Sample records for repeated dose inhalation

  1. Inhalation exposure system used for acute and repeated-dose methyl isocyanate exposures of laboratory animals. (United States)

    Adkins, B; O'Connor, R W; Dement, J M


    Laboratory animals were exposed by inhalation for 2 hr/day (acute) or 6 hr/day (four consecutive days, repeated dose) to methyl isocyanate (MIC). Exposures were conducted in stainless steel and glass inhalation exposure chambers placed in stainless steel, wire mesh cages. MIC was delivered with nitrogen via stainless steel and Teflon supply lines. Chamber concentrations ranged from 0 to 60 ppm and were monitored continuously with infrared spectrophotometers to 1 ppm and at 2-hr intervals to 20 ppb with a high performance liquid chromatograph equipped with a fluorescence detector. Other operational parameters monitored on a continuous basis included chamber temperature (20-27 degrees C), relative humidity (31-64%), static (transmural) pressure (-0.3 in.), and flow (300-500 L/min). The computer-assistance system interfaced with the inhalation exposure laboratory is described in detail, including the analytical instrumentation calibration system used throughout this investigation.

  2. Metabolite profiles of rats in repeated dose toxicological studies after oral and inhalative exposure. (United States)

    Fabian, E; Bordag, N; Herold, M; Kamp, H; Krennrich, G; Looser, R; Ma-Hock, L; Mellert, W; Montoya, G; Peter, E; Prokudin, A; Spitzer, M; Strauss, V; Walk, T; Zbranek, R; van Ravenzwaay, B


    The MetaMap(®)-Tox database contains plasma-metabolome and toxicity data of rats obtained from oral administration of 550 reference compounds following a standardized adapted OECD 407 protocol. Here, metabolic profiles for aniline (A), chloroform (CL), ethylbenzene (EB), 2-methoxyethanol (ME), N,N-dimethylformamide (DMF) and tetrahydrofurane (THF), dosed inhalatively for six hours/day, five days a week for 4 weeks were compared to oral dosing performed daily for 4 weeks. To investigate if the oral and inhalative metabolome would be comparable statistical analyses were performed. Best correlations for metabolome changes via both routes of exposure were observed for toxicants that induced profound metabolome changes. e.g. CL and ME. Liver and testes were correctly identified as target organs. In contrast, route of exposure dependent differences in metabolic profiles were noted for low profile strength e.g. female rats dosed inhalatively with A or THF. Taken together, the current investigations demonstrate that plasma metabolome changes are generally comparable for systemic effects after oral and inhalation exposure. Differences may result from kinetics and first pass effects. For compounds inducing only weak changes, the differences between both routes of exposure are visible in the metabolome.

  3. 氟氯氰菊酯亚急性吸入毒性实验研究%Inhalation toxicity of cyfluthrin for 28-day repeated dose in rats

    Institute of Scientific and Technical Information of China (English)

    秦珩; 乔善磊; 顾军; 钟义红; 杨洪宝; 王玉邦; 施爱民


    Objective To determine the inhalation toxicity and find the non -observed adverse effect level (NOAEL) of cyfluthrin for a 28-day repeated dose in rats. Methods Clean-grade SD rats were randomly divided into 5 groups with 5 females and 5 males in each. The animals inhaled DMSO or cyfluthrin at the concentration of 0, 7. 81 , 9. 05 and 18. 98 mg/m for 4 weeks (6 h/d, 5 d/w). At the end of inhalation , all the animals were kindly sacrificed. Their organs were collected for histopathological examination . Blood samples were collected for analysis of complete blood count , biochemistry and coagulation. Results The animals in 18. 98 mg/m3 group were found scratching repeatedly around the mouth, listless, fidgeting, trembling, discharging blood around the mouth and nose . However, symptoms in females were less serious than in males. Furthermore , the body mass , feed efficiency , weight of kidney of animals in this dose male group were found decreased compared with the control group . Biochemistry detection revealed that serum AST was elevated markedly in both genders of 18. 98 mg/m3 group and in males of 9. 05 mg/m3 group. No obvious abnormity was found in 7.81 mg/m3 group or control group. Conclusion Based on the results above, the non-observed adverse effect level (NOAEL) of cyfluthrin in SD rats is 7. 81 mg/m3 for 28 d repeated inhalation in this study.%目的 观察氟氯氰菊酯染毒大鼠亚急性吸入毒性.方法 7周龄清洁级SD大鼠随机分成5组,每组雌雄各5只,分别吸入氟氯氰菊酯0,7.81,9.05,18.98 mg/m3及溶剂二甲亚砜,每天6 h,每周5 d,共28 d.实验结束时取血液做常规生化指标、血细胞指标、血凝学指标检测.取心、肝、脾等8种主要脏器称重并做病理组织学检查.结果 18.98 mg/m3组动物在染毒中呈现反复抓挠口周、烦躁不安、鼻有血性分泌物、颤抖,染毒结束后呈现萎靡、蜂腰、四肢无力的体征.雌性动物的毒性表现较雄性低.与溶剂对照组相

  4. [Study of personal best value of peak expiratory flow in patients with asthma--comparison of the highest value of daily PEF under good control and the highest value of daily PEF obtained after using repeated inhaled beta2-agonist during high-dose inhaled steroid treatment]. (United States)

    Watanabe, Naoto; Makino, Sohei; Kihara, Norio; Fukuda, Takeshi


    In the guideline for asthma management, it is important to find the personal best value of peak expiratory flow (best PEF). Recently, we have substituted the highest value of PEF in daily life under good control (daily highest PEF) for the best PEF. In the present study, we considered whether the daily highest PEF could be used as the best PEF or not. Subjects were 30 asthmatics who were well controlled but whose baseline PEF values were less than 80 percent of predicted values. We compared the daily highest PEF and the highest of PEF obtained after repeated inhaled beta2-agonist (salbutamol MDI every 20 minutes three times). All subjects then received 1600 microg/day of beclomethasone dipropionate (BDP) for 4 to 8 weeks. We studied the effect of high-dose inhaled steroid treatment on each PEF value and compared the daily highest PEF and the highest PEF obtained after using repeated salbutamol MDI during high dose inhaled steroid therapy on the examination day again. The baseline PEF, daily highest PEF and the highest PEF obtained after salbutamol MDI were significantly less than the each values obtained after high-dose BDP. The best PEF value of them was the value obtained after repeated salbutamol MDI during high dose BDP. We suggest that the daily highest PEF under good control is not a substitute for best PEF because it changes according to the degree of improvement of airway inflammation. We recommend that a course of high dose inhaled steroid is effective in finding the best value of PEF for each individual with moderate asthma.

  5. The Ozone Layer and Metered Dose Inhalers

    Directory of Open Access Journals (Sweden)

    Louis-Philippe Boulet


    Full Text Available The stratospheric ozone layer plays a crucial role in protecting living organisms against ultraviolet radiation. Chlorofluorocarbons (CFC contained in metered-dose inhalers (MDIs contribute to ozone depletion and in accordance with the Montreal Protocol on Substances That Deplete the Ozone Layer established 10 years ago, phase-out strageies have been developed worldwide for this category of agents. Alternatives to CFC-containing inhalers have been developed, such as powder inhalers and those using hydrofluoroalkanes (HFAs as propellants, which have been shown to be as safe and effective as CFC-containing inhalers and even offer interesting advantages over older inhalers. The transition to non-CFC MDIs requires a major effort to make the new products available and to ensure adequate comparision with the previous ones. It also requires a harmonization of actions taken by industry, government, licencing bodies and patients or health professional associations to ensure adequate information and education to the public and respiratory care providers.

  6. Airway refractoriness to inhaled mannitol after repeated challenge. (United States)

    Suh, Dong In; Lee, Ju Kyung; Kim, Jin-Tack; Koh, Young Yull


    Exercise and inhaled mannitol are thought to cause bronchoconstriction through a similar mechanism in asthma. The response to exercise becomes refractory with repeated challenges. This study aimed to investigate whether repeated challenge with mannitol induces refractoriness, as with exercise. Forty-one children with asthma underwent two consecutive dose-response mannitol challenges (Phase 1); the second challenge proceeded after recovery (FEV(1) : 95% or more of baseline value) from the first. The response to mannitol was expressed as a provocative dose causing a 15% fall in FEV(1) (PD(15) ) and the response-dose ratio (RDR) (% fall in FEV(1) /cumulative dose). In 18 subjects who were deemed to have mannitol refractoriness in Phase 1, a mannitol challenge was performed before and after a methacholine challenge (Phase 2). In Phase 1, the time taken for the FEV(1) to recover after the first mannitol challenge ranged from 20 to 100 min with a median of 50 min. In the 23 subjects with a measurable mannitol PD(15) in both challenges, the geometric mean (95%CI) PD(15) in the second challenge (163 mg [114-232]) was significantly higher than that in the first challenge (66 mg [50-88], P value of 0.083%/mg (0.055-0.125) in the first challenge to 0.029%/mg (0.017-0.048) in the second challenge (P challenge with methacholine or mannitol did not significantly alter subsequent bronchoconstriction to the opposite challenge. Repeated challenge with mannitol resulted in less bronchoconstriction when compared with the initial challenge. This refractoriness seems not to be attributable to functional loss of responsiveness or non-specific effect of prior bronchoconstriction.

  7. The nasal distribution of metered dose inhalers. (United States)

    Newman, S P; Morén, P F; Clarke, S W


    The intranasal distribution of aerosol from a metered dose inhaler has been assessed using a radiotracer technique. Inhalers were prepared by adding 99Tcm-labelled Teflon particles (simulating the drug particles) to chlorofluorocarbon propellants, and scans of the head (and chest) taken with a gamma camera. Ten healthy subjects (age range 19-29 years) each performed two radioaerosol studies with the inhaler held in two different ways: either in a single position (vial pointing upwards) or in two positions (vial pointing upwards and then tilted by 30 degrees in the sagittal plane). The vast majority of the dose (82.5 +/- 2.8 (mean +/- SEM) per cent and 80.7 +/- 3.1 per cent respectively for one-position and two-position studies) was deposited on a single localized area in the anterior one-third of the nose, the initial distribution pattern being identical for each study. No significant radioaerosol was detected in the lungs. Only 18.0 +/- 4.7 per cent and 15.4 +/- 4.1 per cent of the dose had been removed by mucociliary action after 30 minutes, and it is probable that the remainder had not penetrated initially beyond the vestibule. Since the deposition pattern was highly localized and more than half the dose probably failed to reach the turbinates it is possible that the overall effect of nasal MDIs is suboptimal for the treatment of generalized nasal disorders.

  8. Pressurised metered dose inhaler-spacer technique in young children improves with video instruction. (United States)

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


    The importance of good device technique to maximise delivery of aerosolised medications is widely recognised. Pressurised metered dose inhaler (pMDI)-spacer technique was investigated in 122 children, aged 2-7 years, with asthma. Eight individual steps of device technique were evaluated before and after viewing an instructional video for correct device technique. Video measurements were repeated every three months for nine months. Device technique improved directly after video instruction at the baseline study visit (p children scoring maximal (p = 0.02) and near-maximal (p = 0.04) scores. Repeated video instruction over time improves inhaler technique in young children. • Correct device technique is considered essential for sufficient delivery of inhaled medication. • Poor inhaler use is common in young asthmatic children using pressurised metered dose inhalers and spacers. What is New: • Video instruction could be used as a strategy to improve device technique in young children.

  9. Uncertainties on lung doses from inhaled plutonium. (United States)

    Puncher, Matthew; Birchall, Alan; Bull, Richard K


    In a recent epidemiological study, Bayesian uncertainties on lung doses have been calculated to determine lung cancer risk from occupational exposures to plutonium. These calculations used a revised version of the Human Respiratory Tract Model (HRTM) published by the ICRP. In addition to the Bayesian analyses, which give probability distributions of doses, point estimates of doses (single estimates without uncertainty) were also provided for that study using the existing HRTM as it is described in ICRP Publication 66; these are to be used in a preliminary analysis of risk. To infer the differences between the point estimates and Bayesian uncertainty analyses, this paper applies the methodology to former workers of the United Kingdom Atomic Energy Authority (UKAEA), who constituted a subset of the study cohort. The resulting probability distributions of lung doses are compared with the point estimates obtained for each worker. It is shown that mean posterior lung doses are around two- to fourfold higher than point estimates and that uncertainties on doses vary over a wide range, greater than two orders of magnitude for some lung tissues. In addition, we demonstrate that uncertainties on the parameter values, rather than the model structure, are largely responsible for these effects. Of these it appears to be the parameters describing absorption from the lungs to blood that have the greatest impact on estimates of lung doses from urine bioassay. Therefore, accurate determination of the chemical form of inhaled plutonium and the absorption parameter values for these materials is important for obtaining reliable estimates of lung doses and hence risk from occupational exposures to plutonium.

  10. Urine concentrations of repetitive doses of inhaled salbutamol

    DEFF Research Database (Denmark)

    Elers, J; Pedersen, Lars; Henninge, J;


    We examined blood and urine concentrations of repetitive doses of inhaled salbutamol in relation to the existing cut-off value used in routine doping control. We compared the concentrations in asthmatics with regular use of beta2-agonists prior to study and healthy controls with no previous use...... of beta2-agonists. We enrolled 10 asthmatics and 10 controls in an open-label study in which subjects inhaled repetitive doses of 400 microgram salbutamol every second hour (total 1600 microgram), which is the permitted daily dose by the World Anti-Doping Agency (WADA). Blood samples were collected...

  11. Development of an intelligent adapter for metered dose inhalers

    Directory of Open Access Journals (Sweden)

    Zhang Mingrong


    Full Text Available To better coordinate the interaction of inhalation and aerosol release, an intelligent adapter (IA was developed for metered dose inhalers (MDIs. The adapter included three main units: a signal acquisition device, a micro-control-unit (MCU, and an actuation mechanism. To fully study the effectiveness of the intelligent adapter, an inhalation simulation experiment was done, and two bands of MDI were used for the experiment. The results indicated that, when inhalation, the intelligent adapter can press down the MDI automatically; moreover, this intelligent adapter could achieve an aerosol-release time Tr of 0.4 s for MDI A and 0.60 s for MDI B, which compares very well with the existing pure mechanical systems at 0.8 s and 1.0 s.

  12. Accidental Cutaneous Burns Secondary to Salbutamol Metered Dose Inhaler

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    Ashutosh Kale


    Full Text Available We report a case of accidental cutaneous burns caused by salbutamol metered dose inhaler. A 9-year-old boy underwent dental extraction at a children's hospital and was incidentally noted to have burn injuries on dorsum of both hands. On questioning, the boy revealed that a few days ago his 14-year-old brother, who is an asthmatic, playfully sprayed his salbutamol metered dose inhaler on the back of both his hands with the inhaler's mouth piece being in direct contact with the patient's skin. On examination, there was a rectangular area of erythema with superficial peeling on the dorsum of both hands, the dimensions of which exactly matched those of the inhaler's mouthpiece. It is possible that the injury could have been a chemical burn from the pharmaceutical/preservative/propellant aerosol or due to the physical effect of severe cooling of the skin or mechanical abrasive effect of the aerosol blasts or a combination of some or all the above mechanisms. This case highlights the importance of informing children and parents of the potentially hazardous consequences of misusing a metered dose inhaler.

  13. Neuroimmune Effects of Inhaling Low Dose Sarin (United States)


    affect these responses. This was further confirmed by the observation that intracerebroventricular administration of pyridostigmine and edrophonium...intracerebroventricularly) into the brain. These results also suggested that subcutaneous administration of pyridostigmine bromide at doses

  14. Achieving consistent multiple daily low-dose Bacillus anthracis spore inhalation exposures in the rabbit model

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    Roy E Barnewall


    Full Text Available Repeated low-level exposures to Bacillus anthracis could occur before or after the remediation of an environmental release. This is especially true for persistent agents such as Bacillus 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 fifteen 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. 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 x 102, 1 x 103, 1 x 104, and 1 x 105 CFU were used. In the multiple daily exposure experiment, rabbits were exposed multiple days to targeted inhaled doses of 1 x 102, 1 x 103, and 1 x 104 CFU. In all studies, targeted inhaled doses remained fairly 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 multiple exposure days.

  15. The biologically effective dose in inhalation nanotoxicology. (United States)

    Donaldson, Ken; Schinwald, Anja; Murphy, Fiona; Cho, Wan-Seob; Duffin, Rodger; Tran, Lang; Poland, Craig


    In all branches of toxicology, the biologically effective dose (BED) is the fraction of the total dose of a toxin that actually drives any toxic effect. Knowledge of the BED has a number of applications including in building structure-activity relationships, the selection of metrics, the design of safe particles, and the determination of when a nanoparticle (NP) can be considered to be "new" for regulatory purposes. In particle toxicology, we define the BED as "the entity within any dose of particles in tissue that drives a critical pathophysiogically relevant form of toxicity (e.g., oxidative stress, inflammation, genotoxicity, or proliferation) or a process that leads to it." In conventional chemical toxicology, researchers generally use the mass as the metric to describe dose (such as mass per unit tissue or cells in culture) because of its convenience. Concentration, calculated from mass, may also figure in any description of dose. In the case of a nanoparticle dose, researchers use either the mass or the surface area. The mass of nanoparticles is not the only driver of their activity: the surfaces of insoluble particles interact with biological systems, and soluble nanoparticles can release factors that interact with these systems. Nanoparticle shape can modify activity. In this Account, we describe the current knowledge of the BED as it pertains to different NP types. Soluble toxins released by NPs represent one potential indicator of BED for wholly or partially soluble NPs composed of copper or zinc. Rapid dissolution of these NPs into their toxic ions in the acidic environment of the macrophage phagolysosome causes those ions to accumulate, which leads to lysosome destabilization and inflammation. In contrast, soluble NPs that release low toxicity ions, such as magnesium oxide NPs, are not inflammogenic. For insoluble NPs, ζ potential can serve as a BED measurement because the exposure of the particle surface to the acidic milieu of the phagolysosome and

  16. Single- and multiple-dose pharmacokinetics of inhaled indacaterol in healthy Chinese volunteers. (United States)

    Jiang, Ji; Li, Lilly; Yin, Hequn; Woessner, Ralph; Emotte, Corinne; Li, Ruobing; Khindri, Sanjeev; Pei, Hu


    Indacaterol is an inhaled, ultra-long-acting β2-agonist that provides 24-h bronchodilation with once-daily dosing in patients with chronic obstructive pulmonary disorder. This study evaluated the pharmacokinetics, safety, and tolerability of multiple daily inhaled doses of indacaterol 150 or 300 μg once daily in healthy Chinese volunteers. This was a single-center, randomized, double-blind, multiple-dose, parallel-group study, placebo-controlled trial including two doses of indacaterol: 150 and 300 μg. Serum indacaterol was quantified using high-performance liquid chromatography-mass spectrometry with a lower limit of quantification of 0.01 ng/mL. The pharmacokinetic parameters were analyzed using non-compartmental analysis and included C max, T max, and AUC0-24h on Day 1 and AUC0-24h,ss, C max,ss, C min,ss, C av,ss, T max,ss, T 1/2, T 1/2,acc, CL/F, V z/F, and R acc on Day 14 (after repeated once-daily doses). Safety analyses were recorded using physical examination, biochemical tests, and ECG. Indacaterol steady state was achieved after 12-14 days of daily dosing. The mean effective half-life of indacaterol (based on drug accumulation at steady state) was 33.9 and 35.8 h for 150 and 300 μg, respectively. Systemic exposure to indacaterol increased 1.27 and 1.34-fold between the 150- and 300-μg doses on Day 1 (first dose) and Day 14 (repeated dose), respectively. Indacaterol 150 and 300 μg were safe and well tolerated in these volunteers. The pharmacokinetics of multiple inhaled doses of indacaterol 150 and 300 μg (for 14 days) were consistent with moderate systemic accumulation at steady state after repeated once-daily inhalation in healthy Chinese volunteers.

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

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


    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.

  18. Microscopic dose to lung from inhaled alpha emitters in humans

    Energy Technology Data Exchange (ETDEWEB)

    Diel, Joseph; Belosokhov, Maxim; Romanov, Sergey [Southern Urals Biophysics Institute, Ozersk, Chelyabinsk Region (Russian Federation); Guilmette, Raymond [Los Alamos National Laboratory, MS G761, RP-2, Los Alamos, NM 87545 (United States)


    Because of the short range of alpha particles in tissue, the degree of uniformity of irradiation of the lung varies greatly depending on the form of the inhaled material. Animal studies have shown that the degree of dose uniformity influences the risk of lung cancer. This study investigates the radiation dose distribution of plutonium in human lung. Numerical maps of tissue configuration and target cell locations are obtained from histological sections of human lung tissue stained to enhance the identification of putative cell types for parenchymal lung cancers, i.e. alveolar type II cells and Clara cells. Monte Carlo simulations are used to obtain dose distribution around individual particles, and these distributions are used to compute dose distribution in volumes of lung tissue. Lung dose is characterised both by the degree of non-uniformity of irradiation and the relative degree of irradiation of all tissue versus the special cells of interest. (authors)

  19. Acute and repeated inhalation lung injury by 3-methoxybutyl chloroformate in rats: CT-pathologic correlation

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Yeon Soo [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of); Chung, Myung Hee [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of)]. E-mail:; Park, Seog Hee [Department of Radiology, Kangnam St. Mary Hospital, Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040 (Korea, Republic of); Kim, Hyeon-Yeong [Industrial Chemicals Research Center, Industrial Safety and Health Research Institute KISCO, 104-8, Moonji-dong, Yusong-gu, Taejon-si 305-380 (Korea, Republic of); Choi, Byung Gil [Department of Radiology, Kangnam St. Mary Hospital, Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040 (Korea, Republic of); Lim, Hyun Wook [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of); Kim, Jin Ah [Department of Pathology, Holy Family Hospital, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon-si, Kyung gi-do 420-717 (Korea, Republic of); Yoo, Won Jong [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of)


    Objectives: To investigate the acute and repeated pulmonary damage in Sprague-Dawley rats caused by the inhalation of 3-methoxybutyl chloroformate (3-MBCF) using computed tomography (CT), and to correlate these results with those obtained from a pathological study. Methods: Sixty, 7-week-old rats were exposed to 3-MBCF vapor via inhalation (6 h/day) for 1 day (N = 20), 3 days (N = 20), and 28 days (5 days/week) (N = 20) using whole body exposure chambers at a concentration of 0 (control), 3, 6 and 12 ppm. CT examinations including densitometry and histopathologic studies were carried out. For the follow-up study, the rats exposed for 3 days were scanned using CT and their pathology was examined at 7, 14, and 28 days. Results: There was a significant decrease in the parenchymal density in the groups exposed to the 3-MBCF vapors for 1 day at 3 ppm (p = 0.022) or 6 ppm (p = 0.010), compared with the control. The parenchymal density of the rats exposed to12 ppm was significantly higher. The pathological findings in this period, the grades of vascular congestion, tracheobronchial exfoliation, and alveolar rupture were significant. In the groups exposed for 3 days, there was a large decrease in the parenchymal density with increasing dose (control: -675.48 {+-} 32.82 HU, 3 ppm: -720.65 {+-} 34.21 HU, 6 ppm: -756.41 {+-} 41.68 HU, 12 ppm: -812.56 {+-} 53.48 HU) (p = 0.000). There were significant density differences between each dose in the groups exposed for 28 days (p = 0.000). The CT findings include an irregular lung surface, areas of multifocal, wedge-shaped increased density, a heterogeneous lung density, bronchial dilatation, and axial peribronchovascular bundle thickening. The histopathology examination revealed the development of alveolar interstitial thickening and vasculitis, and an aggravation of the mainstem bronchial exudates and bronchial inflammation. The alveolar wall ruptures and bronchial dilatation became severe during this period. On the follow

  20. Electrostatics and inhaled medications: influence on delivery via pressurized metered-dose inhalers and add-on devices

    National Research Council Canada - National Science Library

    Mitchell, Jolyon P; Coppolo, Dominic P; Nagel, Mark W


    .... Spacers and valved holding chambers used with pressurized metered-dose inhalers to treat obstructive lung diseases are particularly prone to this behavior, which increases variability in the amount...

  1. Urine concentrations of repetitive doses of inhaled salbutamol

    DEFF Research Database (Denmark)

    Elers, J; Pedersen, Lars; Henninge, J


    We examined blood and urine concentrations of repetitive doses of inhaled salbutamol in relation to the existing cut-off value used in routine doping control. We compared the concentrations in asthmatics with regular use of beta2-agonists prior to study and healthy controls with no previous use...... of beta2-agonists. We enrolled 10 asthmatics and 10 controls in an open-label study in which subjects inhaled repetitive doses of 400 microgram salbutamol every second hour (total 1600 microgram), which is the permitted daily dose by the World Anti-Doping Agency (WADA). Blood samples were collected...... and the median ranged from 268 to 611 ng×mL (-1). No samples exceeded the WADA threshold value of 1000 ng×mL (-1) when corrected for the urine specific gravity. When not corrected one sample exceeded the cut-off value with urine concentration of 1082 ng×mL (-1). In conclusion we found no differences in blood...

  2. Evaluation of Metered Dose Inhaler Use Technique and Response to Educational Training. (United States)

    Jolly, G P; Mohan, A; Guleria, R; Poulose, Rosemary; George, J


    Prescribing inhalers without imparting adequate education regarding proper technique of their usage may result in suboptimal clinical improvement and wastage of medication. Training interventions using a standard check-list may help improve faulty techniques and enhance drug efficacy. Patients using metered dose inhaler (MDI) were included in the study. Inhaler technique was first evaluated at baseline using a standard check-list of recommended steps (National Institute of Health guidelines; see Table) and scores were given for each step correctly performed. Those who could not perform all steps correctly were given training intervention. The patients were assigned to two methods of educational intervention; one group was trained by providing written material giving step-wise instructions while the other group was given an actual physical demonstration using a placebo device. The technique was re-evaluated and scored following each educational session, and continued till the patient achieved a full score, or for a maximum of 3 sessions, whichever occurred earlier. Median score was calculated after each session and was compared between the two groups. Each patient was followed up after two months and the re-evaluated the same way. One hundred and seventeen subjects were enrolled in the study (59 in the written group and 57 in the practical demonstration group). At baseline, only 1 of the 117 subjects could perform all the steps of inhaler usage correctly. This patient was, therefore, not provided the inhaler technique education. The overall median (range) score of the whole group was 3 (range 1-8). This score rose to 6, 7 and 8 after each of the three subsequent educational intervention sessions. At one-month follow-up, the median score dropped to 7 and improved with a repeat educational session as previously done. A significant difference was observed in the median score improvement achieved in the practical demonstration group compared with the written instruction

  3. Achieving Consistent Multiple Daily Low-Dose Bacillus anthracis Spore Inhalation Exposures in the Rabbit Model (United States)


    daily low-dose Bacillus anthracis spore inhalation exposures in the rabbit model Roy E. Barnewall 1, Jason E. Comer 1, Brian D. Miller 1, BradfordW...multiple exposure days. Keywords: Bacillus anthracis , inhalation exposures, low-dose, subchronic exposures, spores, anthrax, aerosol system INTRODUCTION... Bacillus Anthracis Spore Inhalation Exposures In The Rabbit Model 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d

  4. Pharmacokinetic Comparison of a Unit Dose Dry Powder Inhaler with a Multidose Dry Powder Inhaler for Delivery of Fluticasone Furoate. (United States)

    Mehta, Rashmi; Moore, Alison; Riddell, Kylie; Joshi, Shashidhar; Chan, Robert


    The unit dose dry powder inhaler (UD-DPI) is being considered as an alternative inhaler platform that, if developed, has the potential to improve access to inhaled respiratory medicines in developing countries. This study compared the systemic exposure of fluticasone furoate after delivery from the UD-DPI with that from the ELLIPTA(®) inhaler. This open-label, five-way cross-over, randomized, single-dose study in healthy subjects evaluated fluticasone furoate systemic exposure of three dose strengths (using four inhalations), 4 × 80 μg [320 μg], 4 × 100 μg [400 μg], and 4 × 140 μg [560 μg]), and two percentages of drug in lactose blends (0.6% and 0.8% by weight) after delivery from the UD-DPI compared with systemic exposures from the ELLIPTA inhaler (4 × 100 μg [400 μg] dose, 0.8% lactose blend). The primary treatment comparisons were area under the concentration-time curve from time 0 to 6 hours [AUC0-6] and maximum plasma concentration [Cmax]. After single-dose administration of fluticasone furoate, systemic exposure was lower from all UD-DPI formulations versus the ELLIPTA inhaler in terms of both AUC0-6 [AUC0-6 geometric least squares mean (GLM) ratios confidence interval (90% CI) for: UD-DPI (400 μg 0.8% blend)/ELLIPTA: 0.61 (0.55-0.67) and Cmax GLM (90% CI) for: UD-DPI (400 μg 0.8% blend)/ELLIPTA: 0.56 (0.49-0.64)]. Systemic exposures were ∼10% lower for fluticasone furoate UD-DPI for the 0.8% blend versus the 0.6% blend [GLM ratio (90% CI); 0.90 (0.81-1.00) for AUC0-6 and 0.89 (0.77-1.01) for Cmax], and increasing doses of fluticasone furoate from the UD-DPI showed systemic exposures that were approximately dose proportional. All treatments were well tolerated. Fluticasone furoate systemic exposure was lower from the UD-DPI than from the ELLIPTA inhaler, but the UD-DPI formulations did demonstrate detectable systemic levels and approximate dose proportionality. Together with the good tolerability shown

  5. Effect of repeated benzene inhalation exposures on benzene metabolism, binding to hemoglobin, and induction of micronuclei. (United States)

    Sabourin, P J; Sun, J D; MacGregor, J T; Wehr, C M; Birnbaum, L S; Lucier, G; Henderson, R F


    Metabolism of benzene is thought to be necessary to produce the toxic effects, including carcinogenicity, associated with benzene exposure. To extrapolate from the results of rodent studies to potential health risks in man, one must know how benzene metabolism is affected by species, dose, dose rate, and repeated versus single exposures. The purpose of our studies was to determine the effect of repeated inhalation exposures on the metabolism of [14C]benzene by rodents. Benzene metabolism was assessed by characterizing and quantitating urinary metabolites, and by quantitating 14C bound to hemoglobin and micronuclei induction. F344/N rats and B6C3F1 mice were exposed, nose-only, to 600 ppm benzene or to air (control) for 6 hr/day, 5 days/week for 3 weeks. On the last day, both benzene-pretreated and control animals were exposed to 600 ppm, 14C-labeled benzene for 6 hr. Individual benzene metabolites in urine collected for 24 hr after the exposure were analyzed. There was a significant decrease in the respiratory rate of mice (but not rats) pretreated with benzene which resulted in lower levels of urinary [14C]benzene metabolites. The analyses indicated that the only effects of benzene pretreatment on the metabolite profile in rat or mouse urine were a slight shift from glucuronidation to sulfation in mice and a shift from sulfation to glucuronidation in rats. Benzene pretreatment also had no effect, in either species, on formation of [14C]benzene-derived hemoglobin adducts. Mice and rats had similar levels of hemoglobin adduct binding, despite the higher metabolism of benzene by mice. This indicates that hemoglobin adduct formation occurs with higher efficiency in rats. After 1 week of exposure to 600 ppm benzene, the frequency of micronucleated, polychromatic erythrocytes (PCEs) in mice was significantly increased. Exposure to the same level of benzene for an additional 2 weeks did not further increase the frequency of micronuclei in PCEs. These results indicate

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

    DEFF Research Database (Denmark)

    Kaae, Rikke; Agertoft, Lone; Pedersen, Sören


    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 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. RESULTS: Formoterol and terbutaline had significant beta2-adrenergic effects on most outcomes. Apart from the effect on systolic BP, QRS duration...

