaler over a pressurized metered-dose inhaler (OR 2.6), having better asthma control at baseline (OR 2.3), and being more motivated to practice correct inhaler technique (OR 1.2). Contrary to what is typically recommended in previous research, correct inhaler technique maintenance may involve more than repetition of instructions. This study found that past technique education factors had no bearing on technique maintenance, whereas patient psychosocial factors (motivation) did.

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.

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...

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.

Air concentrations of PBDEs on in-flight airplanes and assessment of flight crew inhalation exposure.

PubMed

Allen, Joseph G; Sumner, Ann Louise; Nishioka, Marcia G; Vallarino, Jose; Turner, Douglas J; Saltman, Hannah K; Spengler, John D

2013-07-01

To address the knowledge gaps regarding inhalation exposure of flight crew to polybrominated diphenyl ethers (PBDEs) on airplanes, we measured PBDE concentrations in air samples collected in the cabin air at cruising altitudes and used Bayesian Decision Analysis (BDA) to evaluate the likelihood of inhalation exposure to result in the average daily dose (ADD) of a member of the flight crew to exceed EPA Reference Doses (RfDs), accounting for all other aircraft and non-aircraft exposures. A total of 59 air samples were collected from different aircraft and analyzed for four PBDE congeners-BDE 47, 99, 100 and 209 (a subset were also analyzed for BDE 183). For congeners with a published RfD, high estimates of ADD were calculated for all non-aircraft exposure pathways and non-inhalation exposure onboard aircraft; inhalation exposure limits were then derived based on the difference between the RfD and ADDs for all other exposure pathways. The 95th percentile measured concentrations of PBDEs in aircraft air were <1% of the derived inhalation exposure limits. Likelihood probabilities of 95th percentile exposure concentrations >1% of the defined exposure limit were zero for all congeners with published RfDs.

Inhalants

MedlinePlus

... Drug Facts Chat Day: Inhalants Drug Facts Chat Day: Inhalants Print Expand All Can you get high ... Cool Order Free Materials National Drugs & Alcohol Chat Day Newsletter Sign up to receive National Drug & Alcohol ...

Inhalation therapy in mechanical ventilation

PubMed Central

Maccari, Juçara Gasparetto; Teixeira, Cassiano; Gazzana, Marcelo Basso; Savi, Augusto; Dexheimer-Neto, Felippe Leopoldo; Knorst, Marli Maria

2015-01-01

Patients with obstructive lung disease often require ventilatory support via invasive or noninvasive mechanical ventilation, depending on the severity of the exacerbation. The use of inhaled bronchodilators can significantly reduce airway resistance, contributing to the improvement of respiratory mechanics and patient-ventilator synchrony. Although various studies have been published on this topic, little is known about the effectiveness of the bronchodilators routinely prescribed for patients on mechanical ventilation or about the deposition of those drugs throughout the lungs. The inhaled bronchodilators most commonly used in ICUs are beta adrenergic agonists and anticholinergics. Various factors might influence the effect of bronchodilators, including ventilation mode, position of the spacer in the circuit, tube size, formulation, drug dose, severity of the disease, and patient-ventilator synchrony. Knowledge of the pharmacological properties of bronchodilators and the appropriate techniques for their administration is fundamental to optimizing the treatment of these patients. PMID:26578139

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.

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

Adhesion of nitrile rubber (NBR) to polyethylene terephthalate (PET) fabric. Part 1: PET surface modification by methylenediphenyl di-isocyanate (MDI)

NASA Astrophysics Data System (ADS)

Razavizadeh, Mahmoud; Jamshidi, Masoud

2016-01-01

Fiber to rubber adhesion is an important subject in rubber composite industry. It is well known that surface physical, mechanical and chemical treatments are effective methods to improve interfacial bonding. Ultra violet (UV) light irradiation is an efficient method which is used to increase interfacial interactions. In this research UV assisted chemical modification of PET fabric was used to increase its bonding to nitrile rubber (NBR). NBR is perfect selection to produce fuel and oil resistant rubber parts but it has weak bonding to fabrics. For this purpose at first, the PET fabric was carboxylated under UV irradiation and then methylenediphenyl diisocyanate (MDI) was reacted and grafted to carboxylated PET. T-peel test was used to evaluate PET fabric to NBR bonding strength. Attenuated total reflectance-Fourier transform infrared spectroscopy (FTIR-AT) was used to assess surface modifications of the PET fabrics. The chemical composition of the PET surfaces before and after carboxylation and MDI grafting was investigated by X-ray photoelectron spectroscopy (XPS). It was found that at vulcanizing temperature of 150 °C, carboxylation in contrary to MDI grafting, improved considerably PET to NBR adhesion. Finally effect of curing temperature on PET to NBR bonding strength was determined. It was found that increasing vulcanizing temperature to 170 °C caused considerable improvement (about 134%) in bonding strength.

A Comparison of the Performance of Efficient Data Analysis Versus Fine Particle Dose as Metrics for the Quality Control of Aerodynamic Particle Size Distributions of Orally Inhaled Pharmaceuticals.

PubMed

Tougas, Terrence P; Goodey, Adrian P; Hardwell, Gareth; Mitchell, Jolyon; Lyapustina, Svetlana

2017-02-01

The performance of two quality control (QC) tests for aerodynamic particle size distributions (APSD) of orally inhaled drug products (OIPs) is compared. One of the tests is based on the fine particle dose (FPD) metric currently expected by the European regulators. The other test, called efficient data analysis (EDA), uses the ratio of large particle mass to small particle mass (LPM/SPM), along with impactor sized mass (ISM), to detect changes in APSD for QC purposes. The comparison is based on analysis of APSD data from four products (two different pressurized metered dose inhalers (MDIs) and two dry powder inhalers (DPIs)). It is demonstrated that in each case, EDA is able to detect shifts and abnormalities that FPD misses. The lack of sensitivity on the part of FPD is due to its "aggregate" nature, since FPD is a univariate measure of all particles less than about 5 μm aerodynamic diameter, and shifts or changes within the range encompassed by this metric may go undetected. EDA is thus shown to be superior to FPD for routine control of OIP quality. This finding augments previously reported superiority of EDA compared with impactor stage groupings (favored by US regulators) for incorrect rejections (type I errors) when incorrect acceptances (type II errors) were adjusted to the same probability for both approaches. EDA is therefore proposed as a method of choice for routine quality control of OIPs in both European and US regulatory environments.

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

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

Inhaled glycopyrrolate for the treatment of chronic obstructive pulmonary disease.

PubMed

Tashkin, Donald P; Gross, Nicholas J

2018-01-01

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

U. S. Environmental Protection Agency's inhalation RFD methodology: Risk assessment for air toxics

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

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

1989-01-01

The U.S. Environmental Protection Agency (U.S. EPA) has advocated the establishment of general and scientific guidelines for the evaluation of toxicological data and their use in deriving benchmark values to protect exposed populations from adverse health effects. The Agency's reference dose (RfD) methodology for deriving benchmark values for noncancer toxicity originally addressed risk assessment of oral exposures. The paper presents a brief background on the development of the inhalation reference dose (RFDi) methodology, including concepts and issues related to addressing the dynamics of the respiratory system as the portal of entry. Different dosimetric adjustments are described that were incorporated intomore » the methodology to account for the nature of the inhaled agent (particle or gas) and the site of the observed toxic effects (respiratory or extrarespiratory). Impacts of these adjustments on the extrapolation of toxicity data of inhaled agents for human health risk assessment and future research directions are also discussed.« less

Inhalants

MedlinePlus

... such as computer cleaning dusters) directly into their nose or mouth, or place a chemical- soaked rag in their mouth. Abusers may also inhale fumes from a balloon or a plastic or paper bag. Although the high produced by inhalants usually lasts just a few ...

Treatment of acute asthma: salbutamol via jet nebuliser vs spacer and metered dose inhaler.