  7. Advanced technologies and devices for inhalational anesthetic drug dosing. (United States)

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


    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

  8. Ozone Inhalation Leads to a Dose-Dependent Increase of Cytogenetic Damage in Human Lymphocytes (United States)

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


    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

  9. Assessment of inhalation dose sensitivity by physicochemical properties of airborne particulates containing naturally occurring radioactive materials

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Si Young; Choi, Cheol Kyu; Kim, Yong Geon; Choi, Won Chul; Kim, Kwang Pyo [Kyung Hee University, Seoul (Korea, Republic of)


    Facilities processing raw materials containing naturally occurring radioactive materials (NORM) may give rise to enhanced radiation dose to workers due to chronic inhalation of airborne particulates. Internal radiation dose due to particulate inhalation varies depending on particulate properties, including size, shape, density, and absorption type. The objective of the present study was to assess inhalation dose sensitivity to physicochemical properties of airborne particulates. Committed effective doses to workers resulting from inhalation of airborne particulates were calculated based on International Commission on Radiological Protection 66 human respiratory tract model. Inhalation dose generally increased with decreasing particulate size. Committed effective doses due to inhalation of 0.01μm sized particulates were higher than doses due to 100μm sized particulates by factors of about 100 and 50 for {sup 238}U and {sup 230}Th, respectively. Inhalation dose increased with decreasing shape factor. Shape factors of 1 and 2 resulted in dose difference by about 18 %. Inhalation dose increased with particulate mass density. Particulate mass densities of 11 g·cm{sup -3} and 0.7 g·cm{sup -3} resulted in dose difference by about 60 %. For {sup 238}U, inhalation doses were higher for absorption type of S, M, and F in that sequence. Committed effective dose for absorption type S of {sup 238}U was about 9 times higher than dose for absorption F. For {sup 230}Th, inhalation doses were higher for absorption type of F, M, and S in that sequence. Committed effective dose for absorption type F of {sup 230}Th was about 16 times higher than dose for absorption S. Consequently, use of default values for particulate properties without consideration of site specific physiochemical properties may potentially skew radiation dose estimates to unrealistic values up to 1-2 orders of magnitude. For this reason, it is highly recommended to consider site specific working materials and

  10. Allergic inflammation in the upper respiratory tract of the rat upon repeated inhalation exposure to the contact allergen dinitrochlorobenzene (DNCB).

    NARCIS (Netherlands)

    Triel, J.J. van; Arts, J.H.; Muijser, H.; Kuper, C.F.


    Previously, the contact allergen dinitrochlorobenzene (DNCB) was identified as a sensitizer by inhalation in BALB/c mice; in addition, DNCB induced a lymphocytic infiltrate in the larynx of dermally sensitized Th1-prone Wistar rats upon a single inhalation challenge. In the present study, repeated

  11. Allergic inflammation in the upper respiratory tract of the rat upon repeated inhalation exposure to the contact allergen dinitrochlorobenzene (DNCB).

    NARCIS (Netherlands)

    Triel, J.J. van; Arts, J.H.; Muijser, H.; Kuper, C.F.


    Previously, the contact allergen dinitrochlorobenzene (DNCB) was identified as a sensitizer by inhalation in BALB/c mice; in addition, DNCB induced a lymphocytic infiltrate in the larynx of dermally sensitized Th1-prone Wistar rats upon a single inhalation challenge. In the present study, repeated i

  12. Inhalants (United States)

    ... which open the breathing passages. Inhalers are very safe when used as prescribed by doctors. Inhalants, on the other hand, are common household chemicals that contain a volatile component which can be ...

  13. Periodontal disease and high doses of inhaled corticosteroids alter NTPDase activity in the blood serum of rats. (United States)

    Scarabelot, Vanessa L; Cavagni, Juliano; Medeiros, Liciane F; Detânico, Bernardo; Rozisky, Joanna R; de Souza, Andressa; Daudt, Luciana Dondonis; Gaio, Eduardo José; Ferreira, Maria Beatriz Cardoso; Rösing, Cassiano Kuchenbecker; Battastini, Ana Maria O; Torres, Iraci L S


    Certain drugs such as glucocorticoids may interfere with the modulation of periodontal disease. In contrast, corticosteroid treatment has been associated with a protective effect with regard to periodontal breakdown, depending on the dose, pathway, and exposure time. Considering the potential relevance of nucleotidases in coordinating the cardiovascular system and inflammation processes, the aim of this study was to investigate the nucleotidase activities in the blood serum of rats with periodontal disease exposed chronically to inhaled corticosteroids. Adult male Wistar rats (n=26) were randomly assigned to one of the following four study groups: a control group that received no intervention; a periodontal disease group that received saline solution; a 'low dose' group that received 30 μg of budesonide daily; and a corresponding 'high dose' group that received 100 μg daily over a 15-day time course. The hydrolysis of ATP, ADP, and AMP were analysed in blood serum. Periodontal disease diminished the hydrolysis of ATP and enhanced the hydrolysis of ADP. Repeated administration of either a low or high dose in the periodontal disease model of inhaled corticosteroids reversed the observed increase in ADP hydrolysis, and only the repeated administration of low doses of inhaled corticosteroids was able to reverse the decrease in the hydrolysis of ATP induced by periodontal disease. The variables investigated in this study may be involved in the pathophysiology of periodontal disease and may participate in the mechanisms that mediate the development of some of the side effects of inhaled corticosteroids. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Size aspects of metered-dose inhaler aerosols. (United States)

    Kim, C S; Trujillo, D; Sackner, M A


    The aerodynamic size distribution of several bronchodilator and corticosteroid metered-dose inhaler (MDI) aerosols was estimated in both dry and humid (90% RH) air environments with a six-stage cascade impactor. The distribution of aerosol size that penetrated into a simulated lung model were also measured. The size distributions were approximately log-normal and ranged from 2.4 to 5.5 micron in mass median aerodynamic diameter (MMAD) with geometric standard deviation (GSD) of 1.7 to 2.5 in a dry environment. In humid air, MMAD increased from 1 to 26% above the dry air state, but GSD remained unchanged. The size of aerosol delivered by MDI that penetrated into a simulated lung model fell to 2.4 to 2.8 micron in MMAD (GSD, 1.9 to 2.2). In contrast to aerosols produced by MDI, MMAD of an aerosol of cromolyn sodium powder dispersed by a Spinhaler increased rapidly with increasing humidity, 5.6 +/- 0.3 micron in dry air and 10.1 +/- 0.8 micron in 90% RH air. Finally, the factors influencing size of MDI-delivered aerosols, including formulation, canister pressure, physicochemical properties of propellants, and design of the valve and actuator orifices are discussed. Effective delivery of MDI-generated aerosols into the lung is highly dependent on particle dynamics and jet flow, and no single parameter can produce a unique particle size and jet pattern.

  15. Inhaled corticosteroid metered-dose inhalers: how do variations in technique for solutions versus suspensions affect drug distribution? (United States)

    Robinson, Christie A; Tsourounis, Candy


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

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

    Energy Technology Data Exchange (ETDEWEB)

    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 mode are also printed if requested.

  17. 5-Day repeated inhalation and 28-day post-exposure study of graphene. (United States)

    Shin, Jae Hoon; Han, Sung Gu; Kim, Jin Kwon; Kim, Boo Wook; Hwang, Joo Hwan; Lee, Jong Seong; Lee, Ji Hyun; Baek, Jin Ee; Kim, Tae Gyu; Kim, Keun Soo; Lee, Heon Sang; Song, Nam Woong; Ahn, Kangho; Yu, Il Je


    Graphene has recently been attracting increasing attention due to its unique electronic and chemical properties and many potential applications in such fields as semiconductors, energy storage, flexible electronics, biosensors and medical imaging. However, the toxicity of graphene in the case of human exposure has not yet been clarified. Thus, a 5-day repeated inhalation toxicity study of graphene was conducted using a nose-only inhalation system for male Sprague-Dawley rats. A total of three groups (20 rats per group) were compared: (1) control (ambient air), (2) low concentration (0.68 ± 0.14 mg/m(3) graphene) and (3) high concentration (3.86 ± 0.94 mg/m(3) graphene). The rats were exposed to graphene for 6 h/day for 5 days, followed by recovery for 1, 3, 7 or 28 days. The bioaccumulation and macrophage ingestion of the graphene were evaluated in the rat lungs. The exposure to graphene did not change the body weights or organ weights of the rats after the 5-day exposure and during the recovery period. No statistically significant difference was observed in the levels of lactate dehydrogenase, protein and albumin between the exposed and control groups. However, graphene ingestion by alveolar macrophages was observed in the exposed groups. Therefore, these results suggest that the 5-day repeated exposure to graphene only had a minimal toxic effect at the concentrations and time points used in this study.

  18. Comparison in the calculation of committed effective dose using the ICRP 30 and ICRP 60 models for a repeated incorporation by inhalation of I-125; Comparacion en el calculo de la dosis efectiva comprometida usando los modelos del ICRP 30 y del ICRP 60 para una incorporacion repetida por inhalacion de I-125

    Energy Technology Data Exchange (ETDEWEB)

    Carreno P, A.L.; Cortes C, A. [CNSNS, Dr. Barragan 779, Col. Narvarte, Mexico D.F. (Mexico); Alonso V, G.; Serrano P, F. [IPN, Edificio de Fisica Avanzada Zacatenco, 07300 Mexico D.F. (Mexico)


    Presently work, a comparison in the calculation of committed effective dose using the models of the ICRP 30 and those of the ICRP 60 for the analysis of internal dose due to repeated incorporation of I-125 is shown. The estimations of incorporated activity are obtained starting from the proportionate data for an exercise of inter comparison, with which it should be determined the internal dose later on. For to estimate the initial activity incorporated by repeated dose was assumed that this it was given through of multiple individual incorporations which happened in the middle points of the monitoring periods. The results using the models of the ICRP 30 and of the ICRP 60 are compared and the causes of the differences are analyzed. (Author)

  19. Natural radionuclides in cigarette tobacco from Serbian market and effective dose estimate from smoke inhalation. (United States)

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


    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:

  20. Dose estimation for repeated phosphorus-32 ingestion in human subjects

    Energy Technology Data Exchange (ETDEWEB)

    Chao, J.H.; Tseng, C.L.; Hsieh, W.A.; Hung, D.Z.; Chang, W.P. E-mail:


    Dose estimation was conducted for internal phosphorus-32 exposure in one young male subject from repeated oral mis-ingestion for >1 year. Since disclosure for previous continuous contamination, a series of urine samples were collected from this individual weekly for a period of >2 months. P-32 radioactivity in urine samples were measured by the acid precipitation method. Estimation for retrospective total effective dose equivalent received by this subject was conducted for cumulative internal dose estimation. A minimum of 9.4 mSv was estimated for an assumed single ingestion. As this was a rare case in radiation protection and internal radiation dosimetry, its implications were of considerable significance.

  1. High-dose inhaled terbutaline increases muscle strength and enhances maximal sprint performance in trained men

    DEFF Research Database (Denmark)

    Hostrup, Morten; Kalsen, Anders; Bangsbo, Jens


    PURPOSE: The purpose of the present study was to investigate the effect of high-dose inhaled terbutaline on muscle strength, maximal sprinting, and time-trial performance in trained men. METHODS: Nine non-asthmatic males with a [Formula: see text] of 58.9 ± 3.1 ml min(-1) kg(-1) (mean ± SEM......) participated in a double-blinded randomized crossover study. After administration of inhaled terbutaline (30 × 0.5 mg) or placebo, subjects' maximal voluntary isometric contraction (MVC) of m.quadriceps was measured. After MVC, subjects performed a 30-s Wingate test. Sixty minutes following the Wingate test...... was not different between treatments (P = 0.236). CONCLUSION: High-dose inhaled terbutaline elicits a systemic response that enhances muscle strength and sprint performance. High-dose terbutaline should therefore continue to be restricted in competitive sport....

  2. Time course of pharmacokinetic and hormonal effects of inhaled high-dose salvinorin A in humans. (United States)

    Johnson, Matthew W; MacLean, Katherine A; Caspers, Michael J; Prisinzano, Thomas E; Griffiths, Roland R


    Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the Salvia divinorum plant, which has been used for hallucinogenic effects. Previous research on salvinorin A pharmacokinetics likely underestimated plasma levels typically resulting from the doses administered due to inefficient vaporization and not collecting samples during peak drug effects. Six healthy adults inhaled a single high dose of vaporized salvinorin A (n = 4, 21 mcg/kg; n = 2, 18 mcg/kg). Participant- and monitor-rated effects were assessed every 2 min for 60 min post-inhalation. Blood samples were collected at 13 time points up to 90 min post-inhalation. Drug levels peaked at 2 min and then rapidly decreased. Drug levels were significantly, positively correlated with participant and monitor drug effect ratings. Significant elevations in prolactin were observed beginning 5 min post-inhalation and peaking at 15 min post-inhalation. Cortisol showed inconsistent increases across participants. Hormonal responses were not well correlated with drug levels. This is the first study to demonstrate a direct relationship between changes in plasma levels of salvinorin A and drug effects in humans. The results confirm the efficacy of an inhalation technique for salvinorin A.

  3. Inhalants (United States)

    Skip to main content En español Researchers Medical & Health Professionals Patients & Families Parents & Educators Children & Teens Search Connect with NIDA : ... get treatment for addiction to inhalants? Some people seeking treatment for ... for positive behaviors such as staying drug-free. More research is ...

  4. In vitro dose comparison of Respimat® inhaler with dry powder inhalers for COPD maintenance therapy (United States)

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


    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

  5. In vitro dose comparison of Respimat(®) inhaler with dry powder inhalers for COPD maintenance therapy. (United States)

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


    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.

  6. Prescribed doses of inhaled steroids in Dutch children : too little or too much, for too short a time

    NARCIS (Netherlands)

    Schirm, E.; de Vries, T.W.; Tobi, H.; van den Berg, P.B.; de Jong-van den Berg, L.T.W.


    Aims To investigate the dosage and duration of inhaled steroids prescribed to children and to compare the prescribed doses with recommended doses for the treatment of asthma in children. Methods For 2514 Dutch children aged 0-12 years who had used inhaled steroids in 2002, pharmacy dispensing data w

  7. Prescribed doses of inhaled steroids in Dutch children: too little or too much, for too short a time.

    NARCIS (Netherlands)

    Schirm, E.; Vries, de T.W.; Tobi, H.; Berg, van den P.B.; Jong-van den Berg, de L.T.W.; Lolkje, T.W.


    Aims: To investigate the dosage and duration of inhaled steroids prescribed to children and to compare the prescribed doses with recommended doses for the treatment of asthma in children. Methods: For 2514 Dutch children aged 0-12 years who had used inhaled steroids in 2002, pharmacy dispensing data

  8. Repeated dose pharmacokinetics of pancopride in human volunteers. (United States)

    Salva, P; Costa, J; Pérez-Campos, A; Martínez-Tobed, A


    The aim of this study was to assess the pharmacokinetic profile of pancopride after repeated oral dose administration of 20 mg pancopride in tablet form once a day for 5 d in 12 healthy male volunteers. Plasma levels were measured by HPLC using a solid phase extraction method and automated injection. The minimum quantification limit of pancopride in plasma was 2 ng mL-1. The maximum plasma concentration (mean +/- SD) after the first dose was 92.5 +/- 41.5 ng ML-1 and tmax was 1.7 +/- 0.9 h. The elimination half-life (t1/2) was 14.3 +/- 6.9 h. The area under the concentration-time curve from zero to infinity (AUC) was 997 +/- 396 ng h mL-1. The maximum plasma concentration (mean +/- SD) at steady state (day 5) was 101.8 +/- 36.9 ng mL-1 and tmax was 2.2 +/- 1.2 h. The elimination half-life (t1/2) was 16.3 +/- 2.7 h and the minimum plasma concentration (Cssmin) was 16.6 +/- 6.9 ng mL-1. The area under the concentration-time curve during the dosing interval (AUCss tau) was 995 +/- 389 ng h mL-1. The average plasma concentration at steady state (Cssav) was 43.3 +/- 16.1 ng mL-1 and the experimental accumulation ratio (RAUC) was 1.34 +/- 0.19, whereas the mean theoretical value (R) was 1.40 +/- 0.29. The results obtained showed a good correlation between the experimental plasma levels and the expected values calculated using a repeated dose two-compartment model assessed by means of the Akaike value. It is concluded that the pharmacokinetics of pancopride are not modified after repeated dose administration.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Twenty-eight-day repeated inhalation toxicity study of nano-sized lanthanum oxide in male sprague-dawley rats. (United States)

    Shin, Seo-Ho; Lim, Cheol-Hong; Kim, Yong-Soon; Lee, Yong-Hoon; Kim, Sung-Hwan; Kim, Jong-Choon


    Although the use of lanthanum has increased in field of high-tech industry worldwide, potential adverse effects to human health and to the environment are largely unknown. The present study aimed to investigate the potential toxicity of nano-sized lanthanum oxide (La2 O3 ) following repeated inhalation exposure in male Sprague-Dawley rats. Male rats were exposed nose-only to nano-sized La2 O3 for 28 days (5 days/week) at doses of 0, 0.5, 2.5, and 10 mg/m(3) . In the experimental period, we evaluated treatment-related changes including clinical signs, body weight, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology findings. We also analyzed lanthanum distribution in the major organs and in the blood, bronchoalveolar lavage fluids (BALF), and oxidative stress in lung tissues. Lanthanum level was highest in lung tissues and showed a dose-dependent relation. Alveolar proteinosis was observed in all treatment groups and was accompanied by an increase in lung weight; moreover, lung inflammation was observed in the 2.5 mg/m(3) and higher dose groups and was accompanied by an increase in white blood cells. In the BALF, total cell counts including macrophages and neutrophils, lactate dehydrogenase, albumin, nitric oxide, and tumor necrosis factor-alpha increased significantly in all treatment groups. Furthermore, these changes tended to deteriorate in the 10 mg/m(3) group at the end of the recovery period. In the present experimental conditions, we found that the lowest-observed-adverse-effect level of nano-sized La2 O3 was 0.5 mg/m(3) in male rats, and the target organ was the lung. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1226-1240, 2017. © 2016 Wiley Periodicals, Inc.

  10. Dose and effect of inhaled ozone in resting versus exercising human subjects: comparison with resting rats (United States)

    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...

  11. Dose assessment to inhalation exposure of indoor 222Rn daughters in Korea. (United States)

    Ha, C W; Chang, S Y; Lee, B H


    Long-term, average indoor 222Rn concentrations were measured in 12 residential areas by passive CR-39 radon cups. Corresponding equilibrium-equivalent concentration of radon daughters were derived. The resulting effective dose equivalent for the Korean population due to inhalation exposure of this equilibrium-equivalent concentration of radon daughters was then evaluated.

  12. Inhaled low-dose iloprost for pulmonary hypertension: a prospective, multicenter, open-label study. (United States)

    Sun, Yun-Juan; Xiong, Chang-Ming; Shan, Guang-Liang; Gu, Qing; Zeng, Wei-Jie; Lu, Xian-Ling; Zhu, Feng; Liu, Zhi-Hong; Ni, Xin-Hai; He, Jian-Guo


    Inhaled iloprost (average >30 µg/d) has been considered an effective treatment for severe pulmonary hypertension (PH). Further evidence also showed that low-dose iloprost given intravenously was equally effective as high-dose iloprost in the therapy of systemic sclerosis. Patients with pulmonary hypertension will benefit from inhalation of low-dose iloprost. Sixty-two patients with PH were enrolled and initiated with neubulizedlow-dose iloprost (2.5 µg per inhalation, 6× daily) for 24 weeks in 13 medical centers in China. Efficacy endpoints included changes in 6-minute walk distance (6MWD), World Health Organization functional class (WHO-FC), and hemodynamic parameters. Fourteen patients (22.6%) prematurely discontinued the study: 8 due to clinical worsening (6 in WHO-FCIII-IV at baseline), 4 because of protocol change, and 2 patients lost during follow-up. In the remaining 48 patients, 6MWD was increased from 356 ± 98 meters to 414 ± 99 meters (P iloprost inhalation significantly improved exercise capacity and functional status in patients with PH. It was well tolerated. The improvement of hemodynamics was confirmed in patients with WHO-FCI-II but not in patients with WHO-FCIII-IV, suggesting the importance of early treatment in patients with advanced disease stages. © 2012 Wiley Periodicals, Inc.

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

    Directory of Open Access Journals (Sweden)

    Ciciliani A


    Full Text Available Anna-Maria Ciciliani,1,2 Peter Langguth,1 Herbert Wachtel2 1Institute of Pharmacy and Biochemistry, Faculty 09 (Chemistry, Pharmaceutics and Geosciences, Johannes Gutenberg University, Mainz, 2Analytical Development Department, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany 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

  14. Slope of the dose-response curve: usefulness in assessing bronchial responses to inhaled histamine.


    Cockcroft, D. W.; Berscheid, B A


    The value of determining the slope of the histamine dose-response curve, in addition to the histamine provocation concentration producing a 20% reduction in FEV1 (PC20-FEV1), was assessed by analysis of histamine dose-response curves in 40 patients selected as having a wide range of increased non-specific bronchial responsiveness to inhaled histamine. The histamine dose-response curves were found to be fit the linear curve (dose v response, mean r2 = 0.97) better than the logarithmic curve (l...

  15. Pharmacology of ayahuasca administered in two repeated doses. (United States)

    Dos Santos, Rafael G; Grasa, Eva; Valle, Marta; Ballester, Maria Rosa; Bouso, José Carlos; Nomdedéu, Josep F; Homs, Rosa; Barbanoj, Manel J; Riba, Jordi


    Ayahuasca is an Amazonian tea containing the natural psychedelic 5-HT(2A/2C/1A) agonist N,N-dimethyltryptamine (DMT). It is used in ceremonial contexts for its visionary properties. The human pharmacology of ayahuasca has been well characterized following its administration in single doses. To evaluate the human pharmacology of ayahuasca in repeated doses and assess the potential occurrence of acute tolerance or sensitization. In a double-blind, crossover, placebo-controlled clinical trial, nine experienced psychedelic drug users received PO the two following treatment combinations at least 1 week apart: (a) a lactose placebo and then, 4 h later, an ayahuasca dose; and (b) two ayahuasca doses 4 h apart. All ayahuasca doses were freeze-dried Amazonian-sourced tea encapsulated to a standardized 0.75 mg DMT/kg bodyweight. Subjective, neurophysiological, cardiovascular, autonomic, neuroendocrine, and cell immunity measures were obtained before and at regular time intervals until 12 h after first dose administration. DMT plasma concentrations, scores in subjective and neurophysiological variables, and serum prolactin and cortisol were significantly higher after two consecutive doses. When effects were standardized by plasma DMT concentrations, no differences were observed for subjective, neurophysiological, autonomic, or immunological effects. However, we observed a trend to reduced systolic blood pressure and heart rate, and a significant decrease for growth hormone (GH) after the second ayahuasca dose. Whereas there was no clear-cut tolerance or sensitization in the psychological sphere or most physiological variables, a trend to lower cardiovascular activation was observed, together with significant tolerance to GH secretion.

  16. Relationships between repeated instruction on inhalation therapy, medication adherence, and health status in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Masaya Takemura


    Full Text Available Masaya Takemura1, Katsumi Mitsui2, Ryo Itotani1, Manabu Ishitoko1, Shinko Suzuki1, Masataka Matsumoto1, Kensaku Aihara1, Tsuyoshi Oguma1, Tetsuya Ueda1, Hitoshi Kagioka1, Motonari Fukui11Division of Respiratory Medicine, 2Division of Pharmacy, Tazuke Kofukai, Medical Research Institute, Kitano Hospital, Osaka, JapanPurpose: Adherence to inhalation therapy is a critical determinant of the success of chronic obstructive pulmonary disease (COPD management. However, in practice, nonadherence to inhalation therapy is very common in COPD patients. The effects of adherence to inhalation therapy in COPD have not been fully studied, and less is known about the relationship between medication adherence and quality of life in COPD. Our aim is to assess the factors that contribute to adherence to inhalation therapy and examine their correlation with quality of life.Patients and methods: A cross-sectional analysis of 88 COPD patients was performed using a self-reported adherence questionnaire with responses on a 5-point Likert scale.Results: Of the 88 patients who were potential participants, 55 (63% responded with usable information. The only significant factor associated with the overall mean adherence score was receiving repeated instruction about inhalation techniques (P = 0.032. Of the 55 respondents, 22 (40.0% were given repeated verbal instruction and/or demonstrations of inhalation technique by a respiratory physician. Significant correlations were found between the overall mean adherence score and the health-related quality of life score (St George’s Respiratory Questionnaire: total, r = −0.35, P = 0.023; symptoms, r = −0.43, P = 0.002; impacts, r = −0.35, P = 0.011. Furthermore, patients with repeated instruction showed better quality of life scores than those who did not receive instruction (total, P = 0.030; symptoms, P = 0.038; impacts, P = 0.019.Conclusions: Repeated instruction for inhalation techniques may contribute to adherence to

  17. Dioxin inhalation doses from wood combustion in indoor cookfires (United States)

    Northcross, Amanda L.; Katharine Hammond, S.; Canuz, Eduardo; Smith, Kirk R.


    Approximately 3 billion people worldwide rely on solid biomass fuels for household cooking and space heating, and approximately 50-60% use wood, often indoors in poorly ventilated situations. Daily exposures to high concentrations of smoke from cookstoves inside kitchens create large smoke exposures for women cooks and their small children. The smoke from burning the wood fuel contains hundred of toxic compounds, including dioxins and furans some of the most toxic compounds known to science. Health effects from exposure to dioxins include reproductive and developmental problems, damage the immune system, interference with hormones and also cause cancer. This study measured concentrations of dioxins and furans in a typical Guatemalan village home during open cookfires. Measured concentrations averaged 0.32 ± 0.07 ng m-3 over 31 fires. A Monte Carlo simulation was conducted using parameter estimates based on 8 years of research experience in the study area. The estimated total daily intake of 17 particle phase dioxin and furans for women, a 5-year-old child and a 6-month-old infant were 1.2 (S.D. = 0.4), 1.7 (S.D. = 0.7) and 2.0 (S.D. = 0.5) respectively. The 46% of babies have and estimated total daily intake (TDI) which exceed the WHO TDI guideline for dioxins and furans, 3% of women and 26% of 5-year-old children based solely inhalation of particle phase dioxins in woodsmoke from an open cooking fire. These values maybe underestimates, as they did not include gas phase concentrations or ingestion of dioxins and furans through food, which is the largest route of exposure in the developed world.

  18. In Vitro Dosing Performance of the ELLIPTA® Dry Powder Inhaler Using Asthma and COPD Patient Inhalation Profiles Replicated with the Electronic Lung (eLung™). (United States)

    Hamilton, Melanie; Leggett, Richard; Pang, Cheng; Charles, Stephen; Gillett, Ben; Prime, David


    To evaluate the in vitro dose delivery characteristics of approved asthma and chronic obstructive pulmonary disease (COPD) therapies delivered via the ELLIPTA(®) dry powder inhaler across inhalation endpoints representative of the target patient population, using the Electronic Lung (eLung™) to replicate inhaler-specific patient inhalation profiles that were previously recorded in vivo. Selected profiles, representative of the range of inhalation endpoints achieved by patients with all severities of asthma and COPD, were replicated using the eLung breathing simulator in conjunction with an oropharyngeal cast. A Next Generation Impactor was coupled to the eLung to determine the aerodynamic particle size distribution of the ex-throat dose (ETD) of asthma and COPD therapies delivered via the ELLIPTA inhaler. Delivered dose (DD), ETD, and fine particle dose (FPD; defined as a mass of active substance less than 5 μm) were determined for fluticasone furoate (FF)/vilanterol (VI) 100/25 μg and 200/25 μg (asthma and COPD), umeclidinium (UMEC)/VI 62.5/25 μg (COPD only), FF 100 μg and 200μg monotherapy (asthma only), and UMEC 62.5 μg monotherapy (COPD only). Inhalation profiles replicated by eLung covered a wide range of peak inspiratory flow rates (41.6-136.9 L/min), pressure drops (1.2-13.8 kPa), and inhaled volumes through the inhaler (0.7-4.2L). DD was consistent across the range of patient representative inhalation parameters for all components (FF, VI, and UMEC) of each therapy assessed; although ETD and FPD were also generally consistent, some small variation was observed. Dose delivery was consistent for each of the components, whether delivered as mono- or combination therapy. The in vitro performance of the ELLIPTA inhaler has been demonstrated for the delivery of FF/VI, UMEC/VI, FF monotherapy, and UMEC monotherapy. Across a range of inspiratory profiles, DD was consistent, while ETD and FPD showed little flow dependency.

  19. An evaluation of the toxicological aspects and potential doses from the inhalation of coal combustion products. (United States)

    Liberda, Eric N; Chen, Lung Chi


    This paper reviews toxicological literature pertaining to coal combustion products (CCPs) inhalation and presents case studies on the inhalation of CCPs from the Kingston Fossil Plant area and from the Colbert Fossil Plant CCP landfill site. While most research regarding coal plant emissions focuses on fly ash, this article takes a holistic approach to examining not only emitted particulate matter such as fly ash, but also the theoretical calculated doses of landfilled CCPs. Furthermore, these doses are compared to in vitro and in vivo studies in order to highlight differences between laboratory-based studies and to emphasize the difficulty in extrapolating effects from inhalation exposures. In both case studies, fugitive emissions from the Kingston ash spill or the Colbert CCP-handling operations did not exceed any national ambient air quality standards or reference concentrations for individual components. Adverse effects such as mild pulmonary inflammation noted in the reviewed literature were in response to doses much higher than would be likely to occur in humans exposed to landfilled CCPs. We conclude that the doses for fugitive emissions calculated herein do not appear to be high enough to elicit a measurable adverse response in humans.

  20. Is low dose inhaled corticosteroid therapy as effective for inflammation and remodeling in asthma? : A randomized, parallel group study

    NARCIS (Netherlands)

    Baraket, Melissa; Oliver, Brian G G; Burgess, Janette K; Lim, Sam; King, Gregory G; Black, Judith L


    BACKGROUND: While most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, it is uncertain whether low dose ICSs are as ef

  1. In vitro performance of three combinations of spacers and pressurized metered dose inhalers for treatment in children

    DEFF Research Database (Denmark)

    Berg, E; Madsen, J; Bisgaard, H


    The performance of pressurized metered dose inhalers (pMDIs) and spacers in correct dose recommendations is important, but limited information on dose delivery and fine-particle dose from different combinations of spacers and pMDIs is available. In this study, three combinations of spacers and pM...

  2. Pharmacokinetics and Safety of Single-Dose Inhaled Loxapine in Children and Adolescents. (United States)

    Selim, Sally; Riesenberg, Robert; Cassella, James; Kunta, Jeevan; Hellriegel, Edward; Smith, Mark A; Vinks, Alexander A; Rabinovich-Guilatt, Laura


    This multisite open-label study sought to characterize the pharmacokinetics and safety of a single dose of inhaled loxapine in children and adolescents. Loxapine powder for oral inhalation was administered via a single-use handheld drug device to children and adolescents (aged 10-17 years) with any condition warranting chronic antipsychotic use. Patients were dosed according to body weight and cohort (<50 kg [n = 15], 2.5 or 5 mg; ≥50 kg [n = 15], 5 or 10 mg); the first 6 patients (cohort 1) enrolled in each weight group received the lower dose. Patients were enrolled in the higher-dose group (cohort 2) after an interim pharmacokinetic and safety analysis of data from cohort 1. Blood samples were collected for 48 hours after dosing to determine the pharmacokinetic profile of loxapine and its metabolites. Safety was assessed using adverse event (AE), laboratory value, physical/neurologic examination, vital sign, electrocardiogram, suicidality, and extrapyramidal symptom assessment. Thirty patients were enrolled and evaluable for pharmacokinetics. Loxapine plasma concentrations peaked by 2 to 5 minutes in most patients; systemic exposure increased with dose in both weight subgroups. Loxapine terminal elimination half-life was ∼13 to 17 hours. The most common AEs were sedation and dysgeusia. Sedation was severe in 1 patient in the <50-kg group (2.5-mg dose) and 1 patient in the ≥50-kg group (5-mg dose). No AEs indicative of bronchospasm or other serious AEs were reported. Inhaled loxapine was rapidly absorbed and generally well tolerated in pediatric patients; no new safety signals were observed. © 2017, The American College of Clinical Pharmacology.

  3. Uncertainties in electron-absorbed fractions and lung doses from inhaled beta-emitters. (United States)

    Farfán, Eduardo B; Bolch, Wesley E; Huston, Thomas E; Rajon, Didier A; Huh, Chulhaeng; Bolch, W Emmett


    The computer code LUDUC (Lung Dose Uncertainty Code), developed at the University of Florida, was originally used to investigate the range of potential doses from the inhalation of either plutonium or uranium oxides. The code employs the ICRP Publication 66 Human Respiratory Tract model; however, rather than using simple point estimates for each of the model parameters associated with particle deposition, clearance, and lung-tissue dosimetry, probability density functions are ascribed to these parameters based upon detailed literature review. These distributions are subsequently sampled within LUDUC using Latin hypercube sampling techniques to generate multiple (e.g., approximately 1,000) sets of input vectors (i.e., trials), each yielding a unique estimate of lung dose. In the present study, the dosimetry component of the ICRP-66 model within LUDUC has been extended to explicitly consider variations in the beta particle absorbed fraction due to corresponding uncertainties and biological variabilities in both source and target tissue depths and thicknesses within the bronchi and bronchioles of the thoracic airways. Example dose distributions are given for the inhalation of absorption Type S compounds of 90Sr (Tmax = 546 keV) and 90Y (Tmax = 2,284 keV) as a function of particle size. Over the particle size range of 0.001 to 1 microm, estimates of total lung dose vary by a factor of 10 for 90Sr particles and by a factor of 4 to 10 for 90Y particles. As the particle size increases to 10 microm, dose uncertainties reach a factor of 100 for both radionuclides. In comparisons to identical exposures scenarios run by the LUDEP 2.0 code, Reference Man doses for inhaled beta-emitters were shown to provide slightly conservative estimates of lung dose compared to those in this study where uncertainties in lung airway histology are considered.

  4. Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases. (United States)

    Heard, Kennon; Bui, Alison; Mlynarchek, Sara L; Green, Jody L; Bond, G Randall; Clark, Richard F; Kozer, Eran; Koff, Raymond S; Dart, Richard C


    Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study was to identify and validate reports of liver injury or death in children younger than 6 years who were administered repeated therapeutic doses of acetaminophen. We reviewed US Poison Center data, peer-reviewed literature, US Food and Drug Administration Adverse Event Reports, and US Manufacturer Safety Reports describing adverse effects after acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death after acetaminophen administration to children younger than 6 years were included. The identified reports were double abstracted and then reviewed by an expert panel to determine if the hepatic injury was related to acetaminophen and whether the dose of acetaminophen was therapeutic (≤75 mg/kg) or supratherapeutic. Our search yielded 2531 reports of adverse events associated with acetaminophen use. From these cases, we identified 76 cases of hepatic injury and 26 deaths associated with repeated acetaminophen administration. There were 6 cases of hepatic abnormalities and no deaths associated with what our panel determined to be therapeutic doses. A large proportion of cases could not be fully evaluated due to incomplete case reporting. Although we identified numerous examples of liver injury and death after repeated doses of acetaminophen, all the deaths and all but 6 cases of hepatic abnormalities involved doses more than 75 mg/kg per day. This study suggests that the doses of less than 75 mg/kg per day of acetaminophen are safe for children younger than 6 years.

  5. An in vitro aerosolization efficiency comparison of generic and branded salbutamol metered dose inhalers


    Rahimkhani, Sara; Ghanbarzadeh, Saeed; Nokhodchi, Ali; Hamishehkar, Hamed


    Background: Due to the high rate of pulmonary diseases, respiratory drug delivery systems have been attracted excessive attention for the past decades. Because of limitations and growing drug bill, physicians are encouraged to prescribe generically whenever possible. The purpose of this study was to evaluate whether there was any significant difference in aerosolization performance between a reference brand Salbutamol (A) Metered Dose Inhalers (MDIs) and two generic products (B and C).\\ud \\ud...

  6. Use of Medical Metered Dose Inhalers for Functionality Testing of Bioaerosol Detection and Identification Systems (United States)


    BIOAEROSOL DETECTION AND IDENTIFICATION SYSTEMS ECBC-TR-964 Jana Kesavan Deborah R. Schepers Jerold R. Bottiger RESEARCH AND TECHNOLOGY...Testing Of Bioaerosol Detection And Identification Systems 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...Medical Metered Dose Inhalers for Functionality Testing of Bioaerosol Detection and Identification Systems 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c

  7. Humidity affects the morphology of particles emitted from beclomethasone dipropionate pressurized metered dose inhalers. (United States)

    Ivey, James W; Bhambri, Pallavi; Church, Tanya K; Lewis, David A; McDermott, Mark T; Elbayomy, Shereen; Finlay, Warren H; Vehring, Reinhard


    The effects of propellant type, cosolvent content, and air humidity on the morphology and solid phase of the particles produced from solution pressurized metered dose inhalers containing the corticosteroid beclomethasone dipropionate were investigated. The active ingredient was dissolved in the HFA propellants 134a and 227ea with varying levels of the cosolvent ethanol and filled into pressurized metered dose inhalers. Inhalers were actuated into an evaporation chamber under controlled temperature and humidity conditions and sampled using a single nozzle, single stage inertial impactor. Particle morphology was assessed qualitatively using field emission scanning electron microscopy and focused ion beam-helium ion microscopy. Drug solid phase was assessed using Raman microscopy. The relative humidity of the air during inhaler actuation was found to have a strong effect on the particle morphology, with solid spheroidal particles produced in dry air and highly porous particles produced at higher humidity levels. Air humidification was found to have no effect on the solid phase of the drug particles, which was predominantly amorphous for all tested formulations. A critical level of air relative humidity was required to generate porous particles for each tested formulation. This critical relative humidity was found to depend on the amount of ethanol used in the inhaler, but not on the type of propellant utilized. The results indicate that under the right circumstances water vapor saturation followed by nucleated water condensation or ice deposition occurs during particle formation from evaporating propellant-cosolvent-BDP droplets. This finding reveals the importance of condensed water or ice as a templating agent for porosity when particle formation occurs at saturated conditions, with possible implications on the pharmacokinetics of solution pMDIs and potential applications in particle engineering for drug delivery.

  8. Influence of particle size distribution on inhalation doses to workers in the Florida phosphate industry. (United States)

    Kim, Kwang Pyo; Wu, Chang-Yu; Birky, Brian K; Bolch, Wesley E


    Previous studies have indicated that inhalation exposures to TENORM aerosols are potentially a major contributor to the annual total effective dose to workers in the Florida phosphate industry. Further research was deemed necessary to characterize the particle size distribution of these aerosols containing various radionuclides of the U decay series. In the present study, individualized assessments of worker committed effective doses are reported in which detailed information is used on the particle size distribution, particle density, particle shape, and radioactivity concentrations from sampled aerosols at 6 different phosphate facilities and at various worker areas within these facilities. Inhalation dose assessments are calculated using the ICRP 66 human respiratory tract model as implemented within the LUDEP and IMBA computer codes. Under the least conservative assumptions of radionuclide-specific lung solubility, the annual total effective doses are shown to be 0.31+/-0.12, 0.27+/-0.07, and 0.22+/-0.02 mSv at granulator, storage, and shipping areas, respectively, and thus all annual doses are below the annual limits to the members of the general public (1 mSv y). In contrast, the most conservative assumptions of lung solubility by radionuclide yield annual total effective doses of 2.24+/-2.53 mSv at granulator areas, 1.26+/-1.19 mSv at storage areas, and 0.56+/-0.36 mSv at shipping areas. In this later case, some 44%, 31%, and 15% of individual dose assessments yield worker doses above the annual dose limit. The study thus demonstrates the importance of facility- and area-specific particle solubility data in dose assessments for regulatory compliance and for making decisions regarding worker respiratory protection.

  9. Repeated dose of ketamine effect to the rat hippocampus tissue

    Directory of Open Access Journals (Sweden)

    Mehtap Okyay Karaca


    Full Text Available Aim: We aimed to determine the neurotoxic effect of repeated ketamine administration on brain tissue and if neurotoxic effect was present, whether this effect continued 16 days later using histological stereological method, a quantitative and objective method. Materials and Methods: Female rats were divided into three groups, each containing five rats. Rats in Group I were given 0.9% saline solution 4 times a day for 5 days. The rats in Groups II and III were given ketamine as intraperitoneal injections. Rats in Groups I and II were sacrificed on 5 th day while the ones in Group III on 21 st day. Cornu ammonis (CA and gyrus dentatus (GD regions in hippocampus tissue of rats were studied using optic fractionation method. Findings: There were significantly less number of cells in hippocampal CA and GD regions of rats from Groups II and III compared to the ones from Group I. Difference in cell number was also significantly higher in Group III than in Group II, but this difference was not as pronounced as the one between Groups III and I. Conclusion: Repeated ketamine doses caused neurotoxicity in rat hippocampus.

  10. 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

    Directory of Open Access Journals (Sweden)

    Komase Y


    Full Text Available Yuko Komase,1 Akimoto Asako,2 Akihiro Kobayashi,3 Raj Sharma4 1Department of Respiratory Internal Medicine, St Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama, Kanagawa, Japan; 2MA Respiratory Department, Development and Medical Affairs Unit, GlaxoSmithKline KK, Tokyo, Japan; 3Biomedical Data Sciences Department, GlaxoSmithKline KK, Tokyo, Japan; 4Global Respiratory Franchise Medical Department, GSK, Stockley Park, UK 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

  11. Dose-dependent anti-inflammatory effect of inhaled mometasone furoate/formoterol in subjects with asthma

    DEFF Research Database (Denmark)

    Nolte, Hendrik; Pavord, Ian; Backer, Vibeke;


    A well-controlled study in patients with allergic asthma was warranted to assess dose-dependency between fractional concentration of exhaled nitric oxide (FeNO) and sputum eosinophils to a combination of an inhaled corticosteroid plus a long-acting β2-agonist. We sought to characterize the dose-d...

  12. The ELLIPTA® Dry Powder Inhaler: Design, Functionality, In Vitro Dosing Performance and Critical Task Compliance by Patients and Caregivers. (United States)

    Grant, Andrew C; Walker, Richard; Hamilton, Melanie; Garrill, Karl


    Dry powder inhalers (DPIs) are commonly used for the delivery of inhaled medications, and should provide consistent, efficient dosing, be easy to use correctly, and be liked by patients; these attributes can all affect patient compliance and therefore treatment efficacy. The ELLIPTA(®) DPI was developed for the delivery of once-daily therapies for the treatment of asthma and chronic obstructive pulmonary disease. It has moderate resistance to airflow and can hold one or two blister strips, with each blister containing a sealed single dose of medication. Monotherapies can be delivered by the single-strip configuration and, in the two-strip configuration, one dose from each strip can be aerosolized simultaneously to allow combination therapies to be delivered, which enables the formulations for each product to be developed individually, since they are stored separately until the point of administration. There are three principal operating steps to administer a dose: open, inhale, close. This article summarizes the design, functionality, and in vitro dose-delivery characteristics of the ELLIPTA inhaler, and describes the results of human factors validation tests, designed to assess the performance of critical tasks required to use the inhaler. Results from the in vitro studies indicate that the ELLIPTA inhaler performs consistently with respect to in vitro dose delivery characteristics at a range of flow rates that can be achieved by the target population (≥30 L/min) and over its 30-day in-use life. Data from the human factors validation tests demonstrated that almost all participants (≥97%) were able to complete each of the steps required to prepare a dose for inhalation without error. Overall, the ELLIPTA inhaler has a versatile single- or two-strip design that allows it to be used for the delivery of a range of treatment options. It also improves patient ease-of-use when compared with the DISKUS(®) DPI.

  13. Comparison of the effect of high-dose inhaled budesonide and fluticasone on adrenal function in patients with severe chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Ahmed Fahim


    Conclusion: Inhaled budesonide and fluticasone have no significantly different effect on adrenal function in moderate to severe COPD. The adverse event profile of high-dose inhaled steroids should not influence the choice of medication.

  14. Spray pattern analysis for metered dose inhalers I: Orifice size, particle size, and droplet motion correlations. (United States)

    Smyth, H; Hickey, A J; Brace, G; Barbour, T; Gallion, J; Grove, J


    Factors that influence spray pattern measurements of pressurized, metered-dose inhalers have been evaluated. Spray patterns were correlated with changes in actuator orifice diameter, particle size profiles, and calculated estimates of particle-size dynamics of plumes during a spray. Spray patterns, regardless of actuator orifice size, were ellipsoid in the vertical direction. Measures of elliptical ratio, major axis, and minor axis were significantly influenced by orifice size in a non-linear fashion over the range of orifice sizes investigated. Spray patterns also correlated with particle size profile and spray geometry measurements. Spray distribution asymmetry may be related to droplet evaporation and sedimentation processes. However, the spray patterns did not appear sensitive to changes in gravitational force acting on the plume. Instead, it is postulated that elliptical spray patterns may have dependence on fluid dynamic processes within the inhaler actuator. Developing an understanding of these processes may provide a basis for developing spray pattern tests with relevance to product performance.

  15. Behavioral components of tolerance to repeated inhalation of trichloroethylene (TCE) in rats. (United States)

    Bushnell, P J; Oshiro, W M


    The possibility that the acute neurotoxic effects of organic solvents change with repeated exposure will affect risk assessment of these pollutants. We observed previously that rats inhaling trichloroethylene (TCE) showed a progressive attenuation of impairment of signal detection behavior across several weeks of intermittent exposure, suggesting the development of tolerance. Here, we explored the development of tolerance to TCE during two weeks of daily exposures, and the degree to which learned behavioral modifications ("behavioral tolerance") could account for the effect. Adult Long-Evans rats were trained to perform a visual signal detection task (SDT) in which a press on one lever yielded food if a visual stimulus (a "signal") had occurred on that trial, and a press on a second lever produced food if no signal had been presented. In two experiments, with 2000 and 2400 ppm of TCE respectively, trained rats were divided into two groups (n = 8/group) with equivalent accuracy and then exposed to TCE in two-phase studies. In Phase 1, one group of rats received daily SDT tests paired with 70-min TCE exposures, followed by 70-min exposures to clean air after testing. The other group received daily SDT tests in clean air, followed by 70-min exposures to TCE (unpaired exposure and testing). All rats thus received the same number and daily sequence of exposures to TCE that differed only in the pairing with SDT testing. Both concentrations of TCE disrupted performance of the paired groups and this disruption abated over the 9 days of exposure. In Phase 2, the pairing of exposure and test conditions were reversed for the two groups. The groups that were shifted from unpaired to paired exposures (Unpaired-Paired groups) showed qualitatively similar patterns of deficit and recovery as did the rats whose tests were initially paired with TCE (Paired-Unpaired groups), indicating that task-specific learning was involved in the development of tolerance. Quantitative differences

  16. Dependence of dose coefficients for inhaled 239Pu on absorption parameters. (United States)

    Suzuki, K; Sekimoto, H; Ishigure, N


    With regard to dissolution of particles in the respiratory tract after inhalation, the International Commission on Radiological Protection (ICRP) has classified all radionuclides into only three types according to the chemical form of compounds, and default values of absorption parameters are proposed for each type. However, it is just a simplification to estimate doses for practical use, and there is a possibility of unfitness in such an assortment. A code has been developed to reproduce the ICRP's dose coefficients for 239Pu, which is one of the most important elements for occupational exposure. By using this code, the respective absorption parameters were modified, and the effect owing to these changes evaluated. It was shown consequently that changes of absorption parameters do not greatly influence the effective doses of 239Pu for workers.

  17. Improved method to label beta-2 agonists in metered-dose inhalers with technetium-99m

    Energy Technology Data Exchange (ETDEWEB)

    Ballinger, J.R.; Calcutt, L.E.; Hodder, R.V.; Proulx, A.; Gulenchyn, K.Y. (Ottawa Civic Hospital, Ottawa (Canada). Div. of Nuclear Medicine and Respiratory Unit)


    Labelling beta-2 agonists in a metered-dose inhaler (MDI) with technetium-99m allows imaging of the deposition of the aerosol in the respiratory tract. We have developed an improved labeling method in which anhydrous pertechnetate is dissolved in a small volume of ethanol, diluted with a fluorocarbon, and introduced into a commercial MDI. Imaging the MDI demonstrated that the [sup 99m]Tc was associated with the active ingredient, not just the propellant. The method has been used successfully with salbutamol and fenoterol MDIs and should be directly applicable to other MDIs which contain hydrophilic drugs. (Author).

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

    Energy Technology Data Exchange (ETDEWEB)

    Viner, Brian J. [Savannah River National Laboratory, Savannah River Site, Aiken, SC


    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 1.0 x 107Bq 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. The potential for exceeding dose guidelines was mitigated by including plume rise (>2ms-1) or moving a small distance from the fire owing to large concentration gradients near the edge of the fire. This approach can quickly estimate potential dose from airborne radionuclides in wildland fire and assist decision-making to reduce firefighter exposure.

  19. A simple pharmacokinetic method to evaluate the pulmonary dose in clinical practice--analyses of inhaled sodium cromoglycate. (United States)

    Lindström, Maria; Svensson, Jan Olof; Meurling, Lennart; Svartengren, Katharina; Anderson, Martin; Svartengren, Magnus


    When the expected effect of an inhaled drug is not achieved, the cause could be poor inhalation technique and consequently a low pulmonary dose. A simple in vivo test to evaluate the pulmonary dose would be a benefit. This study evaluates the relative and systemic bioavailability following inhalation of nebulized sodium cromoglycate (SCG) in healthy subjects. Blood samples were collected during 240 min and urine was collected in two portions, up to 6 h post-inhalation. Two exposures were performed and comparisons based on the quantification of drug in plasma and urine by a high-performance liquid chromatography (HPLC) procedure were done. In one of the exposures, a pulmonary function test was performed to study if an expected effect of increased absorption could be detected. There was a good correlation between the two exposures shown in the plasma concentrations, but not in the urine analyses. The forced exhaled volume manoeuvres were associated with a higher Cmax and plasma concentrations up to 60 min post-inhalation (P<0.01). This effect was not detected in the urine analyses. We conclude that this pharmacokinetic method with inhaled SCG and plasma analyses could be used to evaluate individual inhalation technique. The HPLC method used was rapid and had adequate sensitivity.

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

    NARCIS (Netherlands)

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

    Objectives To use computational fluid dynamics (CFD) for evaluating and understanding the performance of the high-dose disposable Twincer (TM) dry powder inhaler, as well as to learn the effect of design modifications on dose entrainment, powder dispersion and retention behaviour. Methods Comparison

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

    Energy Technology Data Exchange (ETDEWEB)

    Dunning, D.E.


    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 are given. The gastorintestinal (GI) tract has been represented 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.



  3. An In Vitro Aerosolization Efficiency Comparison of Generic and Branded Salbutamol Metered Dose Inhalers

    Directory of Open Access Journals (Sweden)

    Sara Rahimkhani, Saeed Ghanbarzadeh, Ali Nokhodchi, Hamed Hamishehkar


    Full Text Available Background: Due to the high rate of pulmonary diseases, respiratory drug delivery systems have been attracted excessive attention for the past decades. Because of limitations and growing drug bill, physicians are encouraged to prescribe generically whenever possible. The purpose of this study was to evaluate whether there was any significant difference in aerosolization performance between a reference brand Salbutamol (A Metered Dose Inhalers (MDIs and two generic products (B and C. Methods: The aerosolization performance of MDIs was evaluated by calculating aerosolization indexes including fine particle fraction (FPF, fine particle dose (FPD, geometric standard deviation (GSD and mass median aerodynamic diameters (MMAD by using the next generation impactor. Results: Although aerosolization indexes of MDI A were superior than the Iranian brands, but the differences were not statistically significant. Conclusion: These results verified that generic MDIs deliver similar quantities of Salbutamol to the reference brand and aerosolization performance parameters of generic Salbutamol MDIs did not differ significantly from the reference brand.

  4. Dose assessment for inhalation intakes in complex, energetic environments: experience from the US Capstone study. (United States)

    Guilmette, Raymond A; Parkhurst, Mary Ann


    Because of the lack of existing information needed to evaluate the risks from inhalation exposures to depleted uranium (DU) aerosols of US soldiers during the 1991 Persian Gulf War, the US Department of Defense funded an experimental study to measure the characteristics of DU aerosols created when Abrams tanks and Bradley fighting vehicles are struck with large-caliber DU penetrators, and a dose and risk assessment for individuals present in such vehicles. This paper describes some of the difficulties experienced in dose assessment modelling of the very complex DU aerosols created in the Capstone studies, e.g. high concentrations, heterogeneous aerosol properties, non-lognormal particle size distributions, triphasic in vitro dissolution and rapid time-varying functions of both DU air concentration and particle size. The approaches used to solve these problems along with example results are presented.

  5. Effective dose scaling factors for use with cascade impactor sampling data in tenorm inhalation exposures. (United States)

    Kim, Kwang Pyo; Wu, Chang-Yu; Birky, Brian K; Bolch, Wesley E


    When assessing the effective dose to workers following radio-aerosol inhalation exposures, significant reductions in dose uncertainty can be achieved through direct measurement of the particle-size distribution. The University of Washington Mark III cascade impactor is one such air sampling device that permits the user to determine aerosol mass and radioactivity concentrations as a function of particle size within eight different size intervals (each corresponding to a different impactor stage or end filter). Traditionally, dose assessments made using the LUDEP code or other internal dosimetry software utilize this air sampling information by assigning the radioactivity measured at each stage as concentrated at a single representative size central to the size interval. In this study, we explore more realistic assumptions that the measured radioactivity distributes uniformly, linearly increases, or linearly decreases across the particle size interval for each impactor stage. The concept of an effective dose scaling factor, SF(E), is thus introduced whereby (1) the former approach can be used (which requires less computational effort using the LUDEP code), and (2) the resulting values of effective dose per stage can then be rescaled to values appropriate to a linear radioactivity distribution per stage. For a majority of (238)U-series radionuclides, particle size ranges, and absorption classes, differences in these two approaches are less than 10%, and thus no corrections in effective dose per particle stage are needed. Significant corrections, however, were noted in select cases. For uniform or linearly decreasing radioactivity distributions, end-filter particles (0.03 to 0.35 microm) of type F, M, or S radionuclides were assigned values of SF(E) ranging from 1.15 to 1.44, while 3(rd) stage particles (4.5 to 12 microm) of type M and S radionuclides were assigned values of SF(E) ranging from 1.11 to 1.53. When the cascade impactor measurements indicate a linear

  6. The effects of exercise on dose and dose distribution of inhaled automotive pollutants

    Energy Technology Data Exchange (ETDEWEB)

    Kleinman, M.T.; Mautz, W.J. (Air Pollution Health Effects Laboratory, University of California, Irvine (United States))


    The purpose of this study was to determine how changes in ventilation rate and in the entry route of air pollutants into the respiratory tract (nose versus mouth breathing) affected the respiratory tract uptake and penetration of inhaled gaseous and particulate pollutants associated with automobile emissions. Experiments were performed with female beagle dogs exposed while standing at rest or while exercising on a treadmill at 5 km/hour and a 7.5 percent grade. Dogs were exposed to nitrogen dioxide at concentrations of 1 and 5 parts per million (ppm), to formaldehyde at 2 and 10 ppm, and to an aerosol of ammonium nitrate particles (0.3 micron mass median aerodynamic diameter) at 1 mg/m3. Total respiratory system uptake and effects on breath time, expired tidal volume, fractional expiration time, minute ventilation, respiratory gas exchange, ventilation equivalents for oxygen and carbon dioxide, and dynamic pulmonary resistance and compliance were measured in exercising and resting dogs exposed for two hours to 5 ppm nitrogen dioxide and 10 ppm formaldehyde in combination with 1 mg/m3 of ammonium nitrate particles. Regional penetration of pollutants through oral and nasal airways and pollutant uptake in the lung were measured in a separate group of six tracheostomized dogs standing at rest while being exposed to nitrogen dioxide, formaldehyde, and ammonium nitrate particles. Hypercapnic stimulation was used to modify ventilation rates in the tracheostomized dogs while pollutant penetration and uptake were measured. Dogs exposed to 5 ppm of nitrogen dioxide at rest tended to breathe more rapidly (p less than 0.05) and more shallowly (a nonsignificant trend) than dogs exposed to purified air.

  7. Raman spectroscopy for the process analysis of the manufacturing of a suspension metered dose inhaler. (United States)

    Butz, James; de la Cruz, Luis; DiTonno, Jason; DeBoyace, Kevin; Ewing, Gary; Donovan, Brent; Medendorp, Joseph


    The purpose of this research was to demonstrate the utility of Raman spectroscopy for process analysis of a suspension metered dose inhaler manufacturing process. Chemometric models were constructed for the quantification of ethanol and active pharmaceutical ingredient such that both could be monitored in real-time during the compounding and filling operations via tank measurements and recirculation line flow-cell measurements. Different spectral preprocessing techniques were used to delineate the effects of mixing speed and temperature changes from actual concentration effects. Raman spectroscopy offers advantages in time savings and quality of information over the standard methods of analysis for respiratory formulations, such as a drug content assay via HPLC and ethanol testing via GC. The successful implementation of this work will allow formulation scientists to quantitatively assess both the formulation (e.g., the concentration of active pharmaceutical ingredient (API) and ethanol), as well as the manufacturing process (e.g., determination of mixing endpoints) in real-time.

  8. Economics of "essential use exemptions" for metered-dose inhalers under the Montreal Protocol. (United States)

    DeCanio, Stephen J; Norman, Catherine S


    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.

  9. Use of a statistical model to predict the potential for repeated dose and developmental toxicity of dermally administered crude oil and relation to reproductive toxicity. (United States)

    McKee, Richard H; Nicolich, Mark; Roy, Timothy; White, Russell; Daughtrey, Wayne C


    Petroleum (commonly called crude oil) is a complex substance primarily composed of hydrocarbon constituents. Based on the results of previous toxicological studies as well as occupational experience, the principal acute toxicological hazards are those associated with exposure by inhalation to volatile hydrocarbon constituents and hydrogen sulfide, and chronic hazards are associated with inhalation exposure to benzene and dermal exposure to polycyclic aromatic compounds. The current assessment was an attempt to characterize the potential for repeated dose and/or developmental effects of crude oils following dermal exposures and to generalize the conclusions across a broad range of crude oils from different sources. Statistical models were used to predict the potential for repeated dose and developmental toxicity from compositional information. The model predictions indicated that the empirical data from previously tested crude oils approximated a "worst case" situation, and that the data from previously tested crude oils could be used as a reasonable basis for characterizing the repeated dose and developmental toxicological hazards of crude oils in general.

  10. Repeated-dose liver micronucleus test of 4,4'-methylenedianiline using young adult rats. (United States)

    Sanada, Hisakazu; Koyama, Naomi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi


    Liver micronucleus (MN) tests using partial hepatectomized rats or juvenile rats have been shown to be useful for the detection of hepatic carcinogens. Moreover, Narumi et al. established the repeated-dose liver MN test using young adult rats for integration into general toxicity. In the present study, in order to examine the usefulness of the repeated-dose liver MN test, we investigated MN induction with a 14 or 28 day treatment protocol using young adult rats treated with 4,4′-methylenedianiline (MDA), a known hepatic carcinogen. MDA dose-dependently induced micronuclei in hepatocytes in 14- and 28-day repeated-dose tests. However, although statistically significant increases in micronuclei were observed in bone marrow cells at two dose levels in the 14-day study, there was no dose response and no increases in micronuclei in the 28-day study. These results indicate that the evaluation of genotoxic effects using hepatocytes is effective in cases where chromosomal aberrations are not clearly detectable in bone marrow cells. Moreover, the repeated-dose liver MN test allows evaluation at a dose below the maximum tolerable dose, which is required for the conventional MN test because micronucleated hepatocytes accumulate. The repeated-dose liver MN test employed in the present study can be integrated into the spectrum of general toxicity tests without further procedural modifications.

  11. The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS)

    NARCIS (Netherlands)

    Tluczkiewicz, I.; Batke, M.; Kroese, D.; Buist, H.; Aldenberg, T.; Pauné, E.; Grimm, H.; Kühne, R.; Schüürmann, G.; Mangelsdorf, I.; Escher, S.E.


    In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evalua

  12. Inhalation dose due to radon, thoron, and progenies in dwellings of a hill station. (United States)

    Sivakumar, R


    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.

  13. Mid-Childhood Bone Mass After Exposure to Repeat Doses of Antenatal Glucocorticoids: A Randomized Trial. (United States)

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E


    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity, but could have adverse effects on skeletal development. We assessed whether exposure to repeat antenatal betamethasone alters bone mass in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to a single dose of betamethasone or placebo, ≥7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at children underwent whole-body dual-energy radiograph absorptiometry at 6 to 8 years' corrected age. Of 212 eligible childhood survivors, 185 were studied (87%; 91 repeat betamethasone group; 94 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar whole-body bone mineral content (median repeat betamethasone: 553 g, interquartile range: 442-712 g; placebo: 567 g, interquartile range: 447-750 g; geometric mean ratio: 0.99; 95% confidence interval: 0.94-1.03, P = .55) and bone area (median repeat betamethasone 832 cm(2), interquartile range: 693-963 cm(2); placebo: 822 cm(2), interquartile range: 710-1020 cm(2); geometric mean ratio: 0.99, 95% confidence interval: 0.92-1.07, P = .75). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not alter bone mass in mid-childhood. Copyright © 2017 by the American Academy of Pediatrics.

  14. Influence of dose distribution on risk of lung cancer occurrence after actinide oxide inhalation; Influence de la distribution de dose sur le risque d'apparition de cancers pulmonaires apres inhalation d'oxydes d'actinides

    Energy Technology Data Exchange (ETDEWEB)

    Fritsch, P.; Dudoignon, N.; Guillet, K.; Rateau, G.; Delforge, J. [Lab. de Radiotoxicologie, CEA/DSV/DRR/SRCA, Bruyeres le Chatel (France)


    The aim of this work was to estimate risk of lung tumour occurrence after inhalation of actinide oxides from published studies and rat studies in progress. For the same delivered dose, the risk increases when homogeneity of irradiation increases, i.e., the number of particles deposited after inhalation increases (small particles and (or) low specific alpha activity). The dose-effect relationships reported appear linear up to a few gray, depending on the aerosol considered, and then the slope decreases. This slope, which corresponds with the risk, can vary over one order of magnitude de ending on the aerosol used. An effective threshold at about 1 Gy was not observed for the most homogeneous dose distributions. A dosimetric and biological approach is proposed to provide a more realistic risk estimate. (author)

  15. Dose estimate of inhaled hafnium tritide using the ICRP 66 lung model. (United States)

    Cheng, Yung-Sung; Zhou, Yue; Wang, Yang-Sheng; Inkret, William C; Wermer, Joseph R


    Metal tritide is widely used for research, purification, compression, and storage of tritium. The current understanding of metal tritide and its radiation dosimetry for internal exposure is limited, and ICRP publications do not provide the tritium dosimetry for hafnium tritide. The current radiation protection guidelines for metal tritide particles (including hafnium tritide) are based on the assumption that their biological behavior is similar to tritiated water, which is completely absorbed by the body. However, the solubility of metal tritide particles depends on the chemical form of the material. The biological half-live of hafnium tritide particles and the dosimetry of an inhalation exposure to those particles could be quite different from tritiated water. This paper describes experiments on the dissolution rate of hafnium tritide particles in a simulated lung fluid. The results showed that less than 1% of the tritium was dissolved in the simulated lung fluid for hafnium tritide particles after 215 d. The short-term and long-term dissolution half times were 46 and 4.28 x 10(5) d, respectively. This indicates that hafnium tritide is an extremely insoluble material. Self-absorption of beta rays in the hafnium tritide particles was estimated by a numerical method. The dose coefficients were calculated as a function of particle size using in vitro solubility data and a calculated self-absorption factor. The dose coefficient decreased with aerodynamic diameters in the range of 0.25 to 10 microm, mainly because the self-absorption factor decreased with increasing particle size. For a particle 1 microm in aerodynamic diameter, the dose coefficient of a hafnium tritide particle was about 10 times higher than that of tritiated water but was about 1.4 times lower than that calculated by ICRP Publication 71 for Type S tritiated particles. The ICRP estimate did not include a self-absorption factor and thus might have overestimated the dose. This finding has significant

  16. Sildenafil citrate monohydrate-cyclodextrin nanosuspension complexes for use in metered-dose inhalers. (United States)

    Sawatdee, Somchai; Phetmung, Hirihattaya; Srichana, Teerapol


    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.