PubMed

Robertson, C F; Norden, M A; Fitzgerald, D A; Connor, F L; Van Asperen, P P; Cooper, P J; Francis, P W; Allen, H D

1998-04-01

To compare the efficacy of salbutamol delivered by jet nebuliser (JN) with salbutamol via a pressurised metered dose inhaler (PMDI) and a large volume spacer (Volumatic) for management of acute asthma. A total of 160 children aged from 4 to 12 years presenting to an Emergency Department with acute asthma. The study was of multicentre (n=5) randomised, double blind, parallel design. Children weighing less than 25 kg received salbutamol 2.5 mg via the JN or 600 microg (six puffs) from the PMDI. Children over 25 kg received salbutamol 5 mg via the JN or 1200 microg (12 puffs) via the PMDI. Clinical score (range 0-12) and PEF (over 7 years) were recorded at baseline and 15, 30, 45 and 60 mins post administration. The improvement from baseline at 30 min in the clinical score was 1.87 for JN and 1.43 for PMDI (P=0.09) and at 60 min was 2.15 for JN and 1.12 for PMDI (P=0.0001). The improvement in PEF at 30 min was 51 L min(-1) for JN and 27 L min(-1) for PMDI (P=0.0007) and at 60 min was 57 L min(-1) for JN and 31.5 L min(-1) for PMDI (P=0.001). Administration of salbutamol via a PMDI and a large volume spacer device provides effective relief in the management of acute asthma in children, but to a lesser extent than a jet nebuliser. This difference may represent a dose response effect.

Inhalation Dose and Source Term Studies in a Tribal Area of Wayanad, Kerala, India

PubMed Central

Damodaran, Ravikumar C.; Kumar, Visnuprasad Ashok; Panakal John, Jojo; Bangaru, Danalakshmi; Natarajan, Chitra; Sathiamurthy, Bala Sundar; Mundiyanikal Thomas, Jose; Mishra, Rosaline

2017-01-01

Among radiation exposure pathways to human beings, inhalation dose is the most prominent one. Radon, thoron, and their progeny contribute more than 50 per cent to the annual effective dose due to natural radioactivity. South west coast of India is classified as a High Natural Background Radioactivity Area and large scale data on natural radioactivity and dosimetry are available from these coastal regions including the Neendakara-Chavara belt in the south of Kerala. However, similar studies and reports from the northern part of Kerala are scarce. The present study involves the data collection and analysis of radon, thoron, and progeny concentration in the Wayanad district of Kerala. The radon concentration was found to be within a range of 12–378 Bq/m3. The thoron concentration varied from 15 to 621 Bq/m3. Progeny concentration of radon and thoron and the diurnal variation of radon were also studied. In order to assess source term, wall and floor exhalation studies have been done for the houses showing elevated concentration of radon and thoron. The average values of radon, thoron, and their progeny are found to be above the Indian average as well as the average values reported from the High Natural Background Radioactivity Areas of Kerala. Exhalation studies of the soil samples collected from the vicinity of the houses show that radon mass exhalation rate varied from below detectable limit (BDL) to a maximum of 80 mBq/kg/h. The thoron surface exhalation rate ranged from BDL to 17470 Bq/m2/h. PMID:28611847

A critical role of acute bronchoconstriction in the mortality associated with high-dose sarin inhalation: Effects of epinephrine and oxygen therapies

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

Gundavarapu, Sravanthi; Zhuang, Jianguo; Barrett, Edward G.

Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of sarin exposure is through inhalation and, depending on the dose, sarin leads to acute respiratory failure and death. The mechanism(s) of sarin-induced respiratory failure is poorly understood. Sarin irreversibly inhibits acetylcholine esterase, leading to excessive synaptic levels of acetylcholine and, we have previously shown that sarin causes marked ventilatory changes includingmore » weakened response to hypoxia. We now show that LD{sub 50} sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased hypoxia-induced factor-1α, and severe lung epithelium injury. Transferring animals into 60% oxygen chambers after sarin exposure improved the survival from about 50% to 75% at 24 h; however, many animals died within hours after removal from the oxygen chambers. On the other hand, if LD{sub 50} sarin-exposed animals were administered the bronchodilator epinephrine, > 90% of the animals survived. Moreover, while both epinephrine and oxygen treatments moderated cardiorespiratory parameters, the proinflammatory cytokine surge, and elevated expression of hypoxia-induced factor-1α, only epinephrine consistently reduced the sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD{sub 50} sarin inhalation, and epinephrine may limit the ventilatory, inflammatory, and lethal effects of sarin. - Highlights: • Inhalation exposure of rats to LD{sub 50} sarin causes death through respiratory failure. • Severe bronchoconstriction is the major cause of sarin-induced respiratory failure. • Transfer of sarin exposed rats to 60% oxygen improves the mortality temporarily

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

PubMed

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

2018-01-01

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

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

PubMed Central

Lacalle Muls, Helena; Costello, Richard W.; Reilly, Richard B.

2018-01-01

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

Design and evaluation of a restraint-free small animal inhalation dosing chamber.

PubMed

McConville, Jason T; Williams, Robert O; Carvalho, Thiago C; Iberg, Aimee N; Johnston, Keith P; Talbert, Robert L; Burgess, David; Peters, Jay I

2005-01-01

The aim of research was to design a small, restraint free, low stress animal dosing chamber for inhalation studies, and to investigate distribution of a model drug within the chamber. A small animal dosing chamber was designed that consisted of a polymethylmethacrylate (PMMA) airtight box (40.6 x 11.4 x 21.6 cm) with a hinged top, having a nominal wall thickness of 1.25 cm. The chamber was designed to hold up to 14 mice, each having a floor area of approximately 63 cm2, in accordance with Institutional Animal Care and Use Committee (IACUC) guidelines. A "rodent proof" distribution fan was attached to the center of the hinged closure lid. The chamber was divided into 1 inch2 zones (120 in total) to enable a profile of drug distribution within the chamber to be obtained. Small holes were drilled into the side of the chamber and sealed using Parafilm to allow access to the sampling zones. Syringes (5 mL) with appropriate length polytetrafluoroethylene (PTFE) tubing were inserted into the holes to reach the sampling zones (eight on either side of the chamber giving a total of 16 zones). An aqueous caffeine solution (2% w/v) in glycerol (25% w/v) was prepared and nebulized into the chamber using an Aeroneb Pro nebulizer. Caffeine containing droplets were circulated into the chamber at a flow rate of 1.5 L/min(-1), and the air was recirculated in a closed system for a total of 20 minutes to ensure a high concentration of caffeine droplets throughout. Following nebulization, air samples (5 mL) were withdrawn from the 16 sampling zones of the sealed chamber. The process was repeated in quadruplet until a total of 64 sampling zones had been sampled. The entire experiment was also repeated with the absence of the "rodent-proof" distribution fan. Drug concentrations were calculated from a calibration curve of caffeine using UV absorbance at 272 nm. An average mass of caffeine (Standard Deviation; S.D.) of 5.0 (4.2) mg was detected throughout the chamber when the distribution

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.

Biokinetics and internal dosimetry of inhaled metal tritide particles

NASA Astrophysics Data System (ADS)

Wang, Yansheng

1998-12-01

Metal tritides (MT), stable chemical compounds of tritium, are widely used in nuclear engineering facilities. MT particles can be released as aerosols. Inhaling MT particles is a potential occupational radiation hazard. Little information is available on their dissolution behavior, biokinetics, and dosimetry. The objectives of present dissertation are to estimate dissolution rates, to develop biokinetic models, to improve internal dosimetric considerations, and to classify MT materials. This study consisted of three phases: In vitro dissolution in a simulated lung fluid, In vivo rat experiments on retention and clearance, and biokinetic modeling and dosimetric evaluation. There was a supporting study on self- absorption of tritium beta in MT particles. MT materials used in this study were titanium (Ti) and zirconium (Zr) tritides. Results shows considerable self-absorption of beta particles and their energy, even for respirable MT particles smaller than 5 μm. The self-absorption factors should be required for counting MT particle samples and for estimating absorbed dose to tissues. In vitro and in vivo dissolution data indicate that Ti and Zr tritides are poorly soluble materials. Ti tritide belongs to the W class or M type while Zr tritide can be classified as Y class or S type. Due to long retention time of the MT particles, tritium betas directly from the particles contribute over 90% of the absorbed dose to lung. The lung dose contributes most of the effective dose to the whole body. Dissolved tritium including tritiated water (HTO) and organically bound tritium (OBT) has less effect on the lung dose and effective dose. Results on the annual limit on intake (ALI) indicate that the current radiation protection guideline based on HTO is not adequate for inhalation exposure to MT particles and needs to be modified. The biokinetic models developed in this study have predictive powers to estimate the consequences of a human inhalation exposure to MT aerosols. The

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.