  17. Bronchodilator aerosol administered by metered dose inhaler and spacer in subacute neonatal respiratory distress syndrome. (United States)

    Lee, H; Arnon, S; Silverman, M


    There is increasing evidence that bronchodilators are effective in ventilator dependent preterm infants. The effects of single doses of salbutamol (400 micrograms), ipratropium bromide (72 micrograms), and placebo (four puffs) given by metered dose inhaler and spacer (MDIS) were examined in 10 ventilated preterm infants, with a mean birth weight of 800 g at a postnatal age of 1 week, who were suffering from respiratory distress syndrome. The agents were each given in an open, random design. Blood gases were measured and ventilatory efficiency index (VEI) and arterial/alveolar oxygen tension ratio (PaO2/PAO2) were calculated five minutes before and 30 minutes after administration. Heart rate and mean arterial blood pressure were noted. The mean PaO2 improved by 0.61 kPa and 0.69 kPa after salbutamol and ipratropium bromide, respectively and these changes were significantly greater than the 0.5 kPa fall seen with placebo. The mean arterial carbon dioxide tension fell by 0.98 kPa after salbutamol and 0.59 kPa after ipratropium bromide. After both salbutamol and ipratropium bromide, VEI improved significantly (by 23% and 20% respectively) but there was no significant change in the PaO2/PAO2, suggesting that respiratory mechanics and not ventilation/perfusion balance had improved after a single dose of bronchodilator. We conclude that both salbutamol and ipratropium bromide given by MDIS have useful short term effects in ventilator dependent neonates with respiratory distress syndrome. Precise dose regimens and long term effects remain to be worked out.

  18. Delivery characteristics and patients’ handling of two single-dose dry-powder inhalers used in COPD

    Directory of Open Access Journals (Sweden)

    Chapman KR


    Full Text Available Kenneth R Chapman1, Charles M Fogarty2, Clare Peckitt3, Cheryl Lassen3, Dalal Jadayel3, Juergen Dederichs4, Mukul Dalvi4, Benjamin Kramer5On behalf of the INDEED (indacaterol: handling and preference evaluation of the Breezhaler device in COPD study investigators1University of Toronto, Toronto, Canada; 2Spartanburg Medical Research, Spartanburg, SC, United States; 3Novartis Horsham Research Centre, Horsham, West Sussex, UK; 4Novartis Pharma AG, Basel, Switzerland; 5Novartis Pharmaceuticals, East Hanover, NJ, USAAbstract: For optimal efficacy, an inhaler should deliver doses consistently and be easy for patients to use with minimal instruction. The delivery characteristics, patients’ correct use, and preference of two single-dose dry powder inhalers (Breezhaler and HandiHaler were evaluated in two complementary studies. The first study examined aerodynamic particle size distribution, using inhalation profiles of seven patients with moderate to very severe chronic obstructive pulmonary disease (COPD. The second was an open-label, two-period, 7-day crossover study, evaluating use of the inhalers with placebo capsules by 82 patients with mild to severe COPD. Patients’ correct use of the inhalers was assessed after reading written instructions on Day 1, and after training and 7 days of daily use. Patients’ preference was assessed after completion of both study periods. Patient inhalation profiles showed average peak inspiratory flows of 72 L/minute through Breezhaler and 36 L/minute through HandiHaler. For Breezhaler and HandiHaler, fine particle fractions were 27% and 10%, respectively. In the second study, correct use of Breezhaler and HandiHaler was achieved by >77% of patients for any step after 7 days; 61% of patients showed an overall preference for Breezhaler and 31% for HandiHaler (P = 0.01. Breezhaler is a low-resistance inhaler suitable for use by patients with a range of disease severities. Most patients used both inhalers correctly

  19. Know How to Use Your Asthma Inhaler

    Medline Plus

    Full Text Available ... 260 KB] Using a metered dose inhaler (inhaler in mouth) Your browser does not support iframes Using a metered dose inhaler (inhaler in mouth) [PDF - 370 KB] Your browser does not ...

  20. Quantitative Models of the Dose-Response and Time Course of Inhalational Anthrax in Humans (United States)

    Schell, Wiley A.; Bulmahn, Kenneth; Walton, Thomas E.; Woods, Christopher W.; Coghill, Catherine; Gallegos, Frank; Samore, Matthew H.; Adler, Frederick R.


    Anthrax poses a community health risk due to accidental or intentional aerosol release. Reliable quantitative dose-response analyses are required to estimate the magnitude and timeline of potential consequences and the effect of public health intervention strategies under specific scenarios. Analyses of available data from exposures and infections of humans and non-human primates are often contradictory. We review existing quantitative inhalational anthrax dose-response models in light of criteria we propose for a model to be useful and defensible. To satisfy these criteria, we extend an existing mechanistic competing-risks model to create a novel Exposure–Infection–Symptomatic illness–Death (EISD) model and use experimental non-human primate data and human epidemiological data to optimize parameter values. The best fit to these data leads to estimates of a dose leading to infection in 50% of susceptible humans (ID50) of 11,000 spores (95% confidence interval 7,200–17,000), ID10 of 1,700 (1,100–2,600), and ID1 of 160 (100–250). These estimates suggest that use of a threshold to human infection of 600 spores (as suggested in the literature) underestimates the infectivity of low doses, while an existing estimate of a 1% infection rate for a single spore overestimates low dose infectivity. We estimate the median time from exposure to onset of symptoms (incubation period) among untreated cases to be 9.9 days (7.7–13.1) for exposure to ID50, 11.8 days (9.5–15.0) for ID10, and 12.1 days (9.9–15.3) for ID1. Our model is the first to provide incubation period estimates that are independently consistent with data from the largest known human outbreak. This model refines previous estimates of the distribution of early onset cases after a release and provides support for the recommended 60-day course of prophylactic antibiotic treatment for individuals exposed to low doses. PMID:24058320

  1. Dose coefficients for inhalation of radionuclides generated through the nuclear spallation reaction by high-energy protons

    Energy Technology Data Exchange (ETDEWEB)

    Endo, Akira; Takada, Hiroshi; Yamaguchi, Yasuhiro [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment


    Dose coefficients have been calculated for inhalation of radionuclides generated in spallation neutron targets and not listed in ICRP Publication 68. Eleven radionuclides, generated in large quantities in the targets and having half-lives more than 10 minutes, were selected for the present calculation. The calculation of the dose coefficients was performed with LUDEP, a program implementing the ICRP Publication 66 respiratory tract model, and NUDAT, a decay radiation database processed from ENSDF. Comparisons were made between the dose coefficients calculated by LUDEP and those listed in ICRP Publication 68 in order to validate the calculated dose coefficients. For 228 cases that vary inhaled particle diameters and biokinetic models of 66 radionuclides, the dose coefficients calculated by LUDEP agreed with those of ICRP Publication 68 within {+-} 25% for 213 cases. Discrepancies that exceed the ICRP`s coefficients by {+-} 25% were mainly attributable to the difference of radiation data employed. It was confirmed from the comparisons that the dose coefficients calculated by the present method are reliable ones. Annual limits on intake and derived air concentrations were calculated on the basis of the dose coefficients. It can be concluded that the dose coefficients and limits calculated here are useful from viewpoints of the design of ventilation system and the evaluation of internal exposures in high energy proton accelerator facilities. (author)

  2. Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression

    NARCIS (Netherlands)

    aan het Rot, Marije; Collins, Katherine A.; Murrough, James W.; Perez, Andrew M.; Reich, David L.; Charney, Dennis S.; Mathew, Sanjay J.


    Background: A single subanesthetic (intravenous) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression (TRD). Here we tested the tolerability, safety, and efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days)

  3. Terbutaline: level the playing field for inhaled β2-agonists by introducing a dosing and urine threshold. (United States)

    Jacobson, Glenn A; Hostrup, Morten


    Terbutaline, a short-acting β2-agonist similar to salbutamol, is widely used in Europe in the treatment of asthma and exercise-induced bronchoconstriction. Unlike salbutamol, terbutaline requires therapeutic use exemption (TUE) for therapeutic inhaled use in competitive sport. There is now compelling evidence that supratherapeutic use of terbutaline is performance enhancing, via oral dosing and inhalation. It is likely that the ergogenic effects of terbutaline are class specific for all β2-agonists. The World Anti-Doping Agency (WADA) has introduced dosing and urine threshold and decision limits for other common β2-agonists. This allows athletes to use these drugs for therapeutic purposes while minimising the potential for doping and administrative burden of TUEs. However, no such threshold limits currently exist for terbutaline. For terbutaline, athletes can be granted a TUE, then administer the drug via inhalation at supratherapeutic doses with impunity. The introduction of threshold dosing and urine limits for terbutaline should be a high priority, given the drug's demonstrated ergogenic effects. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

  4. A GPU implementation of a track-repeating algorithm for proton radiotherapy dose calculations

    CERN Document Server

    Yepes, Pablo P; Taddei, Phillip J


    An essential component in proton radiotherapy is the algorithm to calculate the radiation dose to be delivered to the patient. The most common dose algorithms are fast but they are approximate analytical approaches. However their level of accuracy is not always satisfactory, especially for heterogeneous anatomic areas, like the thorax. Monte Carlo techniques provide superior accuracy, however, they often require large computation resources, which render them impractical for routine clinical use. Track-repeating algorithms, for example the Fast Dose Calculator, have shown promise for achieving the accuracy of Monte Carlo simulations for proton radiotherapy dose calculations in a fraction of the computation time. We report on the implementation of the Fast Dose Calculator for proton radiotherapy on a card equipped with graphics processor units (GPU) rather than a central processing unit architecture. This implementation reproduces the full Monte Carlo and CPU-based track-repeating dose calculations within 2%, w...

  5. Determination of physical and chemical stability in pressurised metered dose inhalers: potential new techniques. (United States)

    Ooi, Jesslynn; Traini, Daniela; Boyd, Ben J; Gaisford, Simon; Young, Paul M


    Pressurised metered dose inhalers (pMDIs) are subject to rigorous physical and chemical stability tests during formulation. Due to the time and cost associated with product development studies, there is a need for online techniques to fast screen new formulations in terms of physical and chemical (physico-chemical) stability. The problem with achieving this is that pMDIs are by their definition, pressurised, making the direct observation of physico-chemical properties in situ difficult. This review highlights the characterisation tools that can enhance the product development process for pMDIs. Techniques investigated include: laser diffraction, Raman spectroscopy, isothermal ampoule calorimetry, titration calorimetry and gas perfusion calorimetry. The operational principles behind each technique are discussed and complemented with examples from the literature. Laser diffraction is well placed to analyse real-time physical stability as a function of particle size; however, its use is restricted to suspension pMDIs. Raman spectroscopy can be potentially used to attain both suspension and solution pMDI spectra in real time; however, the majority of experiments are ex-valve chemical composition mapping. Calorimetry is an effective technique in capturing both chemical and physical degradations of APIs in real time but requires redevelopment to withstand pressure for the purposes of pMDI screening.

  6. Reversibility of pulmonary function after inhaling salbutamol in different doses and body postures in asthmatic children

    NARCIS (Netherlands)

    Visser, R.; Kelderman, S.; Jongh, de F.H.C.; Palen, van der J.; Thio, B.J.


    Rationale Pulmonary medication is often delivered in the form of medical aerosols designed for inhalation. Recently, breath actuated inhalers (BAI's) gained popularity as they can be used without spacers. A major drawback of BAI's is the impaction in the upper airway. Stretching the upper airway by

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

    Directory of Open Access Journals (Sweden)

    Reshma Bhaskaran


    Full Text Available 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.

  8. Effect of repeated doses of sucrose during heel stick procedure in preterm neonates. (United States)

    Johnston, C C; Stremler, R; Horton, L; Friedman, A


    The purpose of this randomized clinical trial was to test the efficacy of repeated versus single dose sucrose to decrease pain from routine heel stick procedures in preterm neonates. Infants (n = 48) in the first week of life with a mean gestational age of 31 weeks received 0.05 ml of 24% sucrose solution or sterile water by mouth (1) 2 min prior to actual lancing of the heel; (2) just prior to lancing, and (3) 2 min after lancing. The single-dose group received sucrose for the first dose and water for the second and third dose; the repeated-dose group received sucrose three times, and the placebo group received only water. The Premature Infant Pain Profile (PIPP) scores were obtained for five 30-second blocks from lancing. Both sucrose groups had lower PIPP scores (single sucrose pain scores, 6.8-8.2, p = 0.07; repeated sucrose pain scores, 5.3-6. 2, p < 0.01) than water (pain scores 7.9-9.1), and in the last block, the repeated dose had lower scores than the single dose (6.2 vs. 8. 2, p < 0.05).

  9. Radiation-dose estimates and hazard evaluations for inhaled airborne radionuclides. Annual progress report, July 1981-June 1982

    Energy Technology Data Exchange (ETDEWEB)

    Mewhinney, J.A.


    The objective was to conduct confirmatory research on aerosol characteristics and the resulting radiation dose distribution in animals following inhalation and to provide prediction of health consequences in humans due to airborne radioactivity which might be released in normal operations or under accident conditions during production of nuclear fuel composed of mixed oxides of U and Pu. Four research reports summarize the results of specific areas of research. The first paper details development of a method for determination of specific surface area of small samples of mixed oxide or pure PuO/sub 2/ particles. The second paper details the extension of the biomathematical model previously used to describe retention, distribution and excretion of Pu from these mixed oxide aerosols to include a description of Am and U components of these aerosols. The third paper summarizes the biological responses observed in radiation dose pattern studies in which dogs, monkeys and rate received inhalation exposures to either 750/sup 0/C heat treated UO/sub 2/ + PuO/sub 2/, 1750/sup 0/C heat-treated (U,Pu)O/sub 2/ or 850/sup 0/C heat-treated pure PuO/sub 2/. The fourth paper described dose-response studies in which rats were exposed to (U,Pu)O/sub 2/ or pure PuO/sub 2/. This paper updates earlier reports and summarizes the status of animals through approximately 650 days after inhalation.

  10. Radiation-dose estimates and hazard evaluations for inhaled airborne radionuclides. Annual progress report, July 1981-June 1982

    Energy Technology Data Exchange (ETDEWEB)

    Mewhinney, J.A.


    The objective was to conduct confirmatory research on aerosol characteristics and the resulting radiation dose distribution in animals following inhalation and to provide prediction of health consequences in humans due to airborne radioactivity which might be released in normal operations or under accident conditions during production of nuclear fuel composed of mixed oxides of U and Pu. Four research reports summarize the results of specific areas of research. The first paper details development of a method for determination of specific surface area of small samples of mixed oxide or pure PuO/sub 2/ particles. The second paper details the extension of the biomathematical model previously used to describe retention, distribution and excretion of Pu from these mixed oxide aerosols to include a description of Am and U components of these aerosols. The third paper summarizes the biological responses observed in radiation dose pattern studies in which dogs, monkeys and rate received inhalation exposures to either 750/sup 0/C heat treated UO/sub 2/ + PuO/sub 2/, 1750/sup 0/C heat-treated (U,Pu)O/sub 2/ or 850/sup 0/C heat-treated pure PuO/sub 2/. The fourth paper described dose-response studies in which rats were exposed to (U,Pu)O/sub 2/ or pure PuO/sub 2/. This paper updates earlier reports and summarizes the status of animals through approximately 650 days after inhalation.

  11. 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. (United States)

    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


    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

  12. Comparison of the systemic bioavailability of mometasone furoate after oral inhalation from a mometasone furoate/formoterol fumarate metered-dose inhaler versus a mometasone furoate dry-powder inhaler in patients with chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Kosoglou T


    Full Text Available Teddy Kosoglou,1 James Hubbell,2 Fengjuan Xuan,3 David L Cutler,1 Alan G Meehan,4 Bhavna Kantesaria,5 Bret A Wittmer6,† 1Clinical Pharmacology, 2Exploratory Drug Metabolism, 3Early Development Statistics, 4Medical Communications, 5Drug Metabolism/Pharmacokinetics, Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USA; 6Commonwealth Biomedical Research, LLC, Madisonville, KY, USA†Dr Bret A Wittmer passed away on May 9, 2012.Background: Coadministration of mometasone furoate (MF and formoterol fumarate (F produces additive effects for improving symptoms and lung function and reduces exacerbations in patients with asthma and chronic obstructive pulmonary disease (COPD. The present study assessed the relative systemic exposure to MF and characterized the pharmacokinetics of MF and formoterol in patients with COPD.Methods: This was a single-center, randomized, open-label, multiple-dose, three-period, three-treatment crossover study. The following three treatments were self-administered by patients (n = 14 with moderate-to-severe COPD: MF 400 µg/F 10 µg via a metered-dose inhaler (MF/F MDI; DULERA®/ZENHALE® without a spacer device, MF/F MDI with a spacer, or MF 400 µg via a dry-powder inhaler (DPI; ASMANEX® TWISTHALER® twice daily for 5 days. Plasma samples for MF and formoterol assay were obtained predose and at prespecified time points after the last (morning dose on day 5 of each period of the crossover. The geometric mean ratio (GMR as a percent and the corresponding 90% confidence intervals (CI were calculated for treatment comparisons.Results: Systemic MF exposure was lower (GMR 77%; 90% CI 58, 102 following administration by MF/F MDI compared to MF DPI. Additionally, least squares geometric mean systemic exposures of MF and formoterol were lower (GMR 72%; 90% CI 61, 84 and (GMR 62%; 90% CI 52, 74, respectively, following administration by MF/F MDI in conjunction with a spacer compared to MF/F MDI without a spacer. MF/F MDI had a

  13. Repeated-dose liver micronucleus assay: an investigation with 2-nitropropane, a hepatocarcinogen. (United States)

    Kawakami, Satoru; Araki, Tetsuro; Nakajima, Mikio; Kusuoka, Osamu; Uchida, Keisuke; Sato, Norihiro; Tanabe, Yoko; Takahashi, Kaori; Wako, Yumi; Kawasako, Kazufumi; Tsurui, Kazuyuki


    The utility of the repeated-dose liver micronucleus (RDLMN) assay in the detection of a genotoxic hepatocarcinogen was evaluated. In this paper, a rat hepatocarcinogen, 2-nitropropane (2-NP), was administered orally to young adult rats for 14 and 28 days without a partial hepatectomy or a mitogen, and the micronucleus induction in liver was examined using a simple method to isolate hepatocytes. In addition, a bone marrow micronucleus assay was conducted concomitantly. The frequency of micronucleated hepatocytes induced by 2-NP increased significantly in both the 14- and 28-day repeated-dose studies, while the bone marrow micronucleus assays were negative in each study. These results indicate that the RDLMN assay is useful for detecting a genotoxic hepatocarcinogen that is negative in bone marrow micronucleus assays and is a suitable in vivo genotoxicity test method for integration into a repeated-dose general toxicity study.

  14. Effect of repeated doses of mercuric chloride on the kinetics of iron in rats

    Energy Technology Data Exchange (ETDEWEB)

    Grosicki, A.; Kossakowski, S. [National Veterinary Research Institute, Pulawy (Poland)


    The effect of repeated doses of 0.5 and 1.0 mg HgCl{sub 2}/kg b.w. given intragastrically for 30 days on the absorption and distribution of intragastrically trace dose of {sup 59}FeCl{sub 3} was studied in male Wistar rats. Both doses of mercury distributed the absorption of Fe-59 from the gastrointestinal track. Furthermore, the results revealed a dose-dependent influence of mercury on the content of Fe-59 in the organs and the AUC values. (author). 14 refs, 2 figs, 1 tab.

  15. An In Vitro Aerosolization Efficiency Comparison of Generic and Branded Salbutamol Metered Dose Inhalers

    National Research Council Canada - National Science Library

    Sara Rahimkhani; Saeed Ghanbarzadeh; Ali Nokhodchi; Hamed Hamishehkar


    ... benefit way of treatment if the domestics products passed from their examinations.10-15 Anecdotally, there is no evidence to support that generic inhaled salbutamol is inferior to the branded product...

  16. Two cases of takotsubo cardiomyopathy in patients treated with high doses of inhaled beta-2-agonists

    DEFF Research Database (Denmark)

    Thomsen, Camilla Fjord; Jeppesen, Jørgen Lykke; Stride, Nis Ottesen


    Takotsubo cardiomyopathy (TCM) is characterised by reversible left ventricular dysfunction in patients presenting with acute coronary syndrome (ACS). TCM is considered multifactorial, and the repetitive exposure to inhaled beta-2-agonists has been suspected to induce TCM in predisposed individuals...


    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...

  18. Inhalation therapy in children with asthma. (United States)

    Brand, P L


    Current consensus guidelines advocate the use of inhalation therapy for all children with asthma. In this paper, the published evidence on technical and practical aspects of inhalation therapy in children with asthma is reviewed. For children under 6 yr of age, nebulizers and metered dose inhaler (MDI)/spacer combinations can be used. Nebulizers are cumbersome, bulky, and difficult to operate. They require technical and hygienic maintenance. A number of studies has shown that nebulizers are no more effective in delivering bronchodilator therapy than MDI/spacer combinations. Thus, for young children with asthma, MDI/spacer combinations are the device of choice for inhalation therapy. Due to static charge, the output from plastic spacers is lower than that from metal spacers. Static charge on plastic spacers can be reduced by washing the spacer in detergent and allow it to drip dry. Most children aged 6 yr or over can use a dry powder inhaler (DPI) reliably. Modern DPIs require relatively low inspiratory flow rates for proper operation. Lung deposition from the Turbuhaler is twice as high as that from the Diskus, but the former device is slightly more difficult to operate than the latter. Many children with asthma have a poor inhalation technique. Because a reliable inhalation technique is the key to successful inhalation therapy, inhalation technique should be instructed carefully and checked repeatedly in every asthmatic child using an inhaler device.

  19. Assessing small-volume spinal cord dose for repeat spinal stereotactic body radiotherapy treatments (United States)

    Ma, Lijun; Kirby, Neil; Korol, Renee; Larson, David A.; Sahgal, Arjun


    Spinal cord biologically effective dose (BED) limits are critical to safe spine stereotactic body radiotherapy (SBRT) delivery. In particular, when repeating SBRT to the same site, the problem of adding non-uniform BED distributions within small volumes of spinal cord has yet to be solved. We report a probability-based generalized BED (gBED) model to guide repeat spine SBRT treatment planning. The gBED was formulated by considering the sequential damaging probabilities of repeat spine SBRT treatments. Parameters from the standard linear-quadratic model, such as α/β = 2 Gy for the spinal cord, were applied. We tested the model based on SBRT specific spinal cord tolerance using a simulated and ten clinical repeat SBRT cases. The gBED provides a consistent solution for superimposing non-uniform dose distributions from different fractionation schemes, analogous to the BED for uniform dose distributions. Based on ten clinical cases, the gBED was observed to eliminate discrepancies in the cumulative BED of approximately 5% to 20% within small volumes (e.g. 0.1-2.0 cc) of spinal cord, as compared to a conventional calculation method. When assessing spinal cord tolerance for repeat spinal SBRT treatments, caution should be exercised when applying conventional BED calculations for small volumes of spinal cord irradiated, and the gBED potentially provides more conservative and consistently derived dose surrogates to guide safe treatment planning and treatment outcome modeling.

  20. Measurement of specific parameters for dose calculation after inhalation of aerols containing transuranium elements; Mesure de parametres specifiques pour le calcul de dose apres inhalation d'aerosols renfermant des elements transuraniens

    Energy Technology Data Exchange (ETDEWEB)

    Ramounet-le Gall, B.; Fritsch, P.; Abram, M.C.; Rateau, G.; Grillon, G.; Guillet, K. [Lab. de Radiotoxicologie, CEA/DSV/DRR/SRCA, Bruyeres le Chatel (France); Baude, S. [Lab. de Mesures Specifiques Gaz, CEA/DAM/DASE/SRCE, Bruyeres le Chatel (France); Berard, P. [Cabinet du Conseiller medical du CEA, CEA/DEN/DPS/LABM Saclay, Gif sur Yvette (France); Ansoborlo, E. [CEA/DEN/DRCP/CETAMA, Bagnols sur Ceze (France); Delforge, J. [Lab. de Radiotoxicologie, CEA/DSV/DRR/SRCA, Bruyeres le Chatel (France)


    A review on specific parameter measurements to calculate doses per unit of incorporation according to recommendations of the International Commission of Radiological Protection has been performed for inhaled actinide oxides. Alpha activity distribution of the particles can be obtained by autoradiography analysis using aerosol sampling filters at the work places. This allows us to characterize granulometric parameters of 'pure' actinide oxides, but complementary analysis by scanning electron microscopy is needed for complex aerosols. Dissolution parameters with their standard deviation are obtained after rat inhalation exposure, taking into account both mechanical lung clearance and actinide transfer to the blood estimated from bone retention. In vitro experiments suggest that the slow dissolution rate might decrease as a function of time following exposure. Dose calculation software packages have been developed to take into account granulometry and dissolution parameters as well as specific physiological parameters of exposed individuals. In the case of poorly soluble actinide oxides, granulometry and physiology appear as the main parameters controlling dose value, whereas dissolution only alters dose distribution. Validation of these software packages are in progress. (author)

  1. Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 4 h apart Human pharmacology of MDMA after repeated doses taken 4 h apart. (United States)

    Farré, Magí; Tomillero, Angels; Pérez-Mañá, Clara; Yubero, Samanta; Papaseit, Esther; Roset, Pere-Nolasc; Pujadas, Mitona; Torrens, Marta; Camí, Jordi; de la Torre, Rafael


    3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a popular psychostimulant, frequently associated with multiple administrations over a short period of time. Repeated administration of MDMA in experimental settings induces tolerance and metabolic inhibition. The aim is to determine the acute pharmacological effects and pharmacokinetics resulting from two consecutive 100mg doses of MDMA separated by 4h. Ten male volunteers participated in a randomized, double-blind, crossover, placebo-controlled trial. The four conditions were placebo plus placebo, placebo plus MDMA, MDMA plus placebo, and MDMA plus MDMA. Outcome variables included pharmacological effects and pharmacokinetic parameters. After a second dose of MDMA, most effects were similar to those after a single dose, despite a doubling of MDMA concentrations (except for systolic blood pressure and reaction time). After repeated MDMA administration, a 2-fold increase was observed in MDMA plasma concentrations. For a simple dose accumulation MDMA and MDA concentrations were higher (+23.1% Cmax and +17.1% AUC for MDMA and +14.2% Cmax and +10.3% AUC for MDA) and HMMA and HMA concentrations lower (-43.3% Cmax and -39.9% AUC for HMMA and -33.2% Cmax and -35.1% AUC for HMA) than expected, probably related to MDMA metabolic autoinhibition. Although MDMA concentrations doubled after the second dose, most pharmacological effects were similar or slightly higher in comparison to the single administration, except for systolic blood pressure and reaction time which were greater than predicted. The pharmacokinetic-effects relationship suggests that when MDMA is administered at a 4h interval there exists a phenomenon of acute tolerance to its effects.

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

    CERN Document Server

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


    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 in 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, which are 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 characterize 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 funct...

  3. Acute and repeated dose toxicity studies of different β-cyclodextrin-based nanosponge formulations. (United States)

    Shende, Pravin; Kulkarni, Yogesh A; Gaud, R S; Deshmukh, Kiran; Cavalli, Roberta; Trotta, Francesco; Caldera, Fabrizio


    Nanosponges (NS) show promising results in different fields such as medicine, agriculture, water purification, fire engineering and so on. The present study was designed to evaluate toxicity of different NS formulations (namely, S1-S6) synthesized with different cross-linking agents such as carbonyl diimidazole, pyromellitic dianhydride and hexamethylene diisocynate; and preparation methods in experimental animals. Acute and repeated dose toxicity studies of formulations were carried out as per OECD guidelines 423 and 407, respectively. For acute toxicity study, formulations were administered to female rats at doses of 300 and 2000 mg/kg orally. The general behaviour of the rats was continuously monitored for 1 h after dosing, periodically during the first 24 h and daily thereafter for a total of 14 days. On day 14, animals were fasted overnight, weighed, and sacrificed. After sacrification, animals were subjected to necropsy. For repeated dose toxicity study, rats of either sex were orally administered with formulations at the dose of 300 mg/kg per day for a period of 28 days. The maximally tolerated dose of all formulations was found to be 2000 mg/kg. Repeated administration of formulations for 28 days did not show any significant changes in haematological and biochemical parameters in experimental animals. These results indicate that the formulations are safe, when tested in experimental animals.

  4. Statistical methodology to determine kinetically derived maximum tolerated dose in repeat dose toxicity studies. (United States)

    McFadden, Lisa G; Bartels, Michael J; Rick, David L; Price, Paul S; Fontaine, Donald D; Saghir, Shakil A


    Several statistical approaches were evaluated to identify an optimum method for determining a point of nonlinearity (PONL) in toxicokinetic data. (1) A second-order least squares regression model was fit iteratively starting with data from all doses. If the second order term was significant (αmodel was fit iteratively starting with data from all doses except the highest. The mean response for the omitted dose was compared to the 95% prediction interval. If the omitted dose falls outside the confidence interval it is an estimate of the PONL. (3) Slopes of least squares linear regression lines for sections of contiguous doses were compared. Nonlinearity was suggested when slopes of compared sections differed. A total of 33 dose-response datasets were evaluated. For these toxicokinetic data, the best statistical approach was the least squares regression analysis with a second-order term. Changing the α level for the second-order term and weighting the second-order analysis by the inverse of feed consumption were also considered. This technique has been shown to give reproducible identification of nonlinearities in TK datasets.

  5. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents. (United States)


    ... 40 Protection of Environment 31 2010-07-01 2010-07-01 true TSCA Repeated dose 28-day oral toxicity study in rodents. 799.9305 Section 799.9305 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... strains of young healthy adult animals should be employed. The females should be nulliparous and...

  6. 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. (United States)

    Eisenberg, Elon; Ogintz, Miri; Almog, Shlomo


    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.