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.

[Inhaled corticosteroids and growth: should we be worried?].

PubMed

Pouessel, G; Gueorguieva, I; Bernaczyk, Y; Flammarion, S; Thumerelle, C; Deschildre, A

2015-08-01

Inhaled corticosteroids (ICSs) are the cornerstone and the first stage of asthma treatment. The objective of this study was to synthesize data on the potential effects of ICSs on growth in children. Studies on the short-term impact of ICSs on growth evaluated by knemometry cannot be extrapolated to the medium or long term and therefore have no utility in real life for a given person. In the medium term, the various ICSs given at the usual doses cause a small reduction in growth after 6 months of treatment. This slowdown occurs at the beginning of treatment, especially in younger children, and the growth velocity corrects itself later but without catching up. In the long term, the prolonged use of ICSs seems to induce a small reduction in the final size in adulthood (close to 1cm) occurring in the first 2 years of treatment without worsening over time. The impact of gender, age at onset of treatment, different ICSs, modes of inhalation, and severity of asthma should also be studied further. The benefit of ICSs in asthma treatment is greater than the risk of side effects, including on growth. The majority of the therapeutic effect is obtained for small to moderate doses of ICSs. Regular adjustment of ICS dose for optimal asthma control should also reduce ICS dose and the impact on growth. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

ASSESSMENT OF INHALATION DOSE FROM THE INDOOR 222Rn AND 220Rn USING RAD7 AND PINHOLE CUP DOSEMETERS.

PubMed

Mehra, R; Jakhu, R; Bangotra, P; Kaur, K; Mittal, H M

2016-10-01

Radon is the most important source of natural radiation and is responsible for approximately half of the received dose from all sources. Most of this dose is from inhalation of the radon progeny, especially in closed atmospheres. Concentration of radon ( 222 Rn) and thoron ( 220 Rn) in the different villages of Jalandhar and Kapurthala district of Punjab has been calculated by pinhole cup dosemeters and RAD7. On an average, it has been observed from the study that the values of all the parameters calculated are higher in case of active monitoring than the passive monitoring. The calculated equilibrium equivalent 222 Rn concentration (EEC Rn ) and equilibrium equivalent 220 Rn concentration (EEC Th ) fluctuate in the range from 5.58 to 34.29 and from 0.35 to 2.7 Bq m -3 as estimated by active technique, respectively. Similarly, the observed mean value of the potential alpha energy concentration of 222 Rn (PAEC Rn ) and 220 Rn (PAEC Th ) is 4.55 and 4.34 mWL, respectively. The dose rate to the soft tissues and lung from indoor 222 Rn varies from 0.06 to 0.38 and from 0.50 to 3.05 nGy h -1 , respectively. The total annual effective dose for the residents of the study area is less than 10 mSv. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

EPA Science Inventory

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

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.

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.

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.

Inhaled nano- and microparticles for drug delivery

PubMed Central

El-Sherbiny, Ibrahim M.; El-Baz, Nancy M.; Yacoub, Magdi H.

2015-01-01

The 21st century has seen a paradigm shift to inhaled therapy, for both systemic and local drug delivery, due to the lung's favourable properties of a large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including non-invasive route of administration, low metabolic activity, control environment for systemic absorption and avoids first bypass metabolism. However, because the lung is one of the major ports of entry, it has multiple clearance mechanisms, which prevent foreign particles from entering the body. Although these clearance mechanisms maintain the sterility of the lung, clearance mechanisms can also act as barriers to the therapeutic effectiveness of inhaled drugs. This effectiveness is also influenced by the deposition site and delivered dose. Particulate-based drug delivery systems have emerged as an innovative and promising alternative to conventional inhaled drugs to circumvent pulmonary clearance mechanisms and provide enhanced therapeutic efficiency and controlled drug release. The principle of multiple pulmonary clearance mechanisms is reviewed, including mucociliary, alveolar macrophages, absorptive, and metabolic degradation. This review also discusses the current approaches and formulations developed to achieve optimal pulmonary drug delivery systems. PMID:26779496

Advances in Audio-Based Systems to Monitor Patient Adherence and Inhaler Drug Delivery.

PubMed

Taylor, Terence E; Zigel, Yaniv; De Looze, Céline; Sulaiman, Imran; Costello, Richard W; Reilly, Richard B

2018-03-01

Hundreds of millions of people worldwide have asthma and COPD. Current medications to control these chronic respiratory diseases can be administered using inhaler devices, such as the pressurized metered dose inhaler and the dry powder inhaler. Provided that they are used as prescribed, inhalers can improve patient clinical outcomes and quality of life. Poor patient inhaler adherence (both time of use and user technique) is, however, a major clinical concern and is associated with poor disease control, increased hospital admissions, and increased mortality rates, particularly in low- and middle-income countries. There are currently limited methods available to health-care professionals to objectively and remotely monitor patient inhaler adherence. This review describes recent sensor-based technologies that use audio-based approaches that show promising opportunities for monitoring inhaler adherence in clinical practice. This review discusses how one form of sensor-based technology, audio-based monitoring systems, can provide clinically pertinent information regarding patient inhaler use over the course of treatment. Audio-based monitoring can provide health-care professionals with quantitative measurements of the drug delivery of inhalers, signifying a clear clinical advantage over other methods of assessment. Furthermore, objective audio-based adherence measures can improve the predictability of patient outcomes to treatment compared with current standard methods of adherence assessment used in clinical practice. Objective feedback on patient inhaler adherence can be used to personalize treatment to the patient, which may enhance precision medicine in the treatment of chronic respiratory diseases. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. 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

Inhaled Corticosteroids in Lung Diseases

PubMed Central

Raissy, Hengameh H.; Kelly, H. William; Harkins, Michelle

2013-01-01

Inhaled corticosteroids (ICSs) are used extensively in the treatment of asthma and chronic obstructive pulmonary disease (COPD) due to their broad antiinflammatory effects. They improve lung function, symptoms, and quality of life and reduce exacerbations in both conditions but do not alter the progression of disease. They decrease mortality in asthma but not COPD. The available ICSs vary in their therapeutic index and potency. Although ICSs are used in all age groups, younger and smaller children may be at a greater risk for adverse systemic effects because they can receive higher mg/kg doses of ICSs compared with older children. Most of the benefit from ICSs occurs in the low to medium dose range. Minimal additional improvement is seen with higher doses, although some patients may benefit from higher doses. Although ICSs are the preferred agents for managing persistent asthma in all ages, their benefit in COPD is more controversial. When used appropriately, ICSs have few adverse events at low to medium doses, but risk increases with high-dose ICSs. Although several new drugs are being developed and evaluated, it is unlikely that any of these new medications will replace ICSs as the preferred initial long-term controller therapy for asthma, but more effective initial controller therapy could be developed for COPD. PMID:23370915

Investigating the reactivity of pMDI with wood cell walls using high-resolution solution-state NMR spectroscopy

Treesearch

Daniel J. Yelle; John Ralph; Charles R. Frihart

2009-01-01

The objectives of this study are the following: (1) Use solution-state NMR to assign contours in HSQC spectra of the reaction products between pMDI model compounds and: (a) lignin model compounds, (b) milled-wood lignin, (c) ball-milled wood, (d) microtomed loblolly pine; (2) Determine where and to what degree urethane formation occurs with loblolly pine cell wall...

Practice makes perfect: self-reported adherence a positive marker of inhaler technique maintenance.