  7. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT. (United States)

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E


    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity but could have adverse long-term effects on cardiometabolic health in offspring. We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to betamethasone or placebo treatment, ≥ 7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at children were assessed at 6 to 8 years' corrected age for body composition, insulin sensitivity, ambulatory blood pressure, and renal function. Of 320 eligible childhood survivors, 258 were studied (81%; 123 repeat betamethasone group; 135 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar total fat mass (geometric mean ratio 0.98, 95% confidence interval [CI] 0.78 to 1.23), minimal model insulin sensitivity (geometric mean ratio 0.89, 95% CI 0.74 to 1.08), 24-hour ambulatory blood pressure (mean difference systolic 0 mm Hg, 95% CI -2 to 2; diastolic 0 mm Hg, 95% CI -1 to 1), and estimated glomerular filtration rate (mean difference 1.2 mL/min/1.73 m(2), 95% CI -3.2 to 5.6). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not increase risk factors for cardiometabolic disease at early school age. Copyright © 2015 by the American Academy of Pediatrics.

  8. Preclinical assessment of HIV vaccines and microbicides by repeated low-dose virus challenges.

    Directory of Open Access Journals (Sweden)

    Roland R Regoes


    Full Text Available BACKGROUND: Trials in macaque models play an essential role in the evaluation of biomedical interventions that aim to prevent HIV infection, such as vaccines, microbicides, and systemic chemoprophylaxis. These trials are usually conducted with very high virus challenge doses that result in infection with certainty. However, these high challenge doses do not realistically reflect the low probability of HIV transmission in humans, and thus may rule out preventive interventions that could protect against "real life" exposures. The belief that experiments involving realistically low challenge doses require large numbers of animals has so far prevented the development of alternatives to using high challenge doses. METHODS AND FINDINGS: Using statistical power analysis, we investigate how many animals would be needed to conduct preclinical trials using low virus challenge doses. We show that experimental designs in which animals are repeatedly challenged with low doses do not require unfeasibly large numbers of animals to assess vaccine or microbicide success. CONCLUSION: Preclinical trials using repeated low-dose challenges represent a promising alternative approach to identify potential preventive interventions.

  9. Zanamivir Oral Inhalation (United States)

    ... for inhaling powder) and five Rotadisks (circular foil blister packs each containing four blisters of medication). Zanamivir powder ... put a hole in or open any medication blister pack until inhaling a dose with the Diskhaler.Carefully ...

  10. Changing the dose metric for inhalation toxicity studies: short-term study in rats with engineered aerosolized amorphous silica nanoparticles. (United States)

    Sayes, Christie M; Reed, Kenneth L; Glover, Kyle P; Swain, Keith A; Ostraat, Michele L; Donner, E Maria; Warheit, David B


    Inhalation toxicity and exposure assessment studies for nonfibrous particulates have traditionally been conducted using particle mass measurements as the preferred dose metric (i.e., mg or microg/m(3)). However, currently there is a debate regarding the appropriate dose metric for nanoparticle exposure assessment studies in the workplace. The objectives of this study were to characterize aerosol exposures and toxicity in rats of freshly generated amorphous silica (AS) nanoparticles using particle number dose metrics (3.7 x 10(7) or 1.8 x 10(8) particles/cm(3)) for 1- or 3-day exposures. In addition, the role of particle size (d(50) = 37 or 83 nm) on pulmonary toxicity and genotoxicity endpoints was assessed at several postexposure time points. A nanoparticle reactor capable of producing, de novo synthesized, aerosolized amorphous silica nanoparticles for inhalation toxicity studies was developed for this study. SiO(2) aerosol nanoparticle synthesis occurred via thermal decomposition of tetraethylorthosilicate (TEOS). The reactor was designed to produce aerosolized nanoparticles at two different particle size ranges, namely d(50) = approximately 30 nm and d(50) = approximately 80 nm; at particle concentrations ranging from 10(7) to 10(8) particles/cm(3). AS particle aerosol concentrations were consistently generated by the reactor. One- or 3-day aerosol exposures produced no significant pulmonary inflammatory, genotoxic, or adverse lung histopathological effects in rats exposed to very high particle numbers corresponding to a range of mass concentrations (1.8 or 86 mg/m(3)). Although the present study was a short-term effort, the methodology described herein can be utilized for longer-term inhalation toxicity studies in rats such as 28-day or 90-day studies. The expansion of the concept to subchronic studies is practical, due, in part, to the consistency of the nanoparticle generation method.

  11. Enantioselective disposition of (R)-salmeterol and (S)-salmeterol in urine following inhaled dosing and application to doping control

    DEFF Research Database (Denmark)

    Jacobson, Glenn A; Hostrup, Morten; Narkowicz, Christian K


    Salmeterol (USAN, INN, BAN) is a long-acting beta2-adrenoceptor agonist (LABA) widely used in the treatment of airways disease. Although salmeterol is permitted via inhalation by athletes and supratherapeutic dosing may enhance performance, no urine threshold has been established by the World Anti-Doping....... The present findings are of relevance if a urine threshold limit is to be introduced for salmeterol on the list of prohibited substances. The application of an enantiomer ratio analysis may offer improved discriminatory detection capability for doping control analysis applications....

  12. 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. (United States)

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


    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 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.

  13. Formulation of dry powder tobramycin for the twincertm high dose, disposable inhaler

    NARCIS (Netherlands)

    Hoppentocht, M.; Hagedoorn, P.; Frijlink, H.W.; De Boer, A.H.


    Background: Currently applied nebulisation techniques for the administration of antibiotics to patients with infectious lung diseases are ineffective, time consuming and therefore, burdensome to the patient. Dry powder inhalers may be an interesting alternative as they can be effective, simple, chea

  14. Teaching chronic obstructive airway disease patients usinga metered-dose inhaler

    Institute of Scientific and Technical Information of China (English)

    Ho-Hoi Luk; Po-May Chan; Fong-Fong Lam; Kit-Yu Lau; Sze-Yee Chiu; Yuet-Ling Fung; Janet Pang


    @@ Asthma and chronic obstructive airway disease (COAD) are chronic inflammatory disorders of the airways which are usually associated with widespread airway obstruction that is often relieved by treatment. β2-adrenoreceptor agonists and corticosteriods are the mainstay of the management of this disease. The preferred route of administration of these agents is by inhalation.

  15. Safety and pharmacokinetics of ciprofloxacin dry powder for inhalation in cystic fibrosis: a phase I, randomized, single-dose, dose-escalation study. (United States)

    Stass, Heino; Delesen, Heinz; Nagelschmitz, Johannes; Staab, Doris


    Reliable, reproducible deposition to the lung is a major prerequisite for the clinical use of inhaled drugs. Ciprofloxacin dry powder for inhalation (ciprofloxacin DPI; Bayer HealthCare AG, Leverkusen, Germany) is an antibacterial therapy in development using Novartis' PulmoSphere™ technology (Novartis Pharma AG, Basel, Switzerland) for the targeted delivery of ciprofloxacin to the lung via a T-326 inhaler. This randomized, single-blind, placebo-controlled, dose-escalation study investigated the safety, tolerability, and pharmacokinetics of single-dose ciprofloxacin DPI (32.5 mg [n=6] or 65 mg [n=6]) and matching placebo (n=4) in adult patients with cystic fibrosis and stable pulmonary status (forced expiratory volume in 1 sec ≥30%) who were colonized with Pseudomonas aeruginosa. Peak sputum concentrations of 34.9 mg/L (range 2.03-229) and 376 mg/L (8.95-1283) for ciprofloxacin 32.5 mg and 65 mg, respectively, indicated targeting of ciprofloxacin DPI to the lung. This contrasted with low systemic exposure (peak plasma concentrations: 0.0790 mg/L [32.5 mg] and 0.182 mg/L [65 mg]). Single-dose ciprofloxacin DPI 32.5 mg or 65 mg was well tolerated with similar incidences of adverse events across all groups. No deaths, discontinuations, treatment-related serious adverse events, or clinically relevant changes in laboratory parameters, vital signs, or lung function tests were reported. Lung targeting with high pulmonary concentrations of ciprofloxacin combined with low systemic exposure was confirmed. These results support further study of ciprofloxacin DPI as a potentially more convenient alternative to nebulized antibiotic solutions for managing chronic lung infections.

  16. A method for determining an indicator of effective dose calculation due to inhalation of Radon and its progeny from in vivo measurements

    CERN Document Server

    Estrada, J


    Direct measurement of the absolved dose to lung tissue from inhalation of radon and its progeny is not possible and must be calculated using dosimetric models, taking into consideration the several parameters upon which the dose calculation depends. To asses the dose due to inhalation of radon and its progeny, it is necessary to estimate the cumulative exposure. Historically, this has been done using WLM values estimated with measurements of radon concentration in air. The radon concentration in air varies significantly, however, in space with time, and the exposed individual is also constantly moving around. This makes it almost impossible to obtain a precise estimate of an individual's inhalation exposure. This work describes a pilot study to calculate lung dose from the deposition of radon progeny, via estimates of cumulative exposure derived from in vivo measurements of sup 2 sup 1 sup 0 Pb, in subjects exposed to above-average radon and its progeny concentrations in their home environments. The measureme...

  17. Dose-responses over time to inhaled fluticasone propionate treatment of exercise- and methacholine-induced bronchoconstriction in children with asthma

    NARCIS (Netherlands)

    Hofstra, WB; Neijens, HJ; Duiverman, EJ; Kouwenberg, JM; Mulder, PGH; Kuethe, MC; Sterk, PJ


    When treating bronchial hyperresponsiveness to so-called direct and indirect stimuli, distinct pathophysiological mechanisms might require differences in dose and duration of inhaled corticosteroid therapy. To test this hypothesis in children with asthma, we investigated the time- and dose-dependent

  18. The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS). (United States)

    Tluczkiewicz, Inga; Batke, Monika; Kroese, Dinant; Buist, Harrie; Aldenberg, Tom; Pauné, Eduard; Grimm, Helvi; Kühne, Ralph; Schüürmann, Gerrit; Mangelsdorf, Inge; Escher, Sylvia E


    In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evaluates the conditions under which in vivo non-guideline studies are reliable. In a tiered approach three aspects of these "non-guideline" studies are assessed: the documentation of the study (reliability), the quality of the study design (adequacy) and the scope of examination (validity). The reliability is addressed by the method "Knock-out criteria", which consists of four essential criteria for repeated-dose toxicity studies. A second tool, termed QUANTOS (Quality Assessment of Non-guideline Toxicity Studies), evaluates and weights the adequacy of the study by using intra-criterion and inter-criteria weighting. Finally, the Coverage approach calculates a probability that the detected Lowest-Observed-Effect-Level (LOEL) is similar to the LOEL of a guideline study dependent on the examined targets and organs of the non-guideline study. If the validity and adequacy of the non-guideline study are insufficient for risk assessment, the ITS proposes to apply category approach or the Threshold of Toxicological Concern (TTC) concept, and only as a last resort new animal-testing.

  19. A standard, single dose of inhaled terbutaline attenuates hyperpnea-induced bronchoconstriction and mast cell activation in athletes. (United States)

    Simpson, A J; Bood, J R; Anderson, S D; Romer, L M; Dahlén, B; Dahlén, S-E; Kippelen, P


    Release of bronchoactive mediators from mast cells during exercise hyperpnea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effect of a standard, single dose of an inhaled β2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnea in athletes with EIB. Twenty-seven athletes with EIB completed a randomized, double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled 15 min prior to 8 min of eucapnic voluntary hyperpnea (EVH) with dry air. Pre- and postbronchial challenge, urine samples were analyzed by enzyme immunoassay for 11β-prostaglandin F2α (11β-PGF2α). The maximum fall in forced expiratory volume in 1 s of 14 (12-20)% (median and interquartile range) following placebo was attenuated to 7 (5-9)% with the administration of terbutaline (P < 0.001). EVH caused a significant increase in 11β-PGF2α from 41 (27-57) ng/mmol creatinine at baseline to 58 (43-72) ng/mmol creatinine at its peak post-EVH following placebo (P = 0.002). The rise in 11β-PGF2α was inhibited with administration of terbutaline: 39 (28-44) ng/mmol creatinine at baseline vs. 40 (33-58) ng/mmol creatinine at its peak post-EVH (P = 0.118). These data provide novel in vivo evidence of mast cell stabilization following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB.

  20. Repeated doses of melatonin protects against focal cerebral ischemia in the rat


    Pei, Z; Pang, SF; Cheung, RTF


    We studied the time window of neuroprotection against focal ischemia by a single dose or repeated doses of melatonin (MT) at 5 mg/kg. Adult male Sprague-Dawley rats (280 to 360 g) were anesthetized with sodium pentobarbital (60 mg/kg, I.P.) to undergo reversible right-sided endovascular middle cerebral artery occlusion (MCAO) for 3 hours. Arterial blood pressure, heart rate and cerebral blood flow were monitored, and rectal temperature was kept between 36.5 and 37.5 ºC throughout anesthesia. ...

  1. A Rationale for Going Back to the Future: Use of Disposable Spacers for Pressurised Metered Dose Inhalers

    Directory of Open Access Journals (Sweden)

    Mark Sanders


    Full Text Available The introduction of pressurised metered dose inhalers (MDIs in the mid-1950s completely transformed respiratory treatment. Despite decades of availability and healthcare support and development of teaching aids and devices to promote better use, poor pMDI user technique remains a persistent issue. The main pMDI user aid is the spacer/valved holding chamber (VHC device. Spacer/chamber features (size, shape, configuration, construction material, and hygiene considerations can vie with clinical effectiveness (to deliver the same dose as a correctly used pMDI, user convenience, cost, and accessibility. Unsurprisingly, improvised, low-cost alternatives (plastic drink bottles, paper cups, and paper towel rolls have been pressed into seemingly effective service. A UK law change permitting schools to hold emergency inhalers and spacers has prompted a development project to design a low-cost, user-friendly, disposable, and recyclable spacer. This paper spacer requires neither preuse priming nor washing, and has demonstrated reproducible lung delivery of salbutamol sulphate pMDI, comparable to an industry-standard VHC, an alternative paperboard VHC, and pMDI alone. This new device appears to perform better than these other VHC devices at the low flow rates thought achievable by paediatric patients. The data suggest that this disposable spacer may have a place in the single-use emergency setting.

  2. Moderate dose inhaled corticosteroid-induced symptomatic adrenal suppression: case report and review of the literature. (United States)

    Schwartz, Richard H; Neacsu, Otilia; Ascher, David P; Alpan, Oral


    Inhaled corticosteroids (ICS) are drugs of choice for persistent asthma. Less than 500 µg/d of fluticasone are believed to be safe. We found 92 cases of adrenal suppression in PubMed; among these cases there were 13 children who took 500 µg/d or less of fluticasone. Adrenal insufficiency was diagnosed in a 7-year-old boy on 460 µg ICS for 16 months, with a diagnosis of chronic persistent asthma. A random cortisol was nondetectable as was an early morning cortisol. ICS have greatly improved the day-to-day lives of children with chronic persistent asthma. Parents of children younger than 12 years, who use at least 400 µg of inhaled fluticasone (or bioequivalent), must be given oral and written instructions about warning symptoms of hypocortisolism. Major stress such as surgery, gastrointestinal, bronchopulmonary, or other systemic infections, and heat stress may mandate a written plan of action for use by hospital physicians.

  3. Pharmacokinetics of metadoxine for injection after repeated doses in healthy volunteers

    Institute of Scientific and Technical Information of China (English)

    L(U) Yuan; KANG Zi-sheng; LIU Yan; LI Tian-yun; XIAO Yong-hong


    @@ Alcohol-induced liver disease is one of the main epidemic problems nowadays. Metadoxine is a pyridoxine-pyrrolidone carboxylate with significant scavenging property. Metadoxine is able to accelerate the elimination of alcohol from the blood and tissues, help restore the functional structure of the liver and relieve neuro-psychological disorders associated with alcohol intoxication.1-3 The purpose of the study was to assay the pharmacokinetics of domestic metadoxine after repeated doses.


    Institute of Scientific and Technical Information of China (English)

    李素云; 张升慧; 等


    The dose distribution in the lung is inhomogeneous.The dose to the basal cell layer of trachea and main bronchi is much higher than the dose to total lung both for rabbits at different ages and for different animals.A maximum value of the dose to lung tissue for rabbits at ages of 20-40d is observed.The dose decreases with increasing body weight.The relationship between the dose and body weight can be descreibed by a power function.The dose to total lung increases exponentially with the minute breathing volume per unit of lung weight.

  5. Evaluation of statistical tools used in short-term repeated dose administration toxicity studies with rodents. (United States)

    Kobayashi, Katsumi; Pillai, K Sadasivan; Sakuratani, Yuki; Abe, Takemaru; Kamata, Eiichi; Hayashi, Makoto


    In order to know the different statistical tools used to analyze the data obtained from twenty-eight-day repeated dose oral toxicity studies with rodents and the impact of these statistical tools on interpretation of data obtained from the studies, study reports of 122 numbers of twenty-eight-day repeated dose oral toxicity studies conducted in rats were examined. It was found that both complex and easy routes of decision trees were followed for the analysis of the quantitative data. These tools include Scheffe's test, non-parametric type Dunnett's and Scheffe's tests with very low power. Few studies used the non-parametric Dunnett type test and Mann-Whitney's U test. Though Chi-square and Fisher's tests are widely used for analysis of qualitative data, their sensitivity to detect a treatment-related effect is questionable. Mann-Whitney's U test has better sensitivity to analyze qualitative data than the chi-square and Fisher's tests. We propose Dunnett's test for analysis of quantitative data obtained from twenty-eight-day repeated dose oral toxicity tests and for qualitative data, Mann-Whitney's U test. For both tests, one-sided test with p=0.05 may be applied.

  6. [Twenty-eight days repeated dose toxicity test of N-(fluorodichloromethylthio)phthalimide in rats]. (United States)

    Matsushima, Y; Tsuda, M; Naito, K; Saitoh, M; Isama, K; Ikarashi, Y; Kawasaki, Y; Momma, J; Kitajima, S; Kaniwa, M


    N-(Fluorodichloromethylthio)phthalimide (Fluor-folpet) has been widely used as an anti-mold and anti-bacterial agent. In this study, 28 days repeated-dose oral toxicity study of fluor-folpet was carried out in Slc:Wistar rats. An oral toxicity study for fluor-folpet, the twenty-eight days test, repeated-dose, oral administration, was performed as follows: Five week-old rats, male and female, 10 rats, each/group, were treated with intragastric administration of fluor-folpet with a dose of 0 (1% Sodium CMC, control), 20, 80 and 320 mg/kg, body weight. Recovery test, for 14 days after the last treatment, was examined for the control and the 320 mg/kg groups. The 320 mg/kg groups, both males and females, showed significantly reduced their body-weight gain compared with the control group. In the 320 mg/kg group, five out of 20 male rats and four out of 20 female rats died from dyspnea during the treatment period. In the female rats in the 320 mg/kg group, serum ChE level was decreased to 50% of control level and gamma-GT was increased in a dose-dependent manner, but these serum levels recovered after 14 days non-treatment period. No histopathological change, relating to the treatment, in liver was observed. Increased weight of the kidney and vacuolation in renal tubules were found in both sexes of 320 mg/kg group. Hyperkeratosis and hyperplasia of the stomach epithelium were observed at the dose more than 80 mg/kg in male, and more than 20 mg/kg in female. A supplemental study, repeated-dose, oral administration in rats carried out to examine the dyspnea revealed that severe acute toxic damages in epithelium of nasal cavity and meatus nasopharyngeus were induced by intragastric administration of fluor-folpet. Fluor-folpet is shown to be cytotoxic. In conclusion, the no-observed-effect level (NOEL) for fluor-folpet was not found under the experimental conditions employed in this repeated-dose toxicity study.

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

    Energy Technology Data Exchange (ETDEWEB)

    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 10 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 ± 7.6 c

  8. Evaluation of sildenafil pressurized metered dose inhalers as a vasodilator in umbilical blood vessels of chicken egg embryos. (United States)

    Sawatdee, Somchai; Hiranphan, Phetai; Laphanayos, Kampanart; Srichana, Teerapol


    Sildenafil citrate is a selective phosphodiesterase-5 inhibitor used for the treatment for erectile dysfunction and pulmonary hypertension. The delivery of sildenafil directly to the lung could have several advantages over conventional treatments for pulmonary hypertension because of the local delivery, a more rapid onset of response, and reduced side effects. The major problem of sildenafil citrate is its limited solubility in water. Sildenafil citrate was complexed with cyclodextrins (CDs) to enhance its water solubility prior to development as an inhaled preparation. Four sildenafil citrate inhaled formulations were prepared with the aid of HP-β-CD (#1), α-CD (#2) and γ-CD (#3) and their effects were compared with the formulations without CDs (#4). The sildenafil citrate pressurized metered dose inhalers (pMDI) used ethanol as a solvent, PEG400 as a stabilizing agent, sorbitan monooleate as a surfactant and HFA-134a as a propellant. All formulations consisted of sildenafil citrate equivalent to a sildenafil content of 20μg/puff. These products were evaluated according to a standard guideline of inhalation products. Vasodilation testing was performed to investigate the efficacy of sildenafil pMDIs in relieving a vasoconstricted umbilical blood vessel of the chicken egg embryo. The sildenafil contents of the pMDI formulations #1-#3 were within the acceptance criteria (80-120%). The emitted doses (ED) were 102.3±11.5%, the fine particle fractions (FPF) were 60.5±5.6% and the mass median aerodynamic diameters (MMAD) were 2.3±0.3μm. The vasodilatory activity of those formulations reduced umbilical blood pressure by 67.1-73.7% after treatment by intravenous injection whereas only a 50.1-58.0% reduced blood pressure was obtained after direct spraying of the sildenafil pMDI containing CDs. With sildenafil formulations of a pMDI without CD the blood pressure was reduced by only 39.0% (P-valuevessels of chicken egg embryos after spraying sildenafil-CDs pMDIs was

  9. The 14-day repeated dose liver micronucleus test with methapyrilene hydrochloride using young adult rats. (United States)

    Inoue, Kenji; Ochi, Akimu; Koda, Akira; Wako, Yumi; Kawasako, Kazufumi; Doi, Takaaki


    The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general toxicity study. The assay methods were thoroughly validated by 19 Japanese facilities. Methapyrilene hydrochloride (MP), known to be a non-genotoxic hepatocarcinogen, was examined in the present study. MP was dosed orally at 10, 30 and 100mg/kg/day to 6-week-old male Crl:CD (SD) rats daily for 14 days. Treatment with MP resulted in an increase in micronucleated hepatocytes (MNHEPs) with a dosage of only 100mg/kg/day. At this dose level, cytotoxicity followed by regenerative cell growth was noted in the liver. These findings suggest that MP may induce clastogenic effects indirectly on the liver or hepatotoxicity of MP followed by regeneration may cause increase in spontaneous incidence of MNHEPs.

  10. Treating glioblastoma multiforme with selective high-dose liposomal doxorubicin chemotherapy induced by repeated focused ultrasound

    Directory of Open Access Journals (Sweden)

    Yang FY


    Full Text Available Feng-Yi Yang1, Ming-Che Teng1, Maggie Lu2, Hsiang-Fa Liang2, Yan-Ru Lee1, Chueh-Chuan Yen3, Muh-Lii Liang4,5, Tai-Tong Wong51Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 2Drug Delivery Laboratory, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, 3Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, 4Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, 5Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, TaiwanBackground: High-dose tissue-specific delivery of therapeutic agents would be a valuable clinical strategy. We have previously shown that repeated transcranial focused ultrasound is able to increase the delivery of Evans blue significantly into brain tissue. The present study shows that repeated pulsed high-intensity focused ultrasound (HIFU can be used to deliver high-dose atherosclerotic plaque-specific peptide-1 (AP-1-conjugated liposomes selectively to brain tumors.Methods: Firefly luciferase (Fluc-labeled human GBM8401 glioma cells were implanted into NOD-scid mice. AP-1-conjugated liposomal doxorubicin or liposomal doxorubicin alone was administered followed by pulsed HIFU and the doxorubicin concentration in the treated brains quantified by fluorometer. Growth of the labeled glioma cells was monitored through noninvasive bioluminescence imaging and finally the brain tissue was histologically examined after sacrifice.Results: Compared with the control group, the animals treated with 5 mg/kg injections of AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin followed by repeated pulsed HIFU not only showed significantly enhanced accumulation of drug at the sonicated tumor site but also a significantly elevated tumor-to-normal brain drug

  11. Melatonin prevents the development of hyperplastic urothelium induced by repeated doses of cyclophosphamide. (United States)

    Zupancic, Dasa; Vidmar, Gaj; Jezernik, Kristijan


    Repeated cyclophosphamide (CP) chemotherapy increases the risk of developing bladder cancer, which could be due to the extremely rapid proliferation of urothelial cells observed in hyperplastic urothelium induced by CP treatment. We investigated the effect of melatonin on the development of urothelial hyperplasia induced by repeated CP treatment. Male ICR mice were injected with CP (150 mg/kg) or melatonin (10 mg/kg) with CP once a week for 3, 4 and 5 weeks. Transmission and scanning electron microscopy, immunohistochemistry and Western blot analysis were used to study the ultrastructure, apoptosis, proliferation and differentiation of urothelial cells. Repeated doses of CP caused the development of hyperplastic urothelium with up to ten cell layers and increased proliferation and apoptotic indices regarding Ki-67 and active caspase-3 immunohistochemistry, respectively. Scanning electron microscopy observations, cytokeratin and asymmetrical unit membrane immunohistochemistry and Western blot analysis showed a lower differentiation state of superficial urothelial cells. Melatonin co-treatment prevented the development of hyperplastic urothelium, statistically significantly decreased proliferation and apoptotic indices after four and five doses of CP and caused higher differentiation state of superficial urothelial cells.

  12. Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice (United States)

    Wang, Bing; Feng, Weiyue; Zhu, Motao; Wang, Yun; Wang, Meng; Gu, Yiqun; Ouyang, Hong; Wang, Huajian; Li, Ming; Zhao, Yuliang; Chai, Zhifang; Wang, Haifang


    Olfactory tract has been demonstrated to be an important portal for inhaled solid nanoparticle transportation into the central nervous system (CNS). We have previously demonstrated that intranasally instilled Fe2O3 nanoparticles could transport into the CNS via olfactory pathway. In this study, we investigated the neurotoxicity and size effect of repeatedly low-dose (130 μg) intranasal exposure of nano- and submicron-sized Fe2O3 particles (21 nm and 280 nm) to mice. The biomarkers of oxidative stress, activity of nitric oxide synthases and release of monoamine neurotransmitter in the brain were studied. Our results showed that significant oxidative stress was induced by the two sizes of Fe2O3 particles. The activities of GSH-Px, Cu,Zn-SOD, and cNOS significantly elevated and the total GSH and GSH/GSSG ratio significantly decreased in the olfactory bulb and hippocampus after the nano- and submicron-sized Fe2O3 particle treatment ( p < 0.05). The nano-sized Fe2O3 generally induced greater alteration and more significant dose-effect response than the submicron-sized particle did. Some slight perturbation of monoamine neurotransmitters were found in the hippocampus after exposure to the two sizes of Fe2O3 particle. The TEM image showed that some ultrastructural alterations in nerve cells, including neurodendron degeneration, membranous structure disruption and lysosome increase in the olfactory bulb, slight dilation in the rough endoplasmic reticulum and lysosome increase in the hippocampus were induced by the nano-sized Fe2O3 treatment. In contrast, in the submicron-sized Fe2O3 treated mice, slightly swollen mitochondria and some vacuoles were observed in the olfactory bulb and hippocampus, respectively. These results indicate that intranasal exposure of Fe2O3 nanoparticles could induce more severe oxidative stress and nerve cell damage in the brain than the larger particle did. This is the first study to compare the neurotoxicity of nano- and submicron-sized Fe2O3

  13. Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice

    Energy Technology Data Exchange (ETDEWEB)

    Wang Bing; Feng Weiyue, E-mail:; Zhu Motao; Wang Yun; Wang Meng [Chinese Academy of Sciences, Laboratory for Bio-Environmental Effects of Nanomaterials and Nanosafety and Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics (China); Gu Yiqun [Maternity Hospital of Haidian District (China); Ouyang Hong; Wang Huajian; Li Ming; Zhao Yuliang, E-mail:; Chai Zhifang [Chinese Academy of Sciences, Laboratory for Bio-Environmental Effects of Nanomaterials and Nanosafety and Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics (China); Wang Haifang [Peking University, College of Chemistry and Molecular Engineering (China)


    Olfactory tract has been demonstrated to be an important portal for inhaled solid nanoparticle transportation into the central nervous system (CNS). We have previously demonstrated that intranasally instilled Fe{sub 2}O{sub 3} nanoparticles could transport into the CNS via olfactory pathway. In this study, we investigated the neurotoxicity and size effect of repeatedly low-dose (130 {mu}g) intranasal exposure of nano- and submicron-sized Fe{sub 2}O{sub 3} particles (21 nm and 280 nm) to mice. The biomarkers of oxidative stress, activity of nitric oxide synthases and release of monoamine neurotransmitter in the brain were studied. Our results showed that significant oxidative stress was induced by the two sizes of Fe{sub 2}O{sub 3} particles. The activities of GSH-Px, Cu,Zn-SOD, and cNOS significantly elevated and the total GSH and GSH/GSSG ratio significantly decreased in the olfactory bulb and hippocampus after the nano- and submicron-sized Fe{sub 2}O{sub 3} particle treatment (p < 0.05). The nano-sized Fe{sub 2}O{sub 3} generally induced greater alteration and more significant dose-effect response than the submicron-sized particle did. Some slight perturbation of monoamine neurotransmitters were found in the hippocampus after exposure to the two sizes of Fe{sub 2}O{sub 3} particle. The TEM image showed that some ultrastructural alterations in nerve cells, including neurodendron degeneration, membranous structure disruption and lysosome increase in the olfactory bulb, slight dilation in the rough endoplasmic reticulum and lysosome increase in the hippocampus were induced by the nano-sized Fe{sub 2}O{sub 3} treatment. In contrast, in the submicron-sized Fe{sub 2}O{sub 3} treated mice, slightly swollen mitochondria and some vacuoles were observed in the olfactory bulb and hippocampus, respectively. These results indicate that intranasal exposure of Fe{sub 2}O{sub 3} nanoparticles could induce more severe oxidative stress and nerve cell damage in the brain than the

  14. Toxicological assessment of heavy straight run naphtha in a repeated dose/reproductive toxicity screening test. (United States)

    McKee, Richard H; Steup, David; Schreiner, Ceinwen; Podhasky, Paula; Malley, Linda A; Roberts, Linda


    Gasoline blending stocks (naphthas) are comprised of normal, iso- and cycloparaffins and aromatic hydrocarbons with carbon numbers ranging from C4 to C12. Heavy straight run naphtha (HSRN, CAS number 64741-41-9) was selected for toxicity screening because substances of this type contain relatively high levels (28%) of cycloparaffins by comparison to other naphtha streams and the data complement toxicity information on other gasoline blending streams. Rats were exposed by inhalation to wholly vaporized material at levels of approximately 100, 500, or 3000 parts per million (ppm) daily to screen the potential for systemic toxicity, neurotoxicity, reproductive toxicity, and developmental effects to postnatal day 4. All animals survived the treatment period. Principal effects of repeated exposure included increased liver weights in males and females, increased kidney weights in males, and histological changes in the thyroid, secondary to liver enzyme induction. These changes were not considered to be toxicologically meaningful and are not relevant to humans. There were no treatment-related effects in functional observation tests or motor activity; no significant reductions in fertility or changes in other reproductive parameters; and no evidence of developmental toxicity in offspring. The overall no observed adverse effect concentration was 3000 ppm (approximately 13, 600 mg/m(3)). In conclusion the HSRN effects on liver and kidney are consistent with the results of other studies of volatile fractions or other naphthas or formulated gasoline, and there were no HSRN effects on neurological developmental or reproductive parameters.