PubMed

Azzi, Elizabeth; Srour, Pamela; Armour, Carol; Rand, Cynthia; Bosnic-Anticevich, Sinthia

2017-04-24

Poor inhaler technique and non-adherence to treatment are major problems in the management of asthma. Patients can be taught how to achieve good inhaler technique, however maintenance remains problematic, with 50% of patients unable to demonstrate correct technique. The aim of this study was to determine the clinical, patient-related and/or device-related factors that predict inhaler technique maintenance. Data from a quality-controlled longitudinal community care dataset was utilized. 238 patients using preventer medications where included. Data consisted of patient demographics, clinical data, medication-related factors and patient-reported outcomes. Mixed effects logistic regression was used to identify predictors of inhaler technique maintenance at 1 month. The variables found to be independently associated with inhaler technique maintenance using logistic regression (Χ 2 (3,n = 238) = 33.24, p < 0.000) were inhaler technique at Visit 1 (OR 7.1), device type (metered dose inhaler and dry powder inhalers) (OR 2.2) and self-reported adherent behavior in the prior 7 days (OR 1.3). This research is the first to unequivocally establish a predictive relationship between inhaler technique maintenance and actual patient adherence, reinforcing the notion that inhaler technique maintenance is more than just a physical skill. Inhaler technique maintenance has an underlying behavioral component, which future studies need to investigate. BEHAVIORAL ELEMENT TO CORRECT LONG-TERM INHALER TECHNIQUES: Patients who consciously make an effort to perfect asthma inhaler technique will maintain their skills long-term. Elizabeth Azzi at the University of Sydney, Australia, and co-workers further add evidence that there is a strong behavioral component to patients retaining correct inhaler technique over time. Poor inhaler technique can limit asthma control, affecting quality of life and increasing the chances of severe exacerbations. Azzi's team followed 238 patients to

Modeling of occupational exposure to accidentally released manufactured nanomaterials in a production facility and calculation of internal doses by inhalation

PubMed Central

Vaquero-Moralejo, Celina; Jaén, María; Lopez De Ipiña Peña, Jesús; Neofytou, Panagiotis

2016-01-01

Background Occupational exposure to manufactured nanomaterials (MNMs) and its potential health impacts are of scientific and practical interest, as previous epidemiological studies associate exposure to nanoparticles with health effects, including increased morbidity of the respiratory and the circulatory system. Objectives To estimate the occupational exposure and effective internal doses in a real production facility of TiO2 MNMs during hypothetical scenarios of accidental release. Methods Commercial software for geometry and mesh generation, as well as fluid flow and particle dispersion calculation, were used to estimate occupational exposure to MNMs. The results were introduced to in-house software to calculate internal doses in the human respiratory tract by inhalation. Results Depending on the accidental scenario, different areas of the production facility were affected by the released MNMs, with a higher dose exposure among individuals closer to the particles source. Conclusions Granted that the study of the accidental release of particles can only be performed by chance, this numerical approach provides valuable information regarding occupational exposure and contributes to better protection of personnel. The methodology can be used to identify occupational settings where the exposure to MNMs would be high during accidents, providing insight to health and safety officials. PMID:27670588

Asthma Inhalers

MedlinePlus

... an inhaler into the lungs. But CFCs are ozone-depleting substances (ODSs) that hurt the environment. Manufacturers ... inhalers, that do not rob the atmosphere of ozone. “The FDA [Food and Drug Administration] and various ...

Inhalants in Peru.

PubMed

Lerner, R; Ferrando, D

1995-01-01

In Peru, the prevalence and consequences of inhalant abuse appear to be low in the general population and high among marginalized children. Inhalant use ranks third in lifetime prevalence after alcohol and tobacco. Most of the use appears to be infrequent. Among marginalized children, that is, children working in the streets but living at home or children living in the street, the problem of inhalant abuse is a serious problem. Among children working in the streets but living at home, the lifetime prevalence rate for inhalant abuse is high, ranging from 15 to 45 percent depending on the study being cited. For children living in the streets, the use of inhalant is even more severe. As mentioned earlier in this chapter, most of these street children use inhalants on a daily basis. The lack of research on the problem of inhalant abuse is a serious impediment to development of intervention programs and strategies to address this problem in Peru. Epidemiologic and ethnographic research on the nature and extent of inhalant abuse are obvious prerequisites to targeted treatment and preventive intervention programs. The urgent need for current and valid data is underscored by the unique vulnerability of the youthful population at risk and the undisputed harm that results from chronic abuse of inhalants. Nonetheless, it is important to mention several programs that work with street children. Some, such as the Information and Education Center for the Prevention of Drug Abuse, Generation, and Centro Integracion de Menores en Abandono have shelters where street children are offered transition to a less marginal lifestyle. Teams of street educators provide the children with practical solutions and gain their confidence, as well as offer them alternative socialization experiences to help them survive the streets and avoid the often repressive and counterproductive environments typical of many institutions. Most of the children who go through these programs tend to abandon

Subchronic inhalation toxicity of gold nanoparticles

PubMed Central

2011-01-01

Background Gold nanoparticles are widely used in consumer products, including cosmetics, food packaging, beverages, toothpaste, automobiles, and lubricants. With this increase in consumer products containing gold nanoparticles, the potential for worker exposure to gold nanoparticles will also increase. Only a few studies have produced data on the in vivo toxicology of gold nanoparticles, meaning that the absorption, distribution, metabolism, and excretion (ADME) of gold nanoparticles remain unclear. Results The toxicity of gold nanoparticles was studied in Sprague Dawley rats by inhalation. Seven-week-old rats, weighing approximately 200 g (males) and 145 g (females), were divided into 4 groups (10 rats in each group): fresh-air control, low-dose (2.36 × 104 particle/cm3, 0.04 μg/m3), middle-dose (2.36 × 105 particle/cm3, 0.38 μg/m3), and high-dose (1.85 × 106 particle/cm3, 20.02 μg/m3). The animals were exposed to gold nanoparticles (average diameter 4-5 nm) for 6 hours/day, 5 days/week, for 90-days in a whole-body inhalation chamber. In addition to mortality and clinical observations, body weight, food consumption, and lung function were recorded weekly. At the end of the study, the rats were subjected to a full necropsy, blood samples were collected for hematology and clinical chemistry tests, and organ weights were measured. Cellular differential counts and cytotoxicity measurements, such as albumin, lactate dehydrogenase (LDH), and total protein were also monitored in a cellular bronchoalveolar lavage (BAL) fluid. Among lung function test measurements, tidal volume and minute volume showed a tendency to decrease comparing control and dose groups during the 90-days of exposure. Although no statistically significant differences were found in cellular differential counts, histopathologic examination showed minimal alveoli, an inflammatory infiltrate with a mixed cell type, and increased macrophages in the high-dose rats. Tissue distribution of gold

ACCURATE CHARACTERIZATION OF HIGH-DEGREE MODES USING MDI OBSERVATIONS

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

Korzennik, S. G.; Rabello-Soares, M. C.; Schou, J.

2013-08-01

We present the first accurate characterization of high-degree modes, derived using the best Michelson Doppler Imager (MDI) full-disk full-resolution data set available. A 90 day long time series of full-disk 2 arcsec pixel{sup -1} resolution Dopplergrams was acquired in 2001, thanks to the high rate telemetry provided by the Deep Space Network. These Dopplergrams were spatially decomposed using our best estimate of the image scale and the known components of MDI's image distortion. A multi-taper power spectrum estimator was used to generate power spectra for all degrees and all azimuthal orders, up to l = 1000. We used a largemore » number of tapers to reduce the realization noise, since at high degrees the individual modes blend into ridges and thus there is no reason to preserve a high spectral resolution. These power spectra were fitted for all degrees and all azimuthal orders, between l = 100 and l = 1000, and for all the orders with substantial amplitude. This fitting generated in excess of 5.2 Multiplication-Sign 10{sup 6} individual estimates of ridge frequencies, line widths, amplitudes, and asymmetries (singlets), corresponding to some 5700 multiplets (l, n). Fitting at high degrees generates ridge characteristics, characteristics that do not correspond to the underlying mode characteristics. We used a sophisticated forward modeling to recover the best possible estimate of the underlying mode characteristics (mode frequencies, as well as line widths, amplitudes, and asymmetries). We describe in detail this modeling and its validation. The modeling has been extensively reviewed and refined, by including an iterative process to improve its input parameters to better match the observations. Also, the contribution of the leakage matrix on the accuracy of the procedure has been carefully assessed. We present the derived set of corrected mode characteristics, which includes not only frequencies, but line widths, asymmetries, and amplitudes. We present and

Automated recognition and characterization of solar active regions based on the SOHO/MDI images

NASA Technical Reports Server (NTRS)

Pap, J. M.; Turmon, M.; Mukhtar, S.; Bogart, R.; Ulrich, R.; Froehlich, C.; Wehrli, C.