  15. Repeated exposure to sublethal doses of the organophosphorus compound VX activates BDNF expression in mouse brain. (United States)

    Pizarro, Jose M; Chang, Wenling E; Bah, Mariama J; Wright, Linnzi K M; Saviolakis, George A; Alagappan, Arun; Robison, Christopher L; Shah, Jinesh D; Meyerhoff, James L; Cerasoli, Douglas M; Midboe, Eric G; Lumley, Lucille A


    The highly toxic organophosphorus compound VX [O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day × 5 days/week × 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure.

  16. Tolerability and pharmacokinetics of ebrotidine in healthy subjects given single and repeated oral doses. (United States)

    Farré, M; Roset, P N; Badenas, J M; Ugena, B; Márquez, M; Albet, C; Herrero, E; Ortiz, J A


    The tolerability and safety of ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl] thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) and its basic pharmacokinetic parameters were determined after its oral administration to healthy volunteers. Sixteen subjects were selected to participate in two different studies: an increasing single dose study to determine the maximal tolerated dose (from 25 to 1600 mg), and a multiple dose study (stepped doses from 400 to 1600 mg daily for 12 days). The results of the studies showed that ebrotidine has a good tolerability. Vital signs and laboratory tests were not influenced by the study treatment. No clinically relevant adverse effects were reported during the investigation. Ebrotidine reached peak plasma concentrations 2-3 h after oral administration. Its elimination half-life ranged from 9 to 14 h. In conclusion, ebrotidine was well tolerated after administration of oral single doses of up to 1600 mg, and after repeated administration of up to 800 mg/12 h for 12 days.

  17. Radon-222 in groundwater and effective dose due to ingestion and inhalation in the city of Ibadan, Nigeria. (United States)

    Ademola, Janet Ayobami; Oyeleke, Oyebode Akanni


    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.

  18. Metered-dose inhaler ipratropium bromide in moderate acute asthma in children: A single-blinded randomised controlled trial. (United States)

    Wyatt, Emma L; Borland, Meredith L; Doyle, Sarah K; Geelhoed, Gary C


    To determine if the addition of ipratropium bromide (IB) by metered-dose inhaler in moderate acute asthma in children affects hospital admission rates when compared with inhaled salbutamol and oral prednisolone alone. A prospective, single-blinded, randomised, controlled, equivalence trial in a tertiary paediatric emergency department. Patients aged 2-15 years with acute, moderate asthma were randomised to two groups, one receiving salbutamol, prednisolone and IB, the other receiving only salbutamol and prednisolone. The managing doctor was blinded to treatment. Admission rates were compared, and less than 15% difference was accepted as statistically equivalent. Recruitment ran from June 2007 until January 2011. Three hundred forty-seven subjects were analysed. The admission rate in the IB group was 70.1% (122/174) compared with 64.2% (111/173) in the non-IB group. The absolute difference of +5.9% (95% confidence interval -4.0% to 15.8%) is not statistically equivalent but does not show a statistically significant decrease in admission rates when IB was given. Adverse effects were more prevalent in the IB group, at 13.2% (23/174), compared with 4.6% (8/173) in the non-IB group, a relative risk of 2.86 (95% confidence interval 1.31-6.21). In children with acute asthma of moderate severity who are treated with adequate doses of salbutamol and prednisolone, the addition of IB is not significantly associated with a reduction in admission rates. There is a significantly higher rate of adverse effects if IB is given. IB should be reserved for children with severe asthma exacerbations. © 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  19. An abbreviated repeat dose and reproductive/developmental toxicity test for high production volume chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Scala, R.A.; Bevan, C.; Beyer, B.K. (Exxon Biomedical Sciences, Inc., East Millstone, NJ (United States))


    A novel protocol is described for obtaining preliminary data on repeated dose systemic effects and reproductive/developmental toxicity. The test protocol was developed by a group of experts at the request of the U.S. Environmental Protection Agency (EPA) for use as part of a Screening Information Data Set on high production volume chemicals. Interest in this protocol is shared by several regulatory agencies, including the Organization for Economic Cooperation, the European Community, and the EPA. To validate the study protocol, ethylene glycol monomethyl ether (EGME) was used. After a dosing period of approximately 6 weeks, EGME showed both systemic and reproductive/developmental effects similar to those previously reported using standard protocols. Thus, this test protocol may be used as a screening tool for high production volume chemicals.

  20. Effects of exercise on dose and dose distribution of inhaled automotive pollutants. Research report, Jun 84-Oct 90

    Energy Technology Data Exchange (ETDEWEB)

    Kleinman, M.T.; Mautz, W.J.


    The study evaluated how changes in ventilation rate and the entry route of air pollutants into the respiratory tract (nose versus mouth breathing) affect the respiratory tract uptake and penetration of inhaled gaseous and particle pollutants in automobile emissions. Beagle dogs were exposed at rest or while exercising to nitrogen dioxide (1 and 5 ppm), formaldehyde (2 and 10 ppm), and an aerosol of ammonium nitrate particles (0.3 micro MMAD at 1 mg/m). Total respiratory system uptake and effects on breath time expired tidal volume, fractional expiration time, minute ventilation, respiratory gas exchange, ventilation equivalents for oxygen and carbon dioxide, and dynamic pulmonary resistance and compliance were measured. Regional penetration of pollutants through oral and nasal airways and pollutant uptake in the lung were measured in a separate group of six tracheostomized dogs. Dogs exposed to 5 ppm nitrogen at rest tended to breathe more rapidly and more shallowly than dogs exposed to purified air. Rapid-shallow breathing was not observed when the dogs were exposed during exercise to 5 ppm nitrogen dioxide. Dogs exposed to a mixture of 10 ppm formaldehyde and 1 mg/m 3 ammonium nitrate particles during exercise showed a shift to larger tidal volume breathing. The total respiratory system uptake of formaldehyde in the mixture was larger than that measured for 10 ppm of formaldehyde alone in another exercise and exposure study. In tracheostomized dogs exposed at rest, formaldehyde was rapidly removed from inspired air by the upper airways and penetrated to the trachea, whether breathing was by nose or mouth. Nitrogen dioxide penetrated the upper airways more readily. For both gases, penetration was greater during mouth breathing than during nose breathing, and penetration increased with increased ventilation.

  1. Pharmacokinetics and pharmacodynamics of high doses of pharmaceutically prepared heroin, by intravenous or by inhalation route in opioid-dependent patients

    NARCIS (Netherlands)

    E.J. Rook; J.M. van Ree; W. van den Brink; M.J.X. Hillebrand; A.D.R. Huitema; V.M. Hendriks; J.H. Beijnen


    A pharmacokinetic-pharmacodynamic study was performed in opioid-dependent patients in the Netherlands, who were currently treated with high doses of pharmaceutically prepared heroin on medical prescription. Besides intravenous heroin, heroin was prescribed for inhalation by "chasing the dragon" meth

  2. Benefits of high altitude allergen avoidance in atopic adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids

    NARCIS (Netherlands)

    Grootendorst, DC; Dahlen, SE; Van den Bos, JW; Duiverman, EJ; Veselic-Charvat, M; Vrijlandt, EJLE; O'Sullivan, S; Kumlin, M; Sterk, PJ; Roldaan, AC


    Background Some patients with severe asthma cannot be controlled with high doses of inhaled steroids (ICS), which may be related to ongoing environmental allergen exposure. Objective We investigated whether 10 weeks of high altitude allergen avoidance leads to sustained benefits regarding clinical a

  3. Lack of long-term effects of high-dose inhaled beclomethasone for respiratory syncytial virus bronchiolitis: a randomized placebo-controlled trial

    NARCIS (Netherlands)

    Zomer-Kooijker, K.; Ent, C.K. van der; Ermers, M.J.; Rovers, M.M.; Bont, L.J.


    BACKGROUND: Previously, we showed that high-dose early initiated inhaled corticosteroids during respiratory syncytial virus bronchiolitis partially and transiently prevents subsequent recurrent wheeze. Here, we study treatment effect on lung function at age 6. METHODS: This is a 6-year follow-up

  4. A 13-week dermal repeat-dose neurotoxicity study of hydrodesulfurized kerosene in rats. (United States)

    Breglia, Rudolph; Bui, Quang; Burnett, Donald; Koschier, Francis; Lapadula, Elizabeth; Podhasky, Paula; Schreiner, Ceinwen; White, Russell


    A 13-week dermal repeat-dose toxicity study was conducted with hydrodesulfurized (HDS) kerosene, a test material that also met the commercial specifications for aviation turbine fuel (jet A). The objectives were to assess the potential for target organ toxicity and neurotoxicity. The HDS kerosene was applied to the shaved backs of Sprague-Dawley CD rats, 12/sex/group, 6 h/d, 5 d/wk in doses of 0 (vehicle control), 165 mg/kg (20% HDS kerosene), 330 mg/kg (40% HDS kerosene), or 495 mg/kg (60% HDS kerosene). Additional rats (12/sex) from the control and the high-dose groups were held without treatment for 4 weeks to assess recovery. Standard parameters of toxicity were investigated during the in-life phase. At necropsy, organs were weighed and selected tissues were processed for microscopic evaluation. Neurobehavioral evaluations included tests of motor activity and functional observations that were conducted pretest, at intervals during the exposure period and after recovery. No test substance-related effects on mortality, clinical observations (except dermal irritation), body weight, or clinical chemistry values were observed. A dose-related increase in skin irritation, confirmed histologically as minimal, was evident at the dosing site. The only statistically significant change considered potentially treatment related was an increase in the neutrophil count in females at 13 weeks. No test article-related effects were observed in the neurobehavioral assessments or gross or microscopic findings in the peripheral or central nervous system tissues in any of the dose groups. Excluding skin irritation, the no observed adverse effect level value for all effects was considered 495 mg/kg/d.

  5. Investigation of the toxicity of some organophosphorus pesticides in a repeated dose study in rats. (United States)

    Baconi, Daniela Luiza; Bârcă, Maria; Manda, Gina; Ciobanu, Anne Marie; Bălălău, C


    The study aimed to the investigation of the toxicity of organophosphorus pesticides malathion (MLT) and diazinon (DZN) in Wistar rats in a repeated dose study for 35 days. MLT and DZN in corn oil vehicle were oral administered. Body and organs weights, plasma and brain cholinesterase activities, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, histopathological changes in liver and kidney, and some parameters of the immune function, such as leukocyte formula, spleen weight and cellularity, spleen lymphocytes proliferation in response to concanavalin A (Con A) were investigated; the potential oxidative stress (malondialdehyde in plasma and brain, and blood catalase activity) was also evaluated. No clinical toxicity signs attributed to pesticides were noted; no significant changes in the organ weights have been found. Body weight tends slightly to increase, predominantly in DZN treated rats. The results suggest that plasma cholinesterase is more susceptible than brain cholinesterase to the inhibitory effect of DZN and MLT. Other serum biochemical parameters showed no significant difference. DZN produced a marked increase of the number of spleen lymphocytes without a significant gain of the relative spleen weight. The both pesticides produced an increase of the number of mononuclear cells÷weight spleen. The splenic lymphocyte proliferation has not been influenced by MLT or DZN treatment. Histopathological observations identified some changes (vasodilatation, microvacuoles, and granular dystrophy) in the liver, with MLT, inducing macrovacuolar steatosis. The study indicates that repeated exposure, at subclinical doses, to organophosphorus MLT and DZN causes some biochemical, histopathological and immune alterations in rats.

  6. The role of exposure history on HIV acquisition: insights from repeated low-dose challenge studies.

    Directory of Open Access Journals (Sweden)

    Roland R Regoes

    Full Text Available To assess the efficacy of HIV vaccine candidates or preventive treatment, many research groups have started to challenge monkeys repeatedly with low doses of the virus. Such challenge data provide a unique opportunity to assess the importance of exposure history for the acquisition of the infection. I developed stochastic models to analyze previously published challenge data. In the mathematical models, I allowed for variation of the animals' susceptibility to infection across challenge repeats, or across animals. In none of the studies I analyzed, I found evidence for an immunizing effect of non-infecting challenges, and in most studies, there is no evidence for variation in the susceptibilities to the challenges across animals. A notable exception was a challenge experiment by Letvin et al. Sci Translat Med (2011 conducted with the strain SIVsmE660. The challenge data of this experiment showed significant susceptibility variation from animal-to-animal, which is consistent with previously established genetic differences between the involved animals. For the studies which did not show significant immunizing effects and susceptibility differences, I conducted a power analysis and could thus exclude a very strong immunization effect for some of the studies. These findings validate the assumption that non-infecting challenges do not immunize an animal - an assumption that is central in the argument that repeated low-dose challenge experiments increase the statistical power of preclinical HIV vaccine trials. They are also relevant for our understanding of the role of exposure history for HIV acquisition and forecasting the epidemiological spread of HIV.

  7. Estimates of inhalation doses resulting from the possible use of phospho-gypsum plaster-board in Australian homes. (United States)

    O'Brien, R S; Peggie, J R; Leith, I S


    Current materials used as internal lining in Australian buildings are based on natural gypsum of low radium content. A study was carried out to estimate the contribution to the annual effective dose due to airborne contamination from chemical by-product gypsum plaster-board of higher radium content if it were used as an internal lining. The 226Ra content and 222Rn exhalation rate were measured for several samples of the plaster-board, and the behavior of 222Rn and its progeny (218Po, 214Pb, 214Bi, and 214Po) in a typical building was modeled numerically, using the results of the exhalation rate measurements as input. For building ventilation rates greater than approximately 0.5 air changes per hour, the contribution to the total annual effective dose from inhalation of 222Rn and its progeny exhaled from the phospho-gypsum plaster-board is estimated to be below 1 mSv. This contribution is reduced if the surface of the plaster-board is coated with paint or cardboard, or if the very fine particles are removed from the phospho-gypsum during manufacture of the plaster-board. The effective doses arising from dust generation during the installation of the plaster-board are also estimated to be below 1 mSv. The recommended action level of 200 Bq m-3 for radon in air in Australia corresponds to an annual effective dose of approximately 6 mSv. The study indicates that the suggested acceptable level of 185 Bq kg-1 for the 226Ra concentration in the plaster-board may be too restrictive under Australian conditions.

  8. An evaluation of impact of educational interventions on the technique of use of metered-dose inhaler by patients. (United States)

    Purohit, Avadhi Nirajkumar; Patel, P P; Gandhi, A M; Desai, M K


    The objective of this study is to evaluate the impact of two educational interventions that are demonstration versus pictorial Leaflet in patients using metered-dose inhaler (MDI). This interventional study was done in patients who were prescribed drugs through MDI at Tuberculosis and Chest Department. The patients were enrolled in Group A or Group B as per random number table method. The method of use of MDI was assessed using a checklist based on the technique described in the WHO Guide to good prescribing. Patients in Group A were taught the use of MDI by demonstration of the technique by the investigator. Patients in Group B were educated about the technique by a pictorial leaflet based on the technique. Patients were followed up after 15 days and assessed for correct technique for use of the MDI. A total 100 patients were included in the study and were allotted to Group A (47) and Group B (53). Ninety-five percent of the patients had been taught by the treating physician about the method of use of MDI. All the patients at the baseline placed the lips tightly around the mouthpiece and held the aerosol as indicated in the manufacturer's instructions while the step least followed was coughing up the sputum before inhalation. The average steps correctly followed by the patients in Group A and B at baseline were 5.17 ± 2.07 and 5.11 ± 2.04, respectively. These improved significantly to 9.19 ± 0.67 and 6.67 ± 0.63 in Group A and B, respectively, postintervention. The five essential steps of using MDI were followed by 25.53% and 26.41% patients preintervention. An improvement in the technique of use of MDI was observed in 85.11% and 49.06% patients (P = 0.003) postintervention. All the ten steps of the technique were followed by 34.04% patients from Group A and none from Group B at postintervention evaluation (P = 0.0001). The inhalation technique for the use of MDI used by the patients is inappropriate. Educational interventions such as demonstration or

  9. Indoor inhalation dose estimates due to radon and thoron in some areas of South-Western Punjab, India. (United States)

    Kumar, Sanjeev; Singh, Surinder; Bajwa, Bikramjit Singh; Singh, Bhupinder; Sabharwal, Arvind D; Eappen, K P


    LR-115 (type II)-based radon-thoron discriminating twin-chamber dosemeters have been used for estimating radon ((222)Rn) and thoron ((220)Rn) concentrations in dwellings of south-western Punjab, India. The present study region has shown pronounced cases of cancer incidents in the public [Thakur, Rao, Rajwanshi, Parwana and Kumar (Epidemiological study of high cancer among rural agricultural community of Punjab in Northern India. Int J Environ Res Public Health 2008; 5(5):399-407) and Kumar et al. (Risk assessment for natural uranium in subsurface water of Punjab state, India. Hum Ecol Risk Assess 2011;17:381-93)]. Radon being a carcinogen has been monitored in some dwellings selected randomly in the study area. Results show that the values of radon ((222)Rn)  varied from 21 to 79 Bq m(-3), with a geometric mean of 45 Bq m(-3) [geometric standard deviation (GSD 1.39)], and those of thoron ((220)Rn)  from minimum detection level to 58 Bq m(-3) with a geometric mean of 19 Bq m(-3) (GSD 1.88). Bare card data are used for computing the progeny concentration by deriving the equilibrium factor (F) using a root finding method [Mayya, Eappen and Nambi (Methodology for mixed field inhalation dosimetry in monazite areas using a twin-cup dosemeter with three track detectors. Radiat Prot Dosim 1998;77(3):177-84)]. Inhalation doses have been calculated and compared using UNSCEAR equilibrium factors and by using the calculated F-values. The results show satisfactory comparison between the values.

  10. Performance properties of the population bioequivalence approach for in vitro delivered dose for orally inhaled respiratory products. (United States)

    Morgan, Beth; Strickland, Helen


    Regulatory agencies, industry, and academia have acknowledged that in vitro assessments serve a role in establishing bioequivalence for second-entry drug product approvals as well as innovator post-approval drug product changes. For orally inhaled respiratory products (OIPs), the issues of correctly analyzing in vitro data and interpreting the results within the broader context of therapeutic equivalence have garnered significant attention. One of the recommended statistical tests for in vitro data is the population bioequivalence method (PBE). The current literature for assessing the PBE statistical approach for in vitro data assumes a log normal distribution. This paper focuses on an assessment of that assumption for in vitro delivered dose. Concepts in development of a statistical model are presented. The PBE criterion and hypotheses are written for the case when data follows a normal distribution, rather than log normal. Results of a simulation study are reported, characterizing the performance of the PBE approach when data are expected to be normally distributed, rather than log normal. In these cases, decisions using the PBE approach are not consistent for the same absolute mean difference that the test product is from the reference product. A conclusion of inequivalency will occur more often if the test product dose is lower than the reference product for the same deviation from target. These features suggest that more research is needed for statistical equivalency approaches for in vitro data.

  11. Personal exposure to grass pollen: relating inhaled dose to background concentration

    DEFF Research Database (Denmark)

    Peel, Robert George; Hertel, Ole; Smith, Matt


    lasted for approximately 25 to 30 minutes and was performed at 2-hour intervals from noon to midevening under moderate exercise by 2 individuals. Results: A median ratio of dose rate to background concentration of 0.018 was recorded, with higher ratio values frequently occurring at 12 to 2 PM, the time...

  12. Uncertainty of inhalation dose coefficients for representative physical and chemical forms of iodine-131 (United States)

    Harvey, Richard Paul, III

    Releases of radioactive material have occurred at various Department of Energy (DOE) weapons facilities and facilities associated with the nuclear fuel cycle in the generation of electricity. Many different radionuclides have been released to the environment with resulting exposure of the population to these various sources of radioactivity. Radioiodine has been released from a number of these facilities and is a potential public health concern due to its physical and biological characteristics. Iodine exists as various isotopes, but our focus is on 131I due to its relatively long half-life, its prevalence in atmospheric releases and its contribution to offsite dose. The assumption of physical and chemical form is speculated to have a profound impact on the deposition of radioactive material within the respiratory tract. In the case of iodine, it has been shown that more than one type of physical and chemical form may be released to, or exist in, the environment; iodine can exist as a particle or as a gas. The gaseous species can be further segregated based on chemical form: elemental, inorganic, and organic iodides. Chemical compounds in each class are assumed to behave similarly with respect to biochemistry. Studies at Oak Ridge National Laboratories have demonstrated that 131I is released as a particulate, as well as in elemental, inorganic and organic chemical form. The internal dose estimate from 131I may be very different depending on the effect that chemical form has on fractional deposition, gas uptake, and clearance in the respiratory tract. There are many sources of uncertainty in the estimation of environmental dose including source term, airborne transport of radionuclides, and internal dosimetry. Knowledge of uncertainty in internal dosimetry is essential for estimating dose to members of the public and for determining total uncertainty in dose estimation. Important calculational steps in any lung model is regional estimation of deposition fractions

  13. Study of four week repeated dose toxic test of Sweet Bee Venom in Beagle Dogs

    Directory of Open Access Journals (Sweden)

    Jae-Seuk Park


    Full Text Available Objectives: This study was performed to analyse four week repeated dose toxicity of Sweet Bee Venom(Sweet BV extracted from the bee venom in Beagle dogs. Methods: All experiments were conducted under the regulations of Good Laboratory Practice (GLP at Biotoxtech Company, a non-clinical study authorized institution. Male and female Beagle dogs of 5-6 months old were chosen for the pilot study of four week repeated dose toxicity of Sweet BV which was administered at the level of 0.56㎎/㎏ body weight which is eighty times higher than the clinical application dosage as the high dosage, followed by 0.28 and 0.14㎎/㎏ as midium and low dosage, respectively. Equal amount of excipient(normal saline to the Sweet BV experiment groups was administered as the control group every day for four weeks. Results: 1. No mortality was witnessed in all of the experiment groups. 2. All experiment groups were appealed pain sense in the treating time compared to the control group, and hyperemia and movement disorder were observed around the area of administration in all experiment groups, and higher occurrence in the higher dosage treatment. 3. For weight measurement, Neither male nor female groups showed significant changes. 4. In the urine analysis, CBC and biochemistry didn't show any significant changes in the experiment groups compared with control group. 5. For weight measurement of organs, experiment groups didn't show any significant changes compared with control group. 6. To verify abnormalities of organs and tissues, thigh muscle which treated with Sweet BV, cerebrum, liver, lung, kidney, and spinal cords were removed and conducted histologocal observation with H-E staining. In the histologocal observation of thigh muscle, cell infiltration, inflammatory, degeneration, necrosis of muscle fiber, and fibrosis were found in both thigh tissue. And the changes were depend on the dose of Sweet BV. But another organs were not detected in any abnormalities. 7

  14. Evaluation of inhaled and cutaneous doses of imidacloprid during stapling ornamental plants in tunnels or greenhouses. (United States)

    Aprea, Cristina; Lunghini, Liana; Banchi, Bruno; Peruzzi, Antonio; Centi, Letizia; Coppi, Luana; Bogi, Mirella; Marianelli, Enrico; Fantacci, Mariella; Catalano, Pietro; Benvenuti, Alessandra; Miligi, Lucia; Sciarra, Gianfranco


    The aim of this research was to assess dermal and respiratory exposure of workers to imidacloprid during manual operations with ornamental plants previously treated in greenhouses or tunnels. A total of 10 female workers, 5 in greenhouses and 5 in tunnels, were monitored for 3 or 5 consecutive days. Actual skin contamination, excluding hands, was evaluated using nine filter paper pads placed directly on the skin. To evaluate the efficacy of protective clothing in reducing occupational exposure we also placed four pads on top of the outer clothing. Hand contamination was evaluated by washing with 95% ethanol. Respiratory exposure was evaluated by personal air sampling. Respiratory dose was calculated on the basis of a lung ventilation of 15 l/min. Absorbed doses were calculated assuming a skin penetration of 10% and a respiratory retention of 100%. Dislodgeable foliar residues (DFRs) were determined during the days of re-entry in order to determine the dermal transfer factor. From the dependence of dermal exposure of hands from DFRs, a mean transfer factor was estimated to be 36.4 cm(2)/h. Imidacloprid was determined by liquid chromatography with selective mass detection and electrospray interface in all matrices analysed. Respiratory dose was 4.1+/-4.0 (0.1-14.3)% and 3.0+/-2.0 (0.6-6.9)% (mean+/-SD (range)) of the total real dose during work in tunnels and greenhouses, respectively. The estimated absorbed doses, 0.29+/-0.45 microg/kg (0.06-2.25 microg/kg) body weight and 0.32+/-0.18 microg/kg (0.07-0.66 microg/kg) body weight (mean+/-SD (range)) in tunnels and in greenhouses, respectively, were less than the acceptable operator exposure level of 0.15 mg/kg body weight and than the acceptable daily intake of 0.05 mg/kg body weight. The hands and exposed skin of all workers were found to be contaminated, indicating that greater precautions, such as daily changing of gloves and clothing, are necessary to reduce skin exposure.

  15. Historical cohort study examining comparative effectiveness of albuterol inhalers with and without integrated dose counter for patients with asthma or chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Price DB


    Full Text Available David B Price,1,2 Anna Rigazio,2 Mary Buatti Small,3 Thomas J Ferro,3 1Academic Primary Care, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 2Research in Real-Life Ltd, Cambridge, UK; 3Teva Pharmaceuticals, Frazer, PA, USA Background: Using a metered-dose inhaler (MDI beyond the labeled number of actuations may result in inadequate dosing of medication, which can lead to poor clinical outcomes. This study compared respiratory-related emergency department (ED visit rates in patients with asthma, chronic obstructive pulmonary disease, or both when they used albuterol MDIs with versus without dose counters. Methods: This retrospective study used US claims data to identify patients (ages 4–64 years with asthma, chronic obstructive pulmonary disease, or both, using albuterol MDIs with or without an integrated dose counter. The study comprised a 1-year baseline period for patient characterization and confounder definition and a 1-year outcome period following the first albuterol prescription. The primary end point was the incidence rate of respiratory-related ED visits, compared using a reduced zero-inflated Poisson regression model. We also compared severe exacerbation rates and rescue medication use. Results: A total of 93,980 patients were studied, including 67,251 (72% in the dose counter cohort and 26,729 (28% in the non-dose-counter cohort. The cohorts were broadly similar at baseline (55,069 [59%] female patients; median age, 37 years. The incidence rate of respiratory-related ED visits during the outcome year was 45% lower in the dose counter cohort than in the non-dose-counter cohort (adjusted rate ratio: 0.55; 95% confidence interval: 0.47–0.64. Exacerbation rates and short-acting β-agonist use were similar between cohorts. Conclusion: These findings suggest that dose counter integration into albuterol MDIs is associated with decreased ED visit rates. The presence of integrated dose counters on rescue

  16. Inhaled Corticosteroids

    Directory of Open Access Journals (Sweden)

    Peter J. Barnes


    Full Text Available Inhaled corticosteroids (ICS are the most effective controllers of asthma. They suppress inflammation mainly by switching off multiple activated inflammatory genes through reversing histone acetylation via the recruitment of histone deacetylase 2 (HDAC2. Through suppression of airway inflammation ICS reduce airway hyperresponsiveness and control asthma symptoms. ICS are now first-line therapy for all patients with persistent asthma, controlling asthma symptoms and preventing exacerbations. Inhaled long-acting β2-agonists added to ICS further improve asthma control and are commonly given as combination inhalers, which improve compliance and control asthma at lower doses of corticosteroids. By contrast, ICS provide much less clinical benefit in COPD and the inflammation is resistant to the action of corticosteroids. This appears to be due to a reduction in HDAC2 activity and expression as a result of oxidative stress. ICS are added to bronchodilators in patients with severe COPD to reduce exacerbations. ICS, which are absorbed from the lungs into the systemic circulation, have negligible systemic side effects at the doses most patients require, although the high doses used in COPD has some systemic side effects and increases the risk of developing pneumonia.

  17. Effect of Repeat Dosing of Engineered Oncolytic Herpes Simplex Virus on Preclinical Models of Rhabdomyosarcoma

    Directory of Open Access Journals (Sweden)

    Alicia M. Waters


    Full Text Available Rhabdomyosarcoma (RMS, a tumor of skeletal muscle origin, is the most common sarcoma of childhood. Despite multidrug chemotherapy regimens, surgical intervention, and radiation treatment, outcomes remain poor, especially in advanced disease, and novel therapies are needed for the treatment of these aggressive malignancies. Genetically engineered oncolytic viruses, such as herpes simplex virus-1 (HSV, are currently being explored as treatments for pediatric tumors. M002, an oncolytic HSV, has both copies of the γ134.5 gene deleted, enabling replication in tumor cells but thwarting infection of normal, postmitotic cells. We hypothesized that M002 would infect human RMS tumor cells and lead to decreased tumor cell survival in vitro and impede tumor growth in vivo. In the current study, we demonstrated that M002 could infect, replicate in, and decrease cell survival in both embryonal (ERMS and alveolar rhabdomyosarcoma (ARMS cells. Additionally, M002 reduced xenograft tumor growth and increased animal survival in both ARMS and ERMS. Most importantly, we showed for the first time that repeated dosing of oncolytic virus coupled with low-dose radiation provided improved tumor response in RMS. These findings provide support for the clinical investigation of oncolytic HSV in pediatric RMS.

  18. Repeated dose (14 days) rat intramuscular toxicology study of Her1 vaccine. (United States)

    Mancebo, A; Casacó, A; Sánchez, B; González, B; Gómez, D; León, A; Bada, A M; Arteaga, M E; González, Y; González, C; Pupo, M; Fuentes, Dasha


    Our goal was to assess the toxicity of two strengths (200 and 400 μg) of HER1 cancer vaccine (Center of Molecular Immunology, Cuba), presented in two different formulations, in Sprague Dawley rats after repeated intramuscular administration (14 days). Four groups (5 animals/sex) were established: Control, Placebo (adjuvant), and two Treated groups receiving a dose representing ten times of human total dose (10×), 28.6 and 57.1 μg/kg. Clinical observations, body weight and rectal temperature were measured during the study. Clinical pathology analysis was performed, besides gross necropsy and histological examination of tissues on animals at the end of the assay. The assay ended with a 100% survival. Injection site damage, with the presence of cysts and granulomas, was observed in adjuvant and vaccine treated groups, with most severe cases predominating at higher strength. Administration of Placebo and Her1 vaccine induced increase in polymorphonuclear cells, with relative lymphopenia conditioned by primary neutrophilia. In summary, results suggest that Her1 immunization was capable of inducing an inflammatory effect at the injection site, leading to systemic alterations, more significant at higher strength (400 μg, 57.1 μg/kg), probably affected by the immunizations' schedule used. The vaccine was shown to be well tolerated without any obvious signs of systemic toxicity, with findings largely attributable to the adjuvant used.

  19. Repeated inhalation exposure to octamethylcyclotetrasiloxane produces hepatomegaly, transient hepatic hyperplasia, and sustained hypertrophy in female Fischer 344 rats in a manner similar to phenobarbital. (United States)

    McKim, J M; Kolesar, G B; Jean, P A; Meeker, L S; Wilga, P C; Schoonhoven, R; Swenberg, J A; Goodman, J I; Gallavan, R H; Meeks, R G


    Octamethylcyclotetrasiloxane (D4) has been described as a phenobarbital-like inducer of hepatic enzymes. Phenobarbital (PB) and phenobarbital-like chemicals induce transient hepatic and thyroid hyperplasia and sustained hypertrophy in rats and mice. The extent to which these processes are involved with D4-induced hepatomegaly is not known. The present study has evaluated the effects of repeated inhalation exposure to D4 vapors on hepatic and thyroid cell proliferation and hypertrophy with respect to time and exposure concentration. Female Fischer 344 rats were exposed via whole body inhalation to 0 ppm D4, 700 ppm D4 vapors (6 h/day; 5 days/week), or 0.05% PB in drinking water over a 4-week period. Incorporation of 5'-bromo-2-deoxyuridine (BrdU) and the abundance of proliferating cell nuclear antigen were used as indicators of cell proliferation. Designated animals from each treatment group were euthanized on study days 6, 13, and 27. The effect of D4 exposure concentration on hepatic cell proliferation was evaluated at 0, 7, 30, 70, 150, 300, or 700 ppm. Liver-to-body weight ratios in animals exposed to 700 ppm D4 were increased 18, 20, and 22% over controls while PB-treated animals showed increases of 33, 27, and 27% over controls on days 6, 13, and 27 respectively. Hepatic incorporation of BrdU following exposure to D4 was highest on day 6 (labeling index = 15-22%) and was at or below control values by day 27. This pattern of transient hyperplasia was observed in all hepatic lobes examined and was similar to the pattern observed following treatment with PB.