1997-01-01

The first results of a new method to identify and characterize the various surface structures on the sun, which may contribute to the changes in solar total and spectral irradiance, are shown. The full disk magnetograms (1024 x 1024 pixels) of the Michelson Doppler Imager (MDI) experiment onboard SOHO are analyzed. Use of a Bayesian inference scheme allows objective, uniform, automated processing of a long sequence of images. The main goal is to identify the solar magnetic features causing irradiance changes. The results presented are based on a pilot time interval of August 1996.

The U. S. Environmental Protection Agency's inhalation RfD methodology: Risk assessment for air toxics

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

Jarabek, A.M.; Menache, M.G.; Overton, J.H. Jr.

1990-10-01

The U.S. Environmental Protection Agency (U.S. EPA) has advocated the establishment of general and scientific guidelines for the evaluation of toxicological data and their use in deriving benchmark values to protect exposed populations from adverse health effects. The Agency's reference dose (RfD) methodology for deriving benchmark values for noncancer toxicity originally addressed risk assessment of oral exposures. This paper presents a brief background on the development of the inhalation reference dose (RfDi) methodology, including concepts and issues related to addressing the dynamics of the respiratory system as the portal of entry. Different dosimetric adjustments are described that were incorporated intomore » the methodology to account for the nature of the inhaled agent (particle or gas) and the site of the observed toxic effects (respiratory or extra-respiratory). Impacts of these adjustments on the extrapolation of toxicity data of inhaled agents for human health risk assessment and future research directions are also discussed.« less

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

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.

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...

CATEGORICAL REGRESSION ANALYSIS OF ACUTE INHALATION TOXICITY DATA FOR HYDROGEN SULFIDE

EPA Science Inventory

Categorical regression is one of the tools offered by the U.S. EPA for derivation of acute reference exposures (AREs), which are dose-response assessments for acute exposures to inhaled chemicals. Categorical regression is used as a meta-analytical technique to calculate probabi...

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

Focus on Inhalants.

ERIC Educational Resources Information Center

Challenge: Safe, Disciplines, and Drug-Free Schools, 1994

1994-01-01

The use of inhalants is a major health concern among the school-age population. Information presented in this publication dispels the myths about inhalant use and presents common warning signs that alert teachers to a student's use. The short- and long-term effects of inhalant use are described to shed light on the health risks involved. Lesson…

Hydrazine inhalation hepatotoxicity.

PubMed

Kao, Yung Hsiang; Chong, C H; Ng, W T; Lim, D

2007-10-01

Abstract Hydrazine is a hazardous chemical commonly used as a reactant in rocket and jet fuel cells. Animal studies have demonstrated hepatic changes after hydrazine inhalation. Human case reports of hydrazine inhalation hepatotoxicity are rare. We report a case of mild hepatotoxicity following brief hydrazine vapour inhalation in a healthy young man, which resolved completely on expectant management.

The effect of different coating materials on the prevention of powder bounce in the next generation impactor

PubMed Central

Khalili, Shadi Farshbaf; Ghanbarzadeh, Saeed; Nokhodchi, Ali; Hamishehkar, Hamed

2018-01-01

In the process of quality control of pulmonary drug delivery products, aerosolization efficiency is mainly determined using impactors, e.g. next generation impactor (NGI). However, particle bounce may interfere with the validity and accuracy of results due to the overestimation of the respirable fraction. It is suggested that the coating of impactor's stages may prevent the particle bounce. Therefore, coating materials may influence the results of the aerosolization indexes of pulmonary dosage forms. The aim of this study was to investigate if the aerosolization indices are affected differently by using the different coating materials. In this study, the effects of using different materials including Span® 85, Tween® 80, silicon® oil, glycerin and Brij® 35/glycerin mixture recommended for the coating of NGI stages on the aerosolization indices such as fine particle fraction, fine particle dose, mass median aerodynamic diameter, and geometric standard deviation of salbutamol emitted from a commercial metered dose inhaler (MDI), were assessed. Three statistically different results were obtained on using Tween® 80, Span® 85 and silicon oil, and glycerin and Brij®35/glycerin mixture. It can be concluded that the type of coating material influenced the aerosolization indices of the examined MDI in NGIs. PMID:29853937

The effect of different coating materials on the prevention of powder bounce in the next generation impactor.

PubMed

Khalili, Shadi Farshbaf; Ghanbarzadeh, Saeed; Nokhodchi, Ali; Hamishehkar, Hamed

2018-06-01

In the process of quality control of pulmonary drug delivery products, aerosolization efficiency is mainly determined using impactors, e.g. next generation impactor (NGI). However, particle bounce may interfere with the validity and accuracy of results due to the overestimation of the respirable fraction. It is suggested that the coating of impactor's stages may prevent the particle bounce. Therefore, coating materials may influence the results of the aerosolization indexes of pulmonary dosage forms. The aim of this study was to investigate if the aerosolization indices are affected differently by using the different coating materials. In this study, the effects of using different materials including Span ® 85, Tween ® 80, silicon ® oil, glycerin and Brij ® 35/glycerin mixture recommended for the coating of NGI stages on the aerosolization indices such as fine particle fraction, fine particle dose, mass median aerodynamic diameter, and geometric standard deviation of salbutamol emitted from a commercial metered dose inhaler (MDI), were assessed. Three statistically different results were obtained on using Tween ® 80, Span ® 85 and silicon oil, and glycerin and Brij ® 35/glycerin mixture. It can be concluded that the type of coating material influenced the aerosolization indices of the examined MDI in NGIs.

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.

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...

Pentoxifylline does not alter the response to inhaled grain dust.

PubMed

Jagielo, P J; Watt, J L; Quinn, T J; Knapp, H R; Schwartz, D A

1997-05-01

Pentoxifylline (PTX) has been shown to reduce sepsis-induced neutrophil sequestration in the lung and inhibit endotoxin-mediated release of tumor necrosis factor-alpha (TNF-alpha). Previously, we have shown that endotoxin appears to be the principal agent in grain dust causing airway inflammation and airflow obstruction following grain dust inhalation. To determine whether PTX affects the physiologic and inflammatory events following acute grain dust inhalation, 10 healthy, nonsmoking subjects with normal airway reactivity were treated with PTX or placebo (PL) followed by corn dust extract (CDE) inhalation (0.08 mL/kg), using a single-blinded, crossover design. Subjects received PTX (1,200 mg/d) or PL for 4 days prior to CDE inhalation and 400 mg PTX or PL on the exposure day. Both respiratory symptoms and declines in FEV1 and FVC occurred following CDE exposure in both groups, but there were no significant differences in the frequency of symptoms or percent declines from baseline in the FEV1 and FVC at any of the time points measured in the study. Elevations in peripheral blood leukocyte and neutrophil concentrations and BAL total cell, neutrophil, TNF-alpha, and interleukin-8 concentrations were measured 4 h following exposure to CDE in both the PTX- and PL-treated subjects, but no significant differences were found between treatment groups. These results suggest that pretreatment with PTX prior to inhalation of CDE, in the doses used in this study, does not alter the acute physiologic or inflammatory events following exposure to inhaled CDE.

Inhalation exposure to isocyanates of car body repair shop workers and industrial spray painters.

PubMed

Pronk, Anjoeka; Tielemans, Erik; Skarping, Gunnar; Bobeldijk, Ivana; VAN Hemmen, Joop; Heederik, Dick; Preller, Liesbeth

2006-01-01

As part of a large-scale epidemiological study, occupational isocyanate exposure was assessed in spray-painting environments. The aim was to assess which compounds contribute to isocyanate exposure in car body repair shops and industrial painting companies, and to identify tasks with high risk of isocyanate exposure. Mainly personal task-based samples (n = 566) were collected from 24 car body repair shops and five industrial painting companies using impingers with DBA in toluene. Samples were analysed by LC-MS for isocyanate monomers, oligomers and products of thermal degradation. From the 23 analysed compounds, 20 were detected. Exploratory factor analysis resulted in a HDI, TDI and MDI factor with the thermal degradation products divided over the TDI and MDI factors. The HDI factor mainly consisted of HDI oligomers and was dominant in frequency and exposure levels in both industries. Spray painting of PU lacquers resulted in the highest exposures for the HDI factor (MDI factor was found incidentally during spraying and welding in car body repair shops (

Increased use of inhaled corticosteroids among young Danish adult asthmatics: an observational study.

PubMed

Davidsen, Jesper Rømhild; Søndergaard, Jens; Hallas, Jesper; Siersted, Hans Christian; Lykkegaard, Jesper; Andersen, Morten

2010-12-01

This population-based longitudinal study aimed to investigate trends in use of inhaled corticosteroids (ICS) and determinants of ICS use in young Danish adults with asthma. 106 757 users, aged 18-44 years, of anti-asthmatic drugs were identified in the Danish Register of Medical Product Statistics during 1997-2006. One year prevalences of ICS use were calculated in categories of gender, age, and annual consumption of inhaled beta-2-agonists (IBA) in defined daily doses (DDD) per year. Determinants of ICS use were estimated by logistic regression models. The one year prevalence of ICS use was constant, approximately 64%, during 1997-2000. An annual increase was observed from 67% in 2001 to 77% in 2006. This trend also existed when stratifying on gender, age and IBA use. Using 1997 as baseline, the adjusted odds ratios (ORs) of ICS use in 2000 was 0.98 (95% CI 0.96-1.01) compared to 1.12 (95% CI 1.09-1.15) in 2001, and 1.81 (95% CI 1.75-1.87) in 2006. Other determinants of high ICS use were female gender, young age, and high annual IBA consumption. Among those using at least 400 DDD of IBA per year (corresponding to 4.4 powder inhalations daily), nearly 20% had no ICS prescriptions in 2006. Treatment with ICS among young Danish adult asthmatics has increased since 2001. This apparent improvement was associated with the introduction of fixed dose combination inhalers with ICS and inhaled long-acting beta-2-agonists. However, there is still room for improvement. Copyright © 2010 Elsevier Ltd. All rights reserved.

The pharmacology of chymotrypsin administered by inhalation

PubMed Central

Golberg, L.; Martin, L. E.; Sheard, P.; Harrison, C.

1960-01-01

The ability of chymotrypsin to reach the limits of the bronchial tree has been studied in cats receiving the enzyme by inhalation as a very fine powder. For this purpose derivatives of chymotrypsin were used which had been labelled with a fluorescent molecule or with [131I]. Quantitative measurements of the absorption and distribution of inhaled chymotrypsin- [131I] revealed a rapid removal of radioactivity from the lungs over the first 24 hr. and corresponding excretion of labelled inorganic iodide in the urine. High levels of activity were not attained in the blood or thyroid. Subcutaneous administration of labelled enzyme led to more rapid accumulation of radioactivity in the blood and thyroid. Consideration of these and other results leads to the conclusion that, while some enzyme ascends the respiratory tract by ciliary movement of mucus, a substantial part is absorbed into the lungs and the [131I] subsequently detached from it. The changes in tidal air accompanying inhalation of labelled trypsin and chymotrypsin were followed in anaesthetized cats. Trypsin brings about a decrease in tidal air in distinctly lower doses than does chymotrypsin. Prior administration of mepyramine had an antagonistic effect, and it is suggested that the change in tidal air is essentially the result of bronchial spasm. ImagesFIG. 2FIG. 3 PMID:13850540

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.

Effect of inhaled formyl-methionyl-leucyl-phenylalanine on airway function.

PubMed Central

Berend, N; Peters, M J; Armour, C L; Black, J L; Ward, H E

1988-01-01

Formyl-methionyl-leucyl-phenylalanine (FMLP), a synthetic, acylated tripeptide analogous to bacterial chemotactic factors, has been shown to cause bronchoconstriction in guinea pig, rabbit, and human airways in vitro. To determine whether FMLP causes bronchoconstriction in man in vivo, a preliminary study was undertaken in which five non-smokers (mean age 35 years, FEV1 94% (SEM 5%) predicted) and five smokers (mean age 34 years, FEV1 93% (6%) predicted) inhaled aerosols of FMLP. None of the subjects showed airway hyperresponsiveness to histamine (the provocative concentrations of histamine causing a fall of greater than or equal to 20% in FEV1 (PC20) were over 8 mg/ml). FMLP dissolved in 50% dimethylsulphoxide and 50% saline in concentrations of 0, 0.06, 0.12, 0.25, 0.5, 1.0, 2.0, and 4.0 mg/ml was administered to the subjects by means of a French-Rosenthal dosimeter, FEV1 being recorded after inhalation of each concentration. Dose dependent falls in FEV1 occurred in five non-smokers (geometric mean 1.76, 95% confidence limits 0.87-3.53 mg/ml) and three smokers (0.23, 0.07-0.78 mg/ml), with two smokers not responding by 20% to the highest concentration of FMLP. On a separate day the FMLP dose-response curves were repeated after nebulisation of 500 micrograms of ipratropium bromide. The PC20 FMLP in the responders more than doubled. In six additional normal subjects a histamine inhalation test was performed before and four and 24 hours after inhalation of FMLP. All subjects remained unresponsive to histamine. These results show that FMLP is a potent bronchoconstrictor in some non-asthmatic individuals in vivo and this may be important in bronchoconstriction related to infection in patients with chronic obstructive lung disease. PMID:2965425

Bioavailability of octamethylcyclotetrasiloxane (D(4)) after exposure to silicones by inhalation and implantation.

PubMed Central

Luu, H M; Hutter, J C

2001-01-01

We developed a physiologically based pharmacokinetic (PBPK) model to predict the target organ doses of octamethylcyclotetrasiloxane (D(4)) after intravenous (IV), inhalation, or implantation exposures. The model used (14)C-D(4) IV disposition data in rats to estimate tissue distribution coefficients, metabolism, and excretion parameters. We validated the model by comparing the predicted blood and tissues concentrations of D(4) after inhalation to experimental results in both rats and humans. We then used the model to simulate D(4) kinetics after single and/or repeated D(4) exposures in rats and humans. The model predicted bioaccumulation of D(4) in fatty tissues (e.g., breast), especially in women. Because of its high lipid solubility (Log P(oct/water) = 5.1), D(4) persisted in fat with a half life of 11.1 days after inhalation and 18.2 days after breast implant exposure. Metabolism and excretion remained constant with repeated exposures, larger doses, and/or different routes of exposure. The accumulation of D(4) in fatty tissues should play an important role in the risk assessment of D(4) especially in women exposed daily to multiple personal care products and silicone breast implants. PMID:11712992

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

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.

Optimizing inhaler use by pharmacist-provided education to community-dwelling elderly.

PubMed

Bouwmeester, Carla; Kraft, Jacqueline; Bungay, Kathleen M

2015-10-01

To assess, using a standard observational tool, the ability of patients to demonstrate and maintain proper inhaled medication administration techniques following pharmacist education. Six-month observational study. Patients' homes or adult day health center. Patients in a Program for All-inclusive Care for the Elderly (PACE) prescribed one or more inhaled medications used at least once daily. Instruction by on-site clinical pharmacist. Hickey's Pharmacies Inhaler Technique assessment (score range: 0-20, higher better). Forty-two patients were evaluated at baseline, taught proper techniques for using inhaled medications, assessed immediately following the education, and re-assessed 4-6 weeks later. The mean pre-assessment score was 14 (SD 4.5, range 0-20), the initial post-assessment score increased to 18 (SD 3, range 10-20). The second post-assessment (4-6 weeks later) score mean was 17.7 (SD 3, range 10-20). Both follow-up scores were significantly improved from baseline (p < 0.05). Multivariable analysis indicated the strongest predictors of second post-training score were: score after initial pharmacist training and being subscribed to auto-refill. These characteristics predicted ∼70% of the variance in the second score (p < 0.001). These results indicate that education by a pharmacist combined with an auto-refill program can improve and sustain appropriate inhaler use by community-dwelling elders in a PACE program. The improved score was maintained 4-6 weeks later indicating a sustained benefit of medication administration education. Optimal inhaler use ensures optimal dosing and supports appropriate inhaler treatment in lieu of oral agents. Copyright © 2015 Elsevier Ltd. All rights reserved.