  20. The effect of actuator nozzle designs on the electrostatic charge generated in pressurised metered dose inhaler aerosols. (United States)

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


    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.

  1. Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs. (United States)

    Smith, C D; Lee, R B; Moran, A V; Sipos, M L


    Chemical warfare nerve agents (CWNAs) are known to cause behavioral abnormalities in cases of human exposures and in animal models. The behavioral consequences of single exposures to CWNAs that cause observable toxic signs are particularly well characterized in animals; however, less is known regarding repeated smaller exposures that may or may not cause observable toxic signs. In the current study, guinea pigs were exposed to fractions (0.1, 0.2, or 0.4) of a medial lethal dose (LD50) of sarin, soman, or VX for two weeks. On each exposure day, and for a post-exposure period, acoustic startle response (ASR) was measured in each animal. Although relatively few studies use guinea pigs to measure behavior, this species is ideal for CWNA-related experiments because their levels of carboxylesterases closely mimic those of humans, unlike rats or mice. Results showed that the 0.4 LD50 doses of soman and VX transiently increased peak startle amplitude by the second week of injections, with amplitude returning to baseline by the second week post-exposure. Sarin also increased peak startle amplitude independent of week. Latencies to peak startle and PPI were affected by agent exposure but not consistently among the three agents. Most of the changes in startle responses returned to baseline following the cessation of exposures. These data suggest that doses of CWNAs not known to produce observable toxic signs in guinea pigs can affect behavior in the ASR paradigm. Further, these deficits are transient and usually return to baseline shortly after the end of a two-week exposure period.

  2. Inhibitory effect of single and repeated doses of nilotinib on the pharmacokinetics of CYP3A substrate midazolam. (United States)

    Zhang, Hefei; Sheng, Jennifer; Ko, Jin H; Zheng, Cheng; Zhou, Wei; Priess, Petra; Lin, Wen; Novick, Steven


    Effects of single and repeated doses of nilotinib on the pharmacokinetics of midazolam, a cytochrome P450 3A (CYP3A) substrate, were assessed in 2 separate studies. In the single-dose nilotinib study, 18 healthy subjects were randomized to 6 treatment sequences to receive single dose of nilotinib 600 mg, midazolam 4 mg, and coadministration of both in a crossover manner. In the repeated-dose nilotinib study, 19 chronic myeloid leukemia patients took a single dose of midazolam 2 mg on days 1 and 13, and nilotinib 400 mg twice daily from days 2-13. In the single-dose study, the geometric mean ratio of the area under the plasma concentration time curve extrapolated to infinity (AUC(inf)) of midazolam plus nilotinib vs. midazolam was 1.3 (90%CI, 1.2-1.5) and the maximum observed serum concentration (C(max)) was 1.2 (90%CI, 1.0-1.4). In the repeated-dose study, the values for AUC(inf) and C(max) were 2.6 (90%CI, 2.1-3.3) and 2.0 (90%CI, 1.7-2.4), respectively. These results indicate that single-dose and repeated-dose administration of nilotinib results in weak and moderate inhibition of CYP3A, respectively. Therefore, appropriate monitoring and dose adjustment may be needed for drugs that are mainly metabolized by CYP3A, and have narrow therapeutic index, when coadministered with nilotinib.

  3. Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration. (United States)

    Kenward, Hannah; Pelligand, Ludovic; Elliott, Jonathan


    Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.

  4. Real-world healthcare utilization in asthma patients using albuterol sulfate inhalation aerosol (ProAir® HFA with and without integrated dose counters

    Directory of Open Access Journals (Sweden)

    Kerwin EM


    Full Text Available Edward M Kerwin,1 Thomas J Ferro,2 Rinat Ariely,3 Debra E Irwin,4 Ruchir Parikh3 1Clinical Trials Division, Clinical Research Institute of Southern Oregon, PC, Medford, OR, 2Global Medical Affairs, 3Global Health Economics and Outcome Research, Teva Pharmaceuticals, Frazer, PA, 4Outcomes Research, Truven Health Analytics, Durham, NC, USA Background: Accurate tracking of the administered dose of asthma rescue inhalers is critical for optimal disease management and is related to reductions in rates of unscheduled health care utilization in asthma patients. There are few published data on the real-world impact of rescue inhalers with integrated dose counters (IDCs on health care resource utilization (HRU for asthma patients. This study evaluates HRU among users of ProAir® hydrofluoroalkane (HFA (albuterol sulfate inhalation aerosol, with IDC versus without IDC, in asthma patients.Methods: This was a retrospective administrative claims study of asthma patients receiving a new prescription for albuterol inhalation aerosol without IDC during 2 years (January 2011–December 2012 or with IDC during the first full year after IDC implementation in the USA (July 2013–July 2014. Six months of continuous enrollment with medical and prescription drug benefits were required before and after the first prescription during the study period. Data on respiratory-related hospitalizations and emergency department (ED visits were collected during the follow-up period.Results: A total of 135,305 (32% patients used albuterol inhalation aerosol with IDC, and 287,243 (68% patients received albuterol inhalation aerosol without IDC. After adjusting for baseline confounding factors, the odds ratio (OR for experiencing a respiratory-related hospitalization (OR=0.92; 95% confidence interval [CI] 0.88–0.96 or ED visit (OR=0.92; 95% CI 0.90–0.94 was significantly lower among patients using albuterol inhalation aerosol with IDC versus without IDC.Conclusion: In a real

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

    Energy Technology Data Exchange (ETDEWEB)

    Rogers, J.M.; Mole, M.L.; Chernoff, N.; Barbee, B.D.; Turner, C.I.


    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 10,000 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.)

  6. Repeated inhalation exposure of rats to an anionic high molecular weight polymer aerosol: application of prediction models to better understand pulmonary effects and modes of action. (United States)

    Pauluhn, Jürgen


    Opposed to the wealth of information available for kinetic lung overload-related effects of poorly-soluble, low-toxicity particles (PSP), only limited information is available on biodegradable high molecular weight (HMW) organic polymers (molecular weight >20,000 Da). It is hypothesized that such types of polymers may exert a somewhat similar volume displacement-related mode of action in alveolar macrophages as PSP; however, with a differing biokinetics of the material retained in the lung. This polyurethane polymer was examined in single and 2-/13-week repeated exposure rat inhalation bioassays. The design of studies was adapted to that commonly applied for PSP. Rats were nose-only exposed for 6h/day for the respective study duration, followed by 1-, 2- and 4-week postexposure periods in the single, 2- and 13-week studies, respectively. While the findings in bronchoalveolar lavage (BAL) and histopathology were consistent with those typical of PSP, they appear to be superimposed by pulmonary phospholipidosis and a much faster reversibility of pulmonary inflammation. Kinetic modeling designed to estimate the accumulated lung burden of biopersistent PSP was also suitable to simulate the overload-dependent outcomes of this biodegradable polymer as long as the faster than normal elimination kinetics was observed and an additional 'void space volume' was added to adjust for the phagocytosed additional fraction of pulmonary phospholipids. The changes observed following repeated inhalation exposure appear to be consistent with a retention-related etiopathology (kinetic overload). In summary, this study did not reveal evidence of any polymer-specific pulmonary irritation or parenchymal injury. Taking all findings into account, 7 mg polymer/m(3) (exposure 6h/day, 5-days/week on 13 consecutive weeks) constitutes the point of departure for lower respiratory tract findings that represent a transitional state from effects attributable to an overload-dependent pulmonary

  7. Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro. (United States)

    Maschmeyer, Ilka; Hasenberg, Tobias; Jaenicke, Annika; Lindner, Marcus; Lorenz, Alexandra Katharina; Zech, Julie; Garbe, Leif-Alexander; Sonntag, Frank; Hayden, Patrick; Ayehunie, Seyoum; Lauster, Roland; Marx, Uwe; Materne, Eva-Maria


    Systemic repeated dose safety assessment and systemic efficacy evaluation of substances are currently carried out on laboratory animals and in humans due to the lack of predictive alternatives. Relevant international regulations, such as OECD and ICH guidelines, demand long-term testing and oral, dermal, inhalation, and systemic exposure routes for such evaluations. So-called "human-on-a-chip" concepts are aiming to replace respective animals and humans in substance evaluation with miniaturized functional human organisms. The major technical hurdle toward success in this field is the life-like combination of human barrier organ models, such as intestine, lung or skin, with parenchymal organ equivalents, such as liver, at the smallest biologically acceptable scale. Here, we report on a reproducible homeostatic long-term co-culture of human liver equivalents with either a reconstructed human intestinal barrier model or a human skin biopsy applying a microphysiological system. We used a multi-organ chip (MOC) platform, which provides pulsatile fluid flow within physiological ranges at low media-to-tissue ratios. The MOC supports submerse cultivation of an intact intestinal barrier model and an air-liquid interface for the skin model during their co-culture with the liver equivalents respectively at (1)/100.000 the scale of their human counterparts in vivo. To increase the degree of organismal emulation, microfluidic channels of the liver-skin co-culture could be successfully covered with human endothelial cells, thus mimicking human vasculature, for the first time. Finally, exposure routes emulating oral and systemic administration in humans have been qualified by applying a repeated dose administration of a model substance - troglitazone - to the chip-based co-cultures.

  8. Safety of Repeated-Dose Intratympanic Injections with AM-101 in Acute Inner Ear Tinnitus. (United States)

    Staecker, Hinrich; Morelock, Michael; Kramer, Timothy; Chrbolka, Pavel; Ahn, Joong Ho; Meyer, Thomas


    Objective To evaluate the safety and tolerability of repeated intratympanic administration of the gel-formulated NMDA receptor antagonist AM-101 in acute patients with inner ear tinnitus. Study Design Prospective, double-blind, randomized, placebo-controlled study. Setting Sixty-nine secondary and tertiary sites in North America, Europe, and Asia. Subjects and Methods In total, 343 subjects with persistent acute tinnitus after traumatic cochlear injury or otitis media were randomized to receive 3 intratympanic doses of either AM-101 0.87 mg/mL or placebo over 3 to 5 days. They were followed for 84 days. The primary safety end point was the incidence of a clinically meaningful hearing deterioration from baseline to study day 35. Further safety assessments included tympanic membrane closure rates, analysis of adverse events, hematology, blood chemistry, and vital signs. In addition, data were collected on applied anesthetics and injection techniques. Results The treatment was well tolerated, with no intervention-related serious adverse events. The incidence of clinically meaningful hearing deterioration was low, comparable between treatment groups ( P = .82 for the primary safety end point) and not different between treated and untreated ears in unilaterally treated subjects. The rate of treatment and procedure-related adverse events was similar among treatment groups. The tympanic membrane was closed in 92% of subjects within 1 week and in all subjects by study day 84. Blood values and vital signs were inconspicuous. Conclusion Repeated intratympanic injections of AM-101 over a 3- to 5-day period appear to be safe and well tolerated, demonstrating the ability to potentially use this delivery approach over longer time periods.

  9. Strengths and limitations of using repeat-dose toxicity studies to predict effects on fertility. (United States)

    Dent, M P


    The upcoming European chemicals legislation REACH (Registration, Evaluation, and Authorisation of Chemicals) will require the risk assessment of many thousands of chemicals. It is therefore necessary to develop intelligent testing strategies to ensure that chemicals of concern are identified whilst minimising the testing of chemicals using animals. Xenobiotics may perturb the reproductive cycle, and for this reason several reproductive studies are recommended under REACH. One of the endpoints assessed in this battery of tests is mating performance and fertility. Animal tests that address this endpoint use a relatively large number of animals and are also costly in terms of resource, time, and money. If it can be shown that data from non-reproductive studies such as in-vitro or repeat-dose toxicity tests are capable of generating reliable alerts for effects on fertility then some animal testing may be avoided. Available rat sub-chronic and fertility data for 44 chemicals that have been classified by the European Union as toxic to fertility were therefore analysed for concordance of effects. Because it was considered appropriate to read across data for some chemicals these data sets were considered relevant for 73 of the 102 chemicals currently classified as toxic to reproduction (fertility) under this system. For all but 5 of these chemicals it was considered that a well-performed sub-chronic toxicity study would have detected pathology in the male, and in some cases, the female reproductive tract. Three showed evidence of direct interaction with oestrogen or androgen receptors (linuron, nonylphenol, and fenarimol). The remaining chemicals (quinomethionate and azafenidin) act by modes of action that do not require direct interaction with steroid receptors. However, both these materials caused in-utero deaths in pre-natal developmental toxicity studies, and the relatively low NOAELs and the nature of the hazard identified in the sub-chronic tests provides an alert

  10. Anticonvulsant effects of acute treatment with cyane-carvone at repeated oral doses in epilepsy models. (United States)

    Marques, Thiago Henrique Costa; Marques, Maria Leonildes Boavista Gomes Castelo Branco; Medeiros, Jand-Venes Rolim; Lima, Tamires Cardoso; de Sousa, Damião Pergentino; de Freitas, Rivelilson Mendes


    Epilepsy affects about 40 million people worldwide. Many drugs block seizures, but have little effect in preventing or curing this disease. So the search for new drugs for epilepsy treatment using animal models prior to testing in humans is important. Increasingly pharmaceutical industries invest in the Re​search & Drug Development area to seek safe and effective new therapeutic alternatives to the currently available epilepsy treatment. In this perspective, natural compounds have been investigated in epilepsy models, particularly the monoterpenes obtained from medicinal plants. In our study we investigated the effects of cyane-carvone (CC), a synthetic substance prepared from natural a monoterpene, carvone, against pilocarpine- (PILO), pentylenetetrazole- (PTZ) and picrotoxine (PTX)-induced seizures in mice after acute treatment with repeated oral doses (CC 25, 50 and 75 mg/kg) for 14 days. CC in all doses tested showed increase in latency to first seizure, decrease in percentages of seizuring animals as well as reduction percentages of dead animals (pepilepsy models. In addition, our data suggest that CC could act in an allosteric site of GABAA, which would be different from the site in which BDZ acts, since flumazenil was not able to reverse any of CC effects on the modulation of seizure parameters related with epilepsy models investigated. New studies should be conducted to investigate CC effects in other neurotransmitter systems. Nevertheless, our study reinforces the hypothesis that CC could be used, after further research, as a new pharmaceutical formulation and a promising alternative for epilepsy treatment, since it showed anticonvulsant effects. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Dose-ranging study of salmeterol using a novel fluticasone propionate/salmeterol multidose dry powder inhaler in patients with persistent asthma. (United States)

    Miller, David S; Yiu, Gloria; Hellriegel, Edward T; Steinfeld, Jonathan


    New inhalation devices with improved lung delivery may allow the use of lower salmeterol doses for treatment of asthma. To determine the dose of salmeterol administered from a novel fluticasone propionate/salmeterol (FS) inhalation-driven, multidose dry powder inhaler (MDPI), which provides comparable efficacy and safety to FS dry powder inhaler (DPI). This double-blind, six-period crossover, dose-ranging study randomized 72 patients (ages ≥12 years; with persistent asthma and predose maximum forced expiratory volume in 1 second [FEV1] of 40-85% of the predicted normal) to treatment sequences (one dose per treatment), which consisted of FS MDPI 100/6.25, 100/12.5, 100/25, 100/50 μg; fluticasone propionate (Fp) MDPI 100 μg; and open-label FS DPI 100/50 μg. The primary efficacy variable was the baseline-adjusted FEV1 area under the curve over 12 hours after the dose (AUC0-12). Pharmacokinetics and tolerability were also assessed. FEV1 AUC0-12 was significantly higher with all FS MDPI doses and FS DPI versus Fp MDPI (p < 0.0001), and with FS MDPI 100/50 μg versus FS DPI (least squares [LS] mean, 57.88 mL; p = 0.0017). FEV1 AUC0-12 trended toward higher efficacy with FS MDPI 100/25 μg (LS mean, 34.14 mL; p = 0.0624) and was comparable with FS MDPI 100/12.5 μg (LS mean, 3.42 mL; p = 0.8503) versus FS DPI. Salmeterol area under the plasma concentration-versus-time curve from time 0 to the time of the last measurable concentration (AUC0-t) for FS MDPI 100/12.5 μg and 100/25 μg was lower versus FS DPI 100/50 μg; AUC0-t for FS MDPI 100/50 μg was higher than FS DPI 100/50 μg. All FS MDPI doses were generally well tolerated. All FS MDPI doses produced greater efficacy versus Fp MDPI. FS MDPI 100/12.5 μg demonstrated similar efficacy to FS DPI 100/50 μg with less salmeterol exposure. NCT02139644, NCT02175771, and NCT02141854.

  12. Alteration of brain levels of neurotransmitters and amino acids in male F344 rats induced by three-week repeated inhalation exposure to 1-bromopropane. (United States)

    Suda, Megumi; Honma, Takeshi; Miyagawa, Muneyuki; Wang, Rui-Sheng


    The present study investigated the effects of 1-bromopropane (1BP) on brain neuroactive substances of rats to determine the extent of its toxicity to the central nervous system (CNS). We measured the changes in neurotransmitters (acetylcholine, catecholamine, serotonin and amino acids) and their metabolites or precursors in eight brain regions after inhalation exposure to 1BP at 50 to 1,000 ppm for 8 h per day for 7 d per week for 3 wk. Rats were sacrificed at 2 h (Case 1), or at 19 h (Case 2) after the end of exposure. In Case 1, the level of 5-hydroxyindoleacetic acid (5HIAA) was lowered in some brain regions by 1BP exposure. The decrease of 5HIAA in the frontal cortex was statistically significant at 50 ppm 1BP exposure. In Case 2, gamma-amino butyric acid (GABA) and taurine were decreased in many brain regions of exposed rats, and a significant decrease of taurine in the midbrain occurred at 50 ppm 1BP exposure. In both cases of 2-h and 19-h intervals from the end of exposure to sacrifice, aspartate and glutamine levels were elevated in many brain regions, but the acetylcholine level did not change in any brain region. Three-week repeated exposure to 1BP produced significantly changes in amino acid contents of rat brains, particularly at 1,000 ppm.

  13. Mucolytic treatment with N-acetylcysteine L-lysinate metered dose inhaler in dogs: airway epithelial function changes. (United States)

    Tomkiewicz, R P; App, E M; Coffiner, M; Fossion, J; Maes, P; King, M


    N-acetylcysteine L-lysinate Nacystelyn (L-NAC) is a newly synthesized mucolytic agent, of which the action in vivo has not been well defined. In six healthy mongrel dogs, the rheological properties of mucus, its mucociliary and cough clearability, and the transepithelial potential difference (PD) of the tracheobronchial epithelium were evaluated after placebo and L-NAC metered dose inhaler (MDI) aerosols. The principal index of mucus rigidity, log G*, decreased at all airway sites with L-NAC administration, i.e. the mucus became less rigid and more deformable (the overall change in G* was 0.29 log units, i.e. ca. twofold decrease). The viscoelasticity-derived mucus transportability parameters, mucociliary (MCI) and cough (CCI) clearability indices, increased with L-NAC MDI, particularly CCI, which predicts the effect of mucus rheology on cough clearability. PD increased significantly with L-NAC administration at all measurement sites, which appears to be a novel effect for a direct acting mucolytic agent. Tracheal mucus linear velocity (TMV) increased after L-NAC compared with placebo, as did the normalized frog palate transport rate (NFPTR). The increase in NFPTR was greater than that predicted from the mucus rheological properties alone, suggesting that L-NAC still resident in the collected mucus stimulated the frog palate cilia. The index of mucus flux, the collection rate in mg.min-1, was higher with L-NAC compared with placebo. From our results, we conclude that L-NAC shows potential benefit in terms of improving mucus rheological properties and clearability. It may act, in part, by stimulating the fresh secretion of mucus of lower viscoelasticity. The stimulation of mucociliary clearance could be related to ion flux changes, as indicated by the increase in PD.

  14. Comparison of optical particle sizing and cascade impaction for measuring the particle size of a suspension metered dose inhaler. (United States)

    Pu, Yu; Kline, Lukeysha C; Khawaja, Nazia; Van Liew, Melissa; Berry, Julianne


    Optical techniques for the particle size characterization of metered dose inhaler (MDI) suspensions have been developed as an alternative to the labor-intensive and time-consuming impaction method. In this study, a laser diffraction (LD) apparatus with a liquid cell ("wet cell" method) and a "time-of-flight" apparatus named aerodynamic particle sizer (APS) were utilized to assess MDI suspensions with varied formulation compositions and storage conditions. The results were compared with the conventional Anderson cascade impaction (ACI) data. The two optical methods were able to detect the changes in particle size distributions between formulations, yet to a lesser extent than those observed using the cascade impaction methodology. The median aerodynamic particle size measured by the APS method and the median geometric particle size obtained from the LD method were linearly correlated with the corresponding ACI results in the range of 2-5 µm. It was also found that the APS measurement was biased towards the finer particle size region and resulted in overestimated fine particle fraction (FPF) values which were 2-3 times folds of the ACI results. In conclusion, the optical particle sizing techniques may, under some circumstances, be viable techniques for the rapid assessment of MDI suspensions. The "wet cell" LD method, in particular, is found to be a valuable means of detecting active pharmaceutical ingredient (API) particle size changes in an MDI suspension. Using both the LD and the APS methods in early formulation screening followed by a final assessment with cascade impaction analysis can improve the efficiency of MDI formulation development.

  15. In vitro evaluation of the effect of metered-dose inhaler administration technique on aerosolized drug delivery. (United States)

    Shalansky, K F; Htan, E Y; Lyster, D M; Mouat, B; Tweeddale, M G


    The administration of aerosolized metered-dose inhalers (MDIs) to mechanically ventilated patients is labor intensive due to the large number of activations required and the currently recommended 30- to 60-second "wait and shake" between each puff. No studies have been published that assess the relationship between this delay between puffs and drug delivery. To address this issue, we conducted an in vitro, randomized, single-blind study using fenoterol MDI containing technetium-99m pertechnetate. Four modes of MDI administration were tested in triplicate by random sequence. Eight activations of the MDI were performed for each mode according to the following procedures: rapid succession (5 sec apart); 30-second intervals and shaking MDI between two rapid activations; 30-second intervals and shaking between each activation; and 60-second intervals and shaking between each activation. Two closed in vitro systems were designed to collect and measure the radiolabeled aerosol. In the first system, the MDI was activated into a plastic collection container; with the second system, the MDI was administered through an aerosol holding chamber with attached circuit filter positioned on the inspiratory line of the ventilator circuit. Sixty-second intervals between each activation were not tested with the second system. Radioactivity was measured before and after each mode of testing. No difference was found between the various modes of administration other than a 14% decrease in the amount of radioactivity released with the 60-second waiting period between puffs, compared with their rapid succession when using the plastic collection container system. Our results support the hypothesis that the delay after each activation of a MDI may not be necessary.

  16. The influence of actuator materials and nozzle designs on electrostatic charge of pressurised metered dose inhaler (pMDI) formulations. (United States)

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


    To investigate the influence of different actuator materials and nozzle designs on the electrostatic charge properties of a series of solution metered dose inhaler (pMDI) aerosols. Actuators were manufactured with flat and cone nozzle designs using five different materials from the triboelectric series (Nylon, Polyethylene terephthalate, Polyethylene-High density, Polypropylene copolymer and Polytetrafluoroethylene). The electrostatic charge profiles of pMDI containing beclomethasone dipropionate (BDP) as model drug in HFA-134a propellant, with different concentrations of ethanol were studied. Electrostatic measurements were taken using a modified electrical low-pressure impactor (ELPI) and the deposited drug mass assayed chemically using HPLC. The charge profiles of HFA 134a alone have shown strong electronegativity with all actuator materials and nozzle designs, at an average of -1531.34 pC ± 377.34. The presence of co-solvent ethanol significantly reduced the negative charge magnitude. BDP reduced the suppressing effect of ethanol on the negative charging of the propellant. For all tested formulations, the flat nozzle design showed no significant differences in net charge between different actuator materials, whereas the charge profiles of cone designs followed the triboelectric series. The electrostatic charging profiles from a solution pMDI containing BDP and ethanol can be significantly influenced by the actuator material, nozzle design and formulation components. Ethanol concentration appears to have the most significant impact. Furthermore, BDP interactions with ethanol and HFA have an influence on the electrostatic charge of aerosols. By choosing different combinations of actuator materials and orifice design, the fine particle fractions of formulations can be altered.

  17. Know How to Use Your Asthma Inhaler

    Medline Plus

    Full Text Available ... KB] Using a metered dose inhaler one to two inches from mouth Your browser does not support iframes Using a metered dose inhaler one to two inches from mouth [PDF - 356 KB] Your browser ...

  18. Repeatability of dose painting by numbers treatment planning in prostate cancer radiotherapy based on multiparametric magnetic resonance imaging (United States)

    van Schie, Marcel A.; Steenbergen, Peter; Viet Dinh, Cuong; Ghobadi, Ghazaleh; van Houdt, Petra J.; Pos, Floris J.; Heijmink, Stijn W. T. J. P.; van der Poel, Henk G.; Renisch, Steffen; Vik, Torbjørn; van der Heide, Uulke A.


    Dose painting by numbers (DPBN) refers to a voxel-wise prescription of radiation dose modelled from functional image characteristics, in contrast to dose painting by contours which requires delineations to define the target for dose escalation. The direct relation between functional imaging characteristics and DPBN implies that random variations in images may propagate into the dose distribution. The stability of MR-only prostate cancer treatment planning based on DPBN with respect to these variations is as yet unknown. We conducted a test-retest study to investigate the stability of DPBN for prostate cancer in a semi-automated MR-only treatment planning workflow. Twelve patients received a multiparametric MRI on two separate days prior to prostatectomy. The tumor probability (TP) within the prostate was derived from image features with a logistic regression model. Dose mapping functions were applied to acquire a DPBN prescription map that served to generate an intensity modulated radiation therapy (IMRT) treatment plan. Dose calculations were done on a pseudo-CT derived from the MRI. The TP and DPBN map and the IMRT dose distribution were compared between both MRI sessions, using the intraclass correlation coefficient (ICC) to quantify repeatability of the planning pipeline. The quality of each treatment plan was measured with a quality factor (QF). Median ICC values for the TP and DPBN map and the IMRT dose distribution were 0.82, 0.82 and 0.88, respectively, for linear dose mapping and 0.82, 0.84 and 0.94 for square root dose mapping. A median QF of 3.4% was found among all treatment plans. We demonstrated the stability of DPBN radiotherapy treatment planning in prostate cancer, with excellent overall repeatability and acceptable treatment plan quality. Using validated tumor probability modelling and simple dose mapping techniques it was shown that despite day-to-day variations in imaging data still consistent treatment plans were obtained.

  19. Utility of repeated praziquantel dosing in the treatment of schistosomiasis in high-risk communities in Africa: a systematic review.

    Directory of Open Access Journals (Sweden)

    Charles H King


    Full Text Available Controversy persists about the optimal approach to drug-based control of schistosomiasis in high-risk communities. In a systematic review of published studies, we examined evidence for incremental benefits from repeated praziquantel dosing, given 2 to 8 weeks after an initial dose, in Schistosoma-endemic areas of Africa.We performed systematic searches of electronic databases PubMed and EMBASE for relevant data using search terms 'schistosomiasis', 'dosing' and 'praziquantel' and hand searches of personal collections and bibliographies of recovered articles. In 10 reports meeting study criteria, improvements in parasitological treatment outcomes after two doses of praziquantel were greater for S. mansoni infection than for S. haematobium infection. Observed cure rates (positive to negative conversion in egg detection assays were, for S. mansoni, 69-91% cure after two doses vs. 42-79% after one dose and, for S. haematobium, 46-99% cure after two doses vs. 37-93% after a single dose. Treatment benefits in terms of reduction in intensity (mean egg count were also different for the two species-for S. mansoni, the 2-dose regimen yielded an weighted average 89% reduction in standardized egg counts compared to a 83% reduction after one dose; for S. haematobium, two doses gave a 93% reduction compared to a 94% reduction with a single dose. Cost-effectiveness analysis was performed based on Markov life path modeling.Although schedules for repeated treatment with praziquantel require greater inputs in terms of direct costs and community participation, there are incremental benefits to this approach at an estimated cost of $153 (S. mansoni-$211 (S. haematobium per additional lifetime QALY gained by double treatment in school-based programs. More rapid reduction of infection-related disease may improve program adherence, and if, as an externality of the program, transmission can be reduced through more effective coverage, significant additional benefits are

  20. Pharmacokinetic evaluation of pamidronate after oral administration: a study on dose proportionality, absolute bioavailability, and effect of repeated administration

    DEFF Research Database (Denmark)

    Hyldstrup, Lars; Flesch, G; Hauffe, S A


    30 minutes at constant infusion rate. Repeated peroral doses (75 and 150 mg) were administered to 12 females (aged 51-70 years) for 10 consecutive days. Urinary excretion of pamidronate after peroral and i.v. administration was used for estimation of pamidronate absorption. Renal excretion...

  1. Spontaneous and Dosing Route-related Lung Lesions in Beagle Dogs from Oral Gavage and Inhalation Toxicity Studies: Differentiation from Compound-induced Lesions. (United States)

    Mukaratirwa, Sydney; Garcia, Begonya; Isobe, Kaori; Petterino, Claudio; Bradley, Alys


    This study was conducted to characterize lung microscopic lesions in control beagle dogs from inhalation and oral gavage toxicity studies, to determine differences associated with the route of administration, and to discuss distinguishing features from compound-induced lung lesions. Samples from 138 control dogs from oral gavage studies and 124 control dogs from inhalation (vehicle control) studies were evaluated microscopically. There was no significant sex-related difference in the incidence of all lesions. Perivascular mononuclear cell infiltration, centriacinar mixed cell infiltration, bronchopneumonia, subpleural septal fibrosis, and alveolar macrophage accumulation were the most common lesions. Aspiration pneumonia was more common in dogs from gavage studies, suggesting reflux after gavage dosing or accidental administration of test formulation as possible causes. Centriacinar mixed cell infiltration was more common in dogs from inhalation studies, suggesting mild irritation by the vehicles used. Vascular lesions, which included pulmonary arteriopathy and smooth muscle mineralization, were observed in a few animals. Some of the spontaneous lesions are similar to lesions induced by test compounds. Compared to spontaneous lesions, compound-induced lesions tend to be multifocal or diffuse, follow a pattern of distribution (e.g., centriacinar, perivascular, and interstitial), show a dose response in the incidence and severity, and may show cell-specific toxicity.