Developmental toxicity of inhaled methanol in the CD-1 mouse, with quantitative dose-response modeling for estimation of benchmark doses

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

Rogers, J.M.; Mole, M.L.; Chernoff, N.

1993-01-01

Pregnant CD-1 mice were exposed to 1,000, 2,000, 5,000, 7,500, 10,000, or 15,000 ppm on methanol for 7 hr/day on days 6-15 of gestation. On day 17 of gestation, remaining mice were weighed, killed and the gravid uterus was removed. Numbers of implantation sites, live and dead fetuses and resorptions were counted, and fetuses were examined externally and weighed as a litter. Significant increases in the incidence of exencephaly and cleft palate were observed at 5,000 ppm and above, increased postimplantation mortality at 7,500 ppm and above (including an increasing incidence of full-litter resorption), and reduced fetal weight at 10,000more » ppm and above. A dose-related increase in cervical ribs or ossification sites lateral to the seventh cervical vertebra was significant at 2,000 ppm and above. Thus, the NOAEL for the developmental toxicity in this study is 1,000 ppm. The results of this study indicate that inhaled methanol is developmentally toxic in the mouse at exposure levels which were not maternally toxic. Litters of pregnant mice gavaged orally with 4 g methanol/kg displayed developmental toxic effects similar to those seen in the 10,000 ppm methanol exposure group. (Copyright (c) 1993 Wiley-Liss, Inc.)« less

Response to Albuterol MDI Delivered Through an Anti-Static Chamber During Nocturnal Bronchospasm

PubMed Central

Prabhakaran, Sreekala; Shuster, Jonathan; Chesrown, Sarah; Hendeles, Leslie

2013-01-01

BACKGROUND Decreasing electrostatic charge on valved holding chambers increases the amount of drug delivered. However, there are no data demonstrating that this increases bronchodilatation. OBJECTIVE To investigate the influence of reducing electrostatic charge on the bronchodilator response to albuterol inhaler during nocturnal bronchospasm. METHODS This randomized double-blind, double-dummy crossover study included subjects, 18—40 years old, with nocturnal bronchospasm (20% overnight decrease in peak flow on 3 of 7 nights during run-in), FEV1 60–80% predicted during the day, and ≥ 12% increase after albuterol. Subjects slept in the clinical research center up to 3 nights for each treatment. FEV1 and heart rate were measured upon awakening spontaneously or at 4:00 am, and 15 min after each dose of 1, 2, and 4 cumulative puffs of albuterol via metered-dose inhaler. The drug was administered through an anti-static valved holding chamber (AeroChamber Plus Z-Stat) or a conventional valved holding chamber containing a static charge (AeroChamber Plus). RESULTS Of 88 consented subjects, 11 were randomized and 7 completed the study. Most exclusions were due to lack of objective evidence of nocturnal bronchospasm. Upon awakening, FEV1 was 44 ± 9% of predicted before the anti-static chamber and 48 ± 7% of predicted before the static chamber. The mean ± SD percent increase in FEV1 after 1, 2, and 4 cumulative puffs using the anti-static versus the static chamber, respectively, were 52 ± 26% versus 30 ± 19%, 73 ± 28% versus 48 ± 26%, and 90 ± 34% versus 64 ± 35%. The point estimates for the differences (and 95% CIs) between the devices (anti-static vs static) were 21% (4–38%) (P = .03), 23% (6–41%) (P = .02), and 25% (7–42%) (P = .01) for 1, 2, and 4 cumulative puffs, respectively. There was no significant difference in heart rate between treatments. CONCLUSIONS Delivery of albuterol through an anti-static chamber provides a clinically relevant

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

Statistical tools and control of internal lubricant content of inhalation grade HPMC capsules during manufacture.

PubMed

Ayala, Guillermo; Díez, Fernando; Gassó, María T; Jones, Brian E; Martín-Portugués, Rafael; Ramiro-Aparicio, Juan

2016-04-30

The internal lubricant content (ILC) of inhalation grade HPMC capsules is a key factor to ensure good powder release when the patient inhales a medicine from a dry powder inhaler (DPI). Powder release from capsules has been shown to be influenced by the ILC. The characteristics used to measure this are the emitted dose, fine particle fraction and mass median aerodynamic diameter. In addition the ILC level is critical for capsule shell manufacture because it is an essential part of the process that cannot work without it. An experiment has been applied to the manufacture of inhalation capsules with the required ILC. A full factorial model was used to identify the controlling factors and from this a linear model has been proposed to improve control of the process. Copyright © 2016 Elsevier B.V. All rights reserved.

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...

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

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.

IRIS Toxicological Review of Ammonia Noncancer Inhalation ...

EPA Pesticide Factsheets

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

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...

COMPARISONS OF ACUTE REFERENCE VALUES IN DEVELOPING AN ACUTE INHALATION ASSESSMENT METHOD

EPA Science Inventory

A method is being developed for performing assessments of human health risk from acute (less than 24 hour) inhalation exposures. The methodology will be flexible in its ability to utilize variously robust data sets of dose-response information. A supporting task is a comparati...

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.

A review of the in vitro and in vivo valved holding chamber (VHC) literature with a focus on the AeroChamber Plus Flow-Vu Anti-static VHC

PubMed Central

Dissanayake, Sanjeeva; Suggett, Jason

2018-01-01

Valved holding chambers (VHCs) reduce the need for inhalation-actuation coordination with pressurized metered dose inhalers (pMDIs), reduce oropharyngeal drug deposition and may improve lung deposition and clinical outcomes compared to pMDIs used alone. While VHCs are thus widely advocated for use in vulnerable patient groups within clinical and regulatory guidelines, there is less consensus as to whether the performance differences between different VHCs have clinical implications. This review evaluates the VHC literature, in particular the data pertaining to large- versus small-volume chambers, aerosol performance with a VHC adjunct versus a pMDI alone, charge dissipative/conducting versus non-conducting VHCs, and facemasks, to ascertain whether potentially meaningful differences between VHCs exist. Inconsistencies in the literature are examined and explained, and relationships between in vitro and in vivo data are discussed. A particular focus of this review is the AeroChamber Plus® Flow-Vu® Anti-static VHC, the most recent iteration of the AeroChamber VHC family. PMID:29378477

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

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.

Zanamivir Oral Inhalation

MedlinePlus

... prescribed by your doctor.Zanamivir comes with a plastic inhaler called a Diskhaler (device for inhaling powder) ... to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in ...

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

PubMed

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

2014-10-01

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

IRIS Toxicological Review of 1,4-Dioxane (with Inhalation ...

EPA Pesticide Factsheets

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. 1,4-Dioxane is commonly used as a solvent, cleaning agent, chemical stabilizer, surface coating, adhesive agent, and an ingredient in chemical manufacture.

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.

Aspergillus fumigatus viability drives allergic responses to inhaled conidia.

PubMed

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

2018-04-13

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

SU-F-T-444: Quality Improvement Review of Radiation Therapy Treatment Planning in the Presence of Dental Implants

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

Parenica, H; Ford, J; Mavroidis, P

Purpose: To quantify and compare the effect of metallic dental implants (MDI) on dose distributions calculated using Collapsed Cone Convolution Superposition (CCCS) algorithm or a Monte Carlo algorithm (with and without correcting for the density of the MDI). Methods: Seven previously treated patients to the head and neck region were included in this study. The MDI and the streaking artifacts on the CT images were carefully contoured. For each patient a plan was optimized and calculated using the Pinnacle3 treatment planning system (TPS). For each patient two dose calculations were performed, a) with the densities of the MDI and CTmore » artifacts overridden (12 g/cc and 1 g/cc respectively) and b) without density overrides. The plans were then exported to the Monaco TPS and recalculated using Monte Carlo dose calculation algorithm. The changes in dose to PTVs and surrounding Regions of Interest (ROIs) were examined between all plans. Results: The Monte Carlo dose calculation indicated that PTVs received 6% lower dose than the CCCS algorithm predicted. In some cases, the Monte Carlo algorithm indicated that surrounding ROIs received higher dose (up to a factor of 2). Conclusion: Not properly accounting for dental implants can impact both the high dose regions (PTV) and the low dose regions (OAR). This study implies that if MDI and the artifacts are not appropriately contoured and given the correct density, there is potential significant impact on PTV coverage and OAR maximum doses.« less

Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial.

PubMed

Bilton, Diana; Tino, Gregory; Barker, Alan F; Chambers, Daniel C; De Soyza, Anthony; Dupont, Lieven J A; O'Dochartaigh, Conor; van Haren, Eric H J; Vidal, Luis Otero; Welte, Tobias; Fox, Howard G; Wu, Jian; Charlton, Brett

2014-12-01

Bronchiectasis is characterised by excessive production of mucus and pulmonary exacerbations. Inhaled osmotic agents may enhance mucociliary clearance, but few long-term clinical trials have been conducted. To determine the impact of inhaled mannitol on exacerbation rates in patients with non-cystic fibrosis (CF) bronchiectasis. Secondary endpoints included time to first exacerbation, duration of exacerbations, antibiotic use for exacerbations and quality of life (QOL) (St George's Respiratory Questionnaire, SGRQ). Patients with non-CF bronchiectasis and a history of chronic excess production of sputum and ≥2 pulmonary exacerbations in the previous 12 months were randomised (1:1) to 52 weeks treatment with inhaled mannitol 400 mg or low-dose mannitol control twice a day. Patients were 18-85 years of age, baseline FEV1 ≥40% and ≤85% predicted and a baseline SGRQ score ≥30. 461 patients (233 in the mannitol and 228 in the control arm) were treated. Baseline demographics were similar in the two arms. The exacerbation rate was not significantly reduced on mannitol (rate ratio 0.92, p=0.31). However, time to first exacerbation was increased on mannitol (HR 0.78, p=0.022). SGRQ score was improved on mannitol compared with low-dose mannitol control (-2.4 units, p=0.046). Adverse events were similar between groups. Mannitol 400 mg inhaled twice daily for 12 months in patients with clinically significant bronchiectasis did not significantly reduce exacerbation rates. There were statistically significant improvements in time to first exacerbation and QOL. Mannitol therapy was safe and well tolerated. NCT00669331. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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

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

Protective effect of inhalation of hydrogen gas on radiation-induced dermatitis and skin injury in rats

PubMed Central

Watanabe, Sadahiro; Fujita, Masanori; Ishihara, Masayuki; Tachibana, Shoichi; Yamamoto, Yoritsuna; Kaji, Tatsumi; Kawauchi, Toshio; Kanatani, Yasuhiro

2014-01-01

The effect of inhalation of hydrogen-containing gas (1.3% hydrogen + 20.8% oxygen + 77.9% nitrogen) (HCG) on radiation-induced dermatitis and on the healing of healing-impaired skin wounds in rats was examined using a rat model of radiation-induced skin injury. An X-ray dose of 20 Gy was irradiated onto the lower part of the back through two holes in a lead shield. Irradiation was performed before or after inhalation of HCG for 2 h. Inhalation of HCG significantly reduced the severity of radiodermatitis and accelerated healing-impaired wound repair. Staining with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) showed that the proportion of apoptotic keratinocytes and the level of staining in the X-irradiated skin of rats that pre-inhaled HCG were significantly lower than that of rats which did not pre-inhale HCG. Cutaneous full-thickness wounds were then created in the X-irradiated area to examine the time-course of wound healing. X-irradiation significantly increased the time required for wound healing, but the inhalation of HCG prior to the irradiation significantly decreased the delay in wound healing compared with the control and post-inhalation of HCG groups. Therefore, radiation-induced skin injury can potentially be alleviated by the pre-inhalation of HCG. PMID:25034733

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

Effects of Radon Inhalation on Some Biophysical Properties of Blood in Rats

NASA Astrophysics Data System (ADS)

Essa, M. F.; Shahin, Fayez M.; Ahmed, Ashour M.; Abdel-Salam, Omar

2013-03-01

The major source of human exposure to natural radiation arises from the inhalation of radon (222Rn) gas. Exposure to high concentrations of radon 222Rn and its daughters for long period leads to pathological effects like lung cancer, leukaemia, skin cancer and kidney diseases. The present study was performed on rats to investigate the effect of radon exposure on the absorption spectra of hemoglobin. Measurements have been performed in a radon chamber where rats were exposed to radon for 1, 5 or 7 weeks. The inhalation of radon resulted in decrease in intensity of the absorption bands characterizing the hemoglobin molecular structure with increased radon doses.

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

Effectiveness of Inhaled Loxapine in Dual-Diagnosis Patients: A Case Series.

PubMed

Roncero, Carlos; Ros-Cucurull, Elena; Grau-López, Lara; Fadeuilhe, Christian; Casas, Miguel

2016-01-01

Episodes of psychotic agitation are frequent in patients with dual diagnosis, that is, in patients with concomitant psychiatric and substance use disorders. Rapid intervention is needed to treat the agitation at a mild stage to prevent the escalation to aggressive behavior. Inhaled loxapine has been demonstrated to rapidly improve symptoms of mild-to-moderate agitation in adults with psychiatric disorders (schizophrenia and bipolar disorder), but data on patients with dual diagnosis are scarce. This study is a retrospective review of data from a case series of patients with dual diagnosis, which were attended for symptoms of agitation while at the emergency room (n = 9), in the outpatient clinic (n = 4), or during hospitalization (n = 1) at 1 center in Spain. All patients received inhaled loxapine for treating the agitation episodes. Data from 14 patients with dual diagnosis were reviewed. All patients had 1 or more psychiatric disorders (schizophrenia, bipolar I disorder, drug-induced psychotic disorder, posttraumatic stress, borderline or antisocial personality disorder, depression, or anxiety) along with a variety of substance use disorders (alcohol, cocaine, cannabis, amphetamines, hypnotics and antianxiety drugs, caffeine, or street drugs). Overall, only 1 dose of inhaled loxapine (9.1 mg) was needed to calm each patient during an acute episode of agitation. Inhaled loxapine was rapid, effective, and well accepted in all dual-pathology patients presenting with acute agitation in the emergency setting. Inhaled loxapine facilitated both patient cooperation and an adequate management of his or her disease.

Pharmacokinetics of Oral and Inhaled Terbutaline after Exercise in Trained Men

PubMed Central

Dyreborg, Anders; Krogh, Nanna; Backer, Vibeke; Rzeppa, Sebastian; Hemmersbach, Peter; Hostrup, Morten

2016-01-01

Aim: The aim of the study was to investigate pharmacokinetics of terbutaline after oral and inhaled administration in healthy trained male subjects in relation to doping control. Methods: Twelve healthy well-trained young men (27 ±2 years; mean ± SE) underwent two pharmacokinetic trials that compared 10 mg oral terbutaline with 4 mg inhaled dry powder terbutaline. During each trial, subjects performed 90 min of bike ergometer exercise at 65% of maximal oxygen consumption. Blood (0–4 h) and urine (0–24 h) samples were collected before and after administration of terbutaline. Samples were analyzed for concentrations of terbutaline by high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). Results: Pharmacokinetics differed between the two routes of administration. Serum Cmax and area under the serum concentration-time curve (AUC) were lower after oral administration compared to inhalation (Cmax: 4.2 ± 0.3 vs. 8.5 ± 0.7 ng/ml, P ≤ 0.001; AUC: 422 ± 22 vs. 1308 ± 119 ng/ml × min). Urine concentrations (sum of the free drug and the glucuronide) were lower after oral administration compared to inhalation 2 h (1100 ± 204 vs. 61 ± 10 ng/ml, P ≤ 0.05) and 4 h (734 ± 110 vs. 340 ± 48 ng/ml, P ≤ 0.001) following administration, whereas concentrations were higher for oral administration than inhalation 12 h following administration (190 ± 41 vs. 399 ± 108 ng/ml, P ≤ 0.05). Urine excretion rate was lower after oral administration than inhalation the first 2 h following administration (P ≤ 0.001). Systemic bioavailability ratio between the two routes of administration was 3.8:1 (inhaled: oral; P ≤ 0.001). Conclusion: Given the higher systemic bioavailability of inhaled terbutaline compared to oral, our results indicate that it is difficult to differentiate allowed inhaled use of terbutaline from prohibited oral ingestion based on urine concentrations in doping control analysis. However given the potential performance

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).

Temozolomide-based dry powder formulations for lung tumor-related inhalation treatment.