  2. Repeat Gamma-Knife Radiosurgery for Refractory or Recurrent Trigeminal Neuralgia with Consideration About the Optimal Second Dose. (United States)

    Park, Seong-Cheol; Kwon, Do Hoon; Lee, Do Hee; Lee, Jung Kyo


    To investigate adequate radiation doses for repeat Gamma Knife radiosurgery (GKS) for trigeminal neuralgia in our series and meta-analysis. Fourteen patients treated by ipsilateral repeat GKS for trigeminal neuralgia were included. Median age of patients was 65 years (range, 28-78), the median target dose, 140-180). Patients were followed a median of 10.8 months (range, 1-151) after the second gamma-knife surgery. Brainstem dose analysis and vote-counting meta-analysis of 19 studies were performed. After the second gamma-knife radiosurgeries, pain was relieved effectively in 12 patients (86%; Barrow Neurological Institute Pain Intensity Score I-III). Post-gamma-knife radiosurgery trigeminal nerve deficits were mild in 5 patients. No serious anesthesia dolorosa was occurred. The second GKS radiation dose ≤ 60 Gy was significantly associated with worse pain control outcome (P = 0.018 in our series, permutation analysis of variance, and P = 0.009 in the meta-analysis, 2-tailed Fisher's exact test). Cumulative dose ≤ 140-150 Gy was significantly associated with poor pain control outcome (P = 0.033 in our series and P = 0.013 in the meta-analysis, 2-tailed Fisher's exact test). A cumulative brainstem edge dose >12 Gy tended to be associated with trigeminal nerve deficit (P = 0.077). Our study suggests that the second GKS dose is a potentially important factor. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT

    National Research Council Canada - National Science Library

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E


    .... We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial...

  4. Radiation-induced mutation at tandem repeat DNA Loci in the mouse germline: spectra and doubling doses. (United States)

    Dubrova, Yuri E


    The spectra and dose response for mutations at expanded simple tandem repeat (ESTR) loci in the germline of male mice acutely exposed to low-LET X or gamma rays at pre-meiotic stages of spermatogenesis were compared in five strains of laboratory mice. Most mutation events involved the gain or loss of a relatively small number of repeat units, and the distributions of length changes were indistinguishable between the exposed and control males. Overall, a significant bias toward gains of repeats was detected, with approximately 60% of mutants showing gains. The values for ESTR mutation induction did not differ substantially between strains. The highest values of doubling dose were obtained for two genetically related strains, BALB/c and C.B17 (mean value 0.98 Gy). The estimates of doubling dose for three other strains (CBA/H, C57BL/6 x CBA/H F1 and 129SVJ x C57BL/6) were lower, with a mean value of 0.44 Gy. The dose response for ESTR mutation across all five strains was very close to that for the specific loci (Russell 7-locus test). The mechanisms of ESTR mutation induction and applications of this system for monitoring radiation-induced mutation in the mouse germline are discussed.

  5. High-dose inhaled salbutamol has no acute effects on aerobic capacity or oxygen uptake kinetics in healthy trained men

    DEFF Research Database (Denmark)

    Elers, J; Mørkeberg, Jakob; Jansen, T


    oxygen uptake kinetics. During the incremental test, there were no effects of inhaled salbutamol on VO(2max) in absolute or relative terms, and no effect on peak power and lactate threshold. During the submaximal test, we found no effects on the time constant, time delay, the mean response time or O(2...... enrolled nine healthy well-trained men in a randomized, blinded, placebo-controlled crossover study. Subjects were randomized to inhalation of 40 puffs of 0.2 mg salbutamol or two placebo tablets and performed an incremental test to exhaustion and three submaximal tests at 75% of peak power to determine...

  6. Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia

    Directory of Open Access Journals (Sweden)

    Balaji Ramachandran


    Full Text Available EGCG (Epigallocatechin-3-gallate is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal] and limited [p.o (oral] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

  7. Repeated treatment with (-)-sulpiride plus a low dose of SCH 23390 displays wider neuroleptic activity without inducing dopaminergic supersensitivity. (United States)

    Dall'Olio, R; Gandolfi, O; Roncada, P; Vaccheri, A; Montanaro, N


    Combined treatment with (-)-sulpiride plus a low dose of the D1 receptor antagonist SCH 23390, unlike (-)-sulpiride given alone, blocked rat striatal dopaminergic transmission. Five days after the withdrawal of 21-day repeated administration of the combined treatment, no increase in apomorphine-induced stereotyped behaviour was observed. The results suggest that the combination of a D2 blocker and a low dose of a D1 blocker produces a wider spectrum of neuroleptic activity without an overt risk of inducing dopaminergic behavioural supersensitivity.

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

    Energy Technology Data Exchange (ETDEWEB)

    Gundavarapu, Sravanthi; Zhuang, Jianguo; Barrett, Edward G.; Xu, Fadi; Russell, Robert G.; Sopori, Mohan L., E-mail:


    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 including 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.

  9. Who Can Use an Inhaler? (United States)

    ... in a bit harder. Any kid, even a baby, can use a metered dose inhaler with a spacer and a mask. Once a kid is 5 or 6 years old, he or she can learn to use a metered dose inhaler with just a spacer. Most kids that age are also able to use a dry powder inhaler. Your doctor will help you decide what ...

  10. Analysis of metered dose inhaler in chronic obstructive pulmonary disease patients%影响慢性阻塞性肺疾病患者正确使用定量型气雾剂的因素分析及对策

    Institute of Scientific and Technical Information of China (English)



    Objective To explore the essentiality and feasibility of metered dose inhaler for patients with chronic obstructive pulmonary disease(COPD). Methods Totally 120 COPD patients were applied metered dose inhaler.Preliminary application according to the 7-step procedure was recorded and records of application were repeated when patients got out of hospital and two weeks after discharge. Results Eighteen patient in 120(15%)had correctly used metered dose inhaler in preliminary application.The mistakes in the application were inhalation after press(90 times),repeated-consperge before inhalation(30 times),no breath-holding after inhalation(28 times),no mouth-rinse after inhalation(20 times),no shaking before application(18 times)and glucocorticosteroid inhalation ahead β2 receptor agonist(80 times).When discharged,patients with correct usage increased to 88(73%). Conclusions Therapeutic effect is depressed by incorrect use of metered dose inhaler in COPD patients,which can be improved by regular and standardized guidance.%目的 探讨慢性阻塞性肺疾病(COPD)患者正确使用定量型气雾剂的必要性和可行性. 方法 对120例COPD患者使用定量型气雾剂,按使用的7个步骤进行初试记录.出院前复试,出院后2周再次复试.比较患者在初、复试中的正确使用率. 结果 初始时,120例COPD患者中能正确使用定量型气雾剂者18例(15%),常见的错误为:先按压后吸气(90例次)、连喷几次后再吸气(30例次)、吸气后无屏气(28例次)、吸人激素后无漱口(20例次)、使用前无摇匀(18例次)、先吸入糖皮质激素后再吸入β2受体激动剂(80例次).出院前复试时总的正确使用率增至88例(73%).出院2周第二次复试时总的正确使用率降至56%(68例). 结论 定量型气雾剂在COPD患者中使用的正确率低影响疗效.建立规范化的指导和定期培训才能保证使用的正确性和有效性.

  11. Granulometric determinations and inhalation dose assessment for atmospheric aerosol contaminated by {sup 137}Cs; Determinazioni granulometriche e valutazioni di dose da inalazione per aerosol atmosferico contaminato da {sup 137}CS

    Energy Technology Data Exchange (ETDEWEB)

    Castellani, C.M.; Luciani, A. [ENEA, Centro Ricerche `E. Clementel`, Bologna (Italy). Dip. Ambiente; Oliviero, L.; Donato, R. [ENEA, Centro Ricerche Saluggia, Vercelli (Italy). Dip. Ambiente


    During the redevelopment of Brescia freight-yard a measurement campaign of atmospheric aerosol was carried out: in fact a {sup 137}Cs ground contamination, caused by the permanence of wagons carrying iron materials contaminated by this radionuclide, had been found out. During the redevelopment phases of excavation and can filling the workers were exposed to the danger of radioactive aerosol inhalation. The aim of the measurement campaign was to test the aerosol sampling and granulometric analysis methodologies with their sensitivity related to the inhalation dose assessments. The results of both aerosuspended mass and activity, evaluated by means of a portable cascade impactor, are presented. The granulometries have been interpolated with a log normal distribution using an iterative routine minimizing the square deviation between the calculated and experimental data. The results related to the dose assessments are also presented. These evaluations have been carried out using both the granulometric information obtained and the more recent models (ICRP 66) both the total concentration data and the dose coefficients referring to the standard conditions of ICRP 68 and of the Italian law (D.Lgs. 230/95). Furthermore the significance and the reliability of the dose assessments referring to the different methodologies are discussed, also in relation to the possibility of using this sampling methodologies for other radionuclides and different exposure conditions.

  12. Fluticasone and Vilanterol Oral Inhalation (United States)

    ... the inhaler without using your dose, you will waste the medication. The counter will count down by ... it from the foil overwrap or after every blister has been used (when the dose indicator reads ...

  13. Simulation for clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance. (United States)

    Ishida, Kazuya; Kayano, Yuichiro; Taguchi, Masato; Hashimoto, Yukiya


    We performed a simulation for the clinical pharmacokinetic study, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral drug administration to subjects. We estimated the approximate oral clearance (CL/F(approx)) as 2.D/(C(peak).tau+C(trough).tau), where D is the dose, and tau is the dosing interval. The CL/F(approx) value was accurate for drugs with a long-elimination half-life, and the estimation error of the CL/F value was slightly increased for drugs with a shorter elimination half-life. The accuracy of CL/F(approx) in each subject was not affected by the magnitude of the interindividual pharmacokinetic variability, but was significantly decreased by the larger measurement error of drug concentrations (or intraindividual pharmacokinetic variability). We further performed several computer simulations to mimic statistical hypothesis testing following the clinical repeated-dose pharmacokinetic trials. The statistical power to detect the difference of oral clearance between two groups was marginally dependent on the measurement error of drug concentration, but was highly dependent on the interindividual pharmacokinetic variability. These findings suggested that the peak-and-trough sampling design to estimate the CL/F(approx) value is useful for clinical repeated-dose pharmacokinetic trials, and that the study design and protocol should be evaluated carefully by computer simulation prior to a real clinical trial.

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

    Jeong, Hyeran; Park, Donguk


    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.

  15. Plasma concentrations of sodium cromoglycate given by nebulisation and metered dose inhalers in patients with exercise-induced asthma: relationship to protective effect. (United States)

    Patel, K R; Tullett, W M; Neale, M G; Wall, R T; Tan, K M


    Plasma sodium cromoglycate (SCG) concentrations were measured in 11 patients at regular intervals before and after exercise in a double-blind study to assess the protective effect in exercise-induced asthma (EIA) of 2, 10 and 20 mg SCG aerosol and placebo, and (on an open basis) nebulised SCG (10 g l-1). There was a dose related increase in plasma concentration and AUC (0-1 h) with the aerosol formulations; values with nebulised SCG were significantly higher than with any aerosol dose. Protection from EIA increased to a maximum of 66% at plasma concentrations of 4 ng ml-1 and above. Thus measurement of plasma concentration can allow a comparison to be made between the protective effects of SCG following different methods of inhalation. It is important to note, however, that plasma concentration per se is almost certainly not related directly to protective effect. PMID:3082347

  16. Repeated dose liver micronucleus assay using adult mice with multiple genotoxicity assays concurrently performed as a combination test. (United States)

    Hagio, Soichiro; Furukawa, Satoshi; Abe, Masayoshi; Kuroda, Yusuke; Hayashi, Seigo; Ogawa, Izumi


    Recently, the liver micronucleus (MN) assay using young adult rats with repeated administrations has been investigated by employing a new method without partial hepatectomy or in situcollagenase perfusion as the repeated dose liver MN (RDLMN) assay by Narumi et al. (2012). In our study, in order to investigate the possibility of the RDLMN assay using young adult mice instead of rats and the feasibility of employing some genotoxicity assays along with the RDLMN assay as a combination test, two genotoxic carcinogens (N,N-diethylnitrosoamine (DEN) and cisplatin (CIS)) and a nongenotoxic carcinogen (phenobarbital sodium (PHE)) were administered to mice for 15 or 29 days. Then, the liver MN assay, peripheral blood (PB) MN assay and comet assay using the liver and kidney were concurrently performed as a combination test. DEN showed positive responses to all endpoints except MN induction in PB after 15 days of repeat administration. A cross-linking agent, CIS, showed MN induction in liver after 29 days of repeat administration, and in PB after 15 and 29 days of repeat administration, although the comet assay yielded negative responses for both organs at both sampling times. PHE yielded negative responses for all endpoints. In conclusion, it is suggested that the RDLMN assay using mice is a feasible method to be integrated into the general repeated toxicity test along with the combination assays, i.e., comet assay or PB MN assay, which would help in risk assessment for carcinogenicity by comparing the results of combination assays with each other.

  17. Evaluation of 90 day repeated dose oral toxicity and reproductive/developmental toxicity of 3'-hydroxypterostilbene in experimental animals. (United States)

    Majeed, Muhammed; Bani, Sarang; Natarajan, Sankaran; Pandey, Anjali; S, Naveed


    3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed.

  18. Bile Salt Homeostasis in Normal and Bsep Gene Knockout Rats with Single and Repeated Doses of Troglitazone. (United States)

    Cheng, Yaofeng; Chen, Shenjue; Freeden, Chris; Chen, Weiqi; Zhang, Yueping; Abraham, Pamela; Nelson, David M; Humphreys, W Griffith; Gan, Jinping; Lai, Yurong


    The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7.6- and 9.3-fold lower than in WT on day 1 and day 7, respectively, due to increased TS biliary excretion. With Bsep KO, the mRNA levels of multidrug resistance-associated protein 2 (Mrp2), Mrp3, Mrp4, Mdr1, breast cancer resistance protein (Bcrp), sodium taurocholate cotransporting polypeptide, small heterodimer partner, and Sult2A1 were significantly altered in KO rats. Following seven daily TGZ treatments, Cyp7A1 was significantly increased in both WT and KO rats. In the vehicle groups, plasma exposures of individual bile acids demonstrated variable changes in KO rats as compared with WT. WT rats dosed with TGZ showed an increase of many bile acid species in plasma on day 1, suggesting the inhibition of Bsep. Conversely, these changes returned to base levels on day 7. In KO rats, alterations of most bile acids were observed after seven doses of TGZ. Collectively, bile acid homeostasis in rats was regulated through bile acid synthesis and transport in response to Bsep deficiency and TGZ inhibition. Additionally, our study is the first to demonstrate that repeated TGZ doses can upregulate Cyp7A1 in rats. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  19. Airway responses and inflammation in subjects with asthma after four days of repeated high-single-dose allergen challenge

    Directory of Open Access Journals (Sweden)

    Schulze Johannes


    Full Text Available Abstract Background Both standard and low-dose allergen provocations are an established tool in asthma research to improve our understanding of the pathophysiological mechanism of allergic asthma. However, clinical symptoms are less likely to be induced. Therefore, we designed a protocol for repetitive high-dose bronchial allergen challenges to generate clinical symptoms and airway inflammation. Methods A total of 27 patients aged 18 to 40 years with positive skin-prick tests and mild asthma underwent repetitive high-dose allergen challenges with household dust mites for four consecutive days. Pulmonary function and exhaled NO were measured at every visit. Induced sputum was analysed before and after the allergen challenges for cell counts, ECP, IL-5, INF-γ, IL-8, and the transcription factor Foxp3. Results We found a significant decrease in pulmonary function, an increased use of salbutamol and the development of a late asthmatic response and bronchial hyperresponsiveness, as well as a significant induction of eNO, eosinophils, and Th-2 cytokines. Repeated provocation was feasible in the majority of patients. Two subjects had severe adverse events requiring prednisolone to cope with nocturnal asthma symptoms. Conclusions Repeated high-dose bronchial allergen challenges resulted in severe asthma symptoms and marked Th-2-mediated allergic airway inflammation. The high-dose challenge model is suitable only in an attenuated form in diseased volunteers for proof-of-concept studies and in clinical settings to reduce the risk of severe asthma exacerbations. Trial registration ClinicalTrials.govNCT00677209

  20. Repeated-Doses Toxicity Study of the Essential Oil of Hyptis martiusii Benth. (Lamiaceae in Swiss Mice

    Directory of Open Access Journals (Sweden)

    Germana Freire Rocha Caldas


    Full Text Available Hyptis martiusii Benth. (Lamiaceae is found in abundance in Northeastern Brazil where it is used in traditional medicine to treat gastric disorders. Since there are no studies reporting the toxicity and safety profile of this species, we investigated repeated-doses toxicity of the essential oil of Hyptis martiusii (EOHM. Swiss mice of both sexes were orally treated with EOHM (100 and 500 mg/kg for 30 days, and biochemical, hematological, and morphological parameters were determined. No toxicity signs or deaths were recorded during the treatment with EOHM. The body weight gain was not affected, but there was an occasional variation in water and food consumption among mice of both sexes treated with both doses. The hematological and biochemical profiles did not show significant differences except for a decrease in the MCV and an increase in albumin, but these variations are within the limits described for the species. The microscopic analysis showed changes in liver, kidneys, lungs, and spleen; however, these changes do not have clinical relevance since they varied among the groups, including the control group. The results indicate that the treatment of repeated-doses with the essential oil of Hyptis martiusii showed low toxicity in mice.

  1. Repeated Exposure to Sublethal Doses of the Organophosphorus Compound VX Activates BDNF Expression in Mouse Brain (United States)


    cresyl/-4 H-1: 3: 2-benzodioxa- phosphorin-2-oxide (CBDP) on organophosphate poisoning and its therapy. Arch. Toxicol. 42, 207–216. French, S. J... organophosphates or other environmental insults, have a greater FIG. 4. Mice that received repeated exposure to low levels of VX (0.2 LD50 and 0.4 neuro- behavioral deficits and neuropathology. Although exposure to organophosphates such as pesticides has been shown to affect the expression of

  2. Use of a cognitive ergonomics approach to compare usability of a multidose dry powder inhaler and a capsule dry powder inhaler: an open-label, randomized, controlled study. (United States)

    Franks, Mark; Briggs, Pamela


    Usability (ease of use) is an important feature of inhalers to ensure optimal dose delivery The aim of this study was to compare the usability of a multidose dry powder inhaler (mDPI) and a capsule dry powder inhaler (cDPI) in older individuals, using a range of qualitative and quantitative techniques from the field of cognitive ergonomics. Participants aged >50 years were enrolled in this 2-visit, open-label, randomized, controlled, parallel-group study conducted at Northumbria University, Newcastle upon Tyne, United Kingdom. Participants who had used an inhaler or were inhaler naive were randomized to use the mDPI or cDPI. At visit 1, the inhaler procedure was demonstrated twice by the investigator. Participants then repeated the procedure (although they were not expected to inhale because no drug was to be administered) until they made 3 consecutive correct attempts. They also undertook a range of tests to assess their confidence in using the device, manual dexterity, and self-efficacy At visit 2 (2 days later), participants made a single inhaler attempt before receiving any demonstrations from the investigator; this was intended to simulate clinical practice, in which the patient may not use an inhaler for a few days after it is prescribed. Participants then completed the inhaler procedure 10 times while undertaking a concurrent distracter task. The number of critical errors (ie, those having a high impact on dose delivery) was recorded for all attempts. To facilitate subsequent correlation analyses, an overall performance measure was derived from a combination of the results of the single inhaler trial and the 10 trials with a distracter. Eighty individuals (51 women, 29 men; mean [SD] age, 74.1 [7.5] years) participated in the study(40 participants per device). Forty of the participants (50%) had used an inhaler previously; 40 (50%) were inhaler naive. Based on the overall performance measure, participants testing the mDPI made significantly fewer critical

  3. Inhalation Injuries (United States)

    ... you can inhale that can cause acute internal injuries. Particles in the air from fires and toxic ... and lung diseases worse. Symptoms of acute inhalation injuries may include Coughing and phlegm A scratchy throat ...

  4. The haemotoxicity of azathioprine in repeat dose studies in the female CD-1 mouse. (United States)

    Molyneux, Gemma; Gibson, Frances M; Chen, Christabelle M; Marway, Harpal K; McKeag, Sean; Mifsud, Charles V J; Pilling, Andrew M; Whayman, Matthew J; Turton, John A


    Azathioprine (AZA) is a cytotoxic immunosuppressive drug used in the prevention of rejection in organ transplants and the treatment of auto-immune diseases. However, AZA is haemotoxic causing significant bone marrow depression. The present studies were to characterize the haemotoxicity of AZA in the female CD-1 mouse. In Experiment 1, a dose-ranging study, with AZA gavaged daily for 10 days, clinical evidence of toxicity was evident at 125 mg/kg and above. Experiment 2 was a dose-response study with AZA gavaged daily for 10 days at 40-120 mg/kg. At day 1 after the final dose, AZA induced a dose-related pancytopaenia, reduced femoral marrow cellularity, increases in serum levels of the cytokine fms-like tyrosine kinase 3 ligand, reduction in granulocyte-monocyte colony-forming units and erythroid colonies, and increased bone marrow apoptosis. Histology demonstrated hepatocyte hypertrophy, thymic atrophy, reduced splenic extramedullary haemopoiesis, and reduced cellularity of sternal bone marrow. In Experiment 3, AZA was dosed for 10 days at 100 mg/kg with autopsies at 1, 3, 9, 22, 29, 43 and 57 days postdosing. At 1, 3 and 9 days, haematological parameters reflected changes in Experiment 2. At 22/29 days, many blood parameters were returning towards normal; at 43/57 days, most parameters compared with controls. However, there was some evidence of a persistent (i.e. residual/late-stage) mild reduction in RBC and erythroid progenitor cell counts at day 43/57. We conclude that the CD-1 mouse provides an acceptable model for the haemotoxicity of AZA in man.

  5. Rats with Chronic, Stable Pulmonary Hypertension Tolerate Low Dose Sevoflurane Inhalation as Well as Normal Rats Do.

    Directory of Open Access Journals (Sweden)

    Xiaoqing Yin

    Full Text Available The effects of low concentration of sevoflurane on right ventricular (RV function and intracellular calcium in the setting of pulmonary arterial hypertension (PAH have not been investigated clearly. We aim to study these effects and associated signaling pathways in rats with PAH.Hemodynamics were assessed with or without sevoflurane inhalation in established PAH rats. We analysis the classic RV function parameters and RV-PA coupling efficiency using steady-state PV loop recordings. The protein levels of SERCA2, PLB and p-PLB expression was analyzed by western blot to assess their relevance in PAH.Rats with PAH presented with RV hypertrophy and increased pulmonary arterial pressure. The values of Ea, R/L ratio, ESP, SW, PRSW, +dP/dtmax and the slope of the dP/dtmax-EDV relationship increased significantly in PAH rats (P<0.05. Sevoflurane induced a concentration-dependent decrease of systemic and pulmonary blood pressure, HR, RV contractility, and increased the R/L ratio in both groups. Sevoflurane reduced the expression of SERCA2 and increased the expression of PLB in both groups. Interestingly, sevoflurane only reduced the p-PLB/PLB ratio in PAH rats, not in normal rats.Rats with chronic, stable pulmonary hypertension tolerate low concentrations of sevoflurane inhalation as well as normal rats do. It may be related to the modulation of the SERCA2-PLB signaling pathway.

  6. Cherry-flavoured electronic cigarettes expose users to the inhalation irritant, benzaldehyde. (United States)

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


    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.

  7. Memory and mood during the night and in the morning after repeated evening doses of MDMA. (United States)

    Kuypers, K P C; Wingen, M; Ramaekers, J G


    Previously it has been shown that MDMA causes memory impairment during daytime testing. However, MDMA is usually taken in the evening or during the night. In addition, it is known that sleep deprivation also causes memory impairment. The present study aimed to assess whether evening doses of MDMA added to, or interacted with the memory impairment due to sleep deprivation. Fourteen healthy subjects participated in a double-blind, placebo-controlled, two-way cross-over study. Treatments consisted of MDMA 75 and 50 mg divided over the evening or double placebo. Memory tests and subjective measures of mood were conducted at baseline and three times post dosing that is at 6.30 pm, 9.30 pm, 1.30 am and 7 am, respectively -1.5, 1.5, 5.5 and 11 h relative to drug intake (first dose). Memory performance detoriated progessively over time as a function of sleep loss, independent of treatment. MDMA added to this impairment as indicated by a significant main effect of MDMA on verbal and spatial memory performance. Mood ratings and response speed revealed an MDMA by Time interaction. After administration of MDMA response speed improved and feelings of vigor, friendliness, elation, anxiety, confusion, arousal and positive mood increased in magnitude during the night, while all these parameters returned to placebo-like levels on the final morning session. It is concluded that evening doses of MDMA selectively impair memory performance, and that this impairment is additional to the effect of sleep deprivation on memory performance.

  8. Chronic obstructive pulmonary disease treated with inhaled medium- or high-dose corticosteroids: a prospective and randomized study focusing on clinical efficacy and the risk of pneumonia

    Directory of Open Access Journals (Sweden)

    Cheng SL


    Full Text Available Shih-Lung Cheng,1,2 Kang-Cheng Su,3 Hao-Chien Wang,4,* Diahn-Warng Perng,3,* Pan-Chyr Yang4 1Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, 2Department of Chemical Engineering and Materials Science, Yuan Ze University, Zhongli City, Taoyuan County, 3Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, 4Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan *These authors contributed equally to this work Purpose: Complications of pneumonia development in patients with chronic obstructive pulmonary disease (COPD receiving inhaled corticosteroid (ICS therapy have been documented. The aim of this study was to focus on clinical efficacy and the incidence of pneumonia between COPD patients receiving medium and high doses of ICS. Patients and methods: This prospective, randomized study included COPD patients identified from three tertiary medical centers from 2010 to 2012. The patients were randomized into two groups: high dose (HD; fluticasone 1,000 µg + salmeterol 100 µg/day and medium dose (MD; fluticasone 500 µg + salmeterol 100 µg/day. Lung function with forced expiratory volume in 1 second (FEV1, forced vital capacity, and COPD-assessment test (CAT were checked every 2 months. The frequency of acute exacerbations and number of pneumonia events were measured. The duration of the study period was 1 year. Results: In total, 237 COPD patients were randomized into the two treatment arms (115 in the HD group, 122 in the MD group. The FEV1 level was significantly improved in the patients in the HD group compared with those in the MD group (HD 103.9±26.6 mL versus MD 51.4±19.7 mL, P<0.01 at the end of the study. CAT scores were markedly improved in patients using an HD compared to those using an MD (HD 13±5 versus MD 16±7, P=0.05. There was a significant difference in the percentage of annual rates in acute exacerbations (HD 0.16 versus MD 0.34, P<0.01 between the

  9. The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing. (United States)

    Kohonen, Pekka; Benfenati, Emilio; Bower, David; Ceder, Rebecca; Crump, Michael; Cross, Kevin; Grafström, Roland C; Healy, Lyn; Helma, Christoph; Jeliazkova, Nina; Jeliazkov, Vedrin; Maggioni, Silvia; Miller, Scott; Myatt, Glenn; Rautenberg, Michael; Stacey, Glyn; Willighagen, Egon; Wiseman, Jeff; Hardy, Barry


    The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web-accessible shared repository of research data and protocols, a physical compounds repository, reference or "gold compounds" for use across the cluster (available via, and a reference resource for biomaterials. Core technologies used in the data warehouse include the ISA-Tab universal data exchange format, REpresentational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements, the implementation based on open standards, and finally the underlying concepts and initial results of a data analysis utilizing public data related to the gold compounds. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Intra-tumor distribution of PEGylated liposome upon repeated injection: No possession by prior dose. (United States)

    Nakamura, Hiroyuki; Abu Lila, Amr S; Nishio, Miho; Tanaka, Masao; Ando, Hidenori; Kiwada, Hiroshi; Ishida, Tatsuhiro


    Liposomes have proven to be a viable means for the delivery of chemotherapeutic agents to solid tumors. However, significant variability has been detected in their intra-tumor accumulation and distribution, resulting in compromised therapeutic outcomes. We recently examined the intra-tumor accumulation and distribution of weekly sequentially administered oxaliplatin (l-OHP)-containing PEGylated liposomes. In that study, the first and second doses of l-OHP-containing PEGylated liposomes were distributed diversely and broadly within tumor tissues, resulting in a potent anti-tumor efficacy. However, little is known about the mechanism underlying such a diverse and broad liposome distribution. Therefore, in the present study, we investigated the influence of dosage interval on the intra-tumor accumulation and distribution of "empty" PEGylated liposomes. Intra-tumor distribution of sequentially administered "empty" PEGylated liposomes was altered in a dosing interval-dependent manner. In addition, the intra-tumor distribution pattern was closely related to the chronological alteration of tumor blood flow as well as vascular permeability in the growing tumor tissue. These results suggest that the sequential administrations of PEGylated liposomes in well-spaced intervals might allow the distribution to different areas and enhance the total bulk accumulation within tumor tissue, resulting in better therapeutic efficacy of the encapsulated payload. This study may provide useful information for a better design of therapeutic regimens involving multiple administrations of nanocarrier drug delivery systems.

  11. Repeated measures dose-finding design with time-trend detection in the presence of correlated toxicity data. (United States)

    Yin, Jun; Paoletti, Xavier; Sargent, Daniel J; Mandrekar, Sumithra J


    Phase I trials are designed to determine the safety, tolerability, and recommended phase 2 dose of therapeutic agents for subsequent testing. The dose-finding paradigm has thus traditionally focused on identifying the maximum tolerable dose of an agent or combination therapy under the assumption that there is a non-decreasing relationship between dose-toxicity and dose-efficacy. The dose is typically determined based on the probability of severe toxicity observed during the first treatment cycle. A novel endpoint, the total toxicity profile, was previously developed to account for the multiple toxicity types and grades experienced in the first cycle. More recently, this was extended to a repeated measures design based on the total toxicity profile to account for longitudinal toxicities over multiple treatment cycles in the absence of within-patient correlation. In this work, we propose to extend the design in the presence of within-patient correlation. Furthermore, we provide a framework to detect a toxicity time trend (toxicity increasing, decreasing, or stable) over multiple treatment cycles. We utilize a linear mixed model in the Bayesian framework, with the addition of Bayesian risk functions for decision-making in dose assignment. The performance of this design was evaluated using simulation studies and real data from a phase I trial. We demonstrated that using available toxicity data from all cycles of treatment improves the accuracy of maximum tolerated dose identification and allows for the detection of a time trend. The performance is consistent regardless of the strength of the within-patient correlation. In addition, the use of a quasi-continuous total toxicity profile score significantly increased the power to detect time trends compared to when binary data only were used. The increased interest in molecularly targeted agents and immunotherapies in oncology necessitates innovative phase I study designs. Our proposed framework provides a tool to tackle

  12. Twelve-week efficacy and safety study of mometasone furoate/formoterol 200/10 microg and 400/10 microg combination treatments in patients with persistent asthma previously receiving high-dose inhaled corticosteroids

    DEFF Research Database (Denmark)

    Weinstein, Steven F; Corren, Jonathan; Murphy, Kevin;


    A significant unmet medical need exists in patients with uncontrolled asthma. The purpose of this study was to evaluate the efficacy and safety of mometasone furoate/formoterol (MF/F) 400/10 microg versus MF 400 microg administered twice-daily (b.i.d.) via metered-dose inhaler in patients...

  13. Higher lung deposition with Respimat® Soft Mist™ Inhaler than HFA-MDI in COPD patients with poor technique

    Directory of Open Access Journals (Sweden)

    Peter Brand


    Full Text Available Peter Brand1, Bettina Hederer2, George Austen3, Helen Dewberry3, Thomas Meyer41RWTH, Aachen, Germany; 2Boehringer Ingelheim, Ingelheim, Germany; 3Boehringer Ingelheim, Bracknell, UK; 4Inamed Research, Gauting, GermanyAbstract: Aerosols delivered by Respimat® Soft Mist™ Inhaler (SMI are slower-moving and longer-lasting than those from pressurized metered-dose inhalers (pMDIs, improving the efficiency of pulmonary drug delivery to patients. In this four-way cross-over study, adults with chronic obstructive pulmonary disease (COPD and with poor pMDI technique received radiolabelled Berodual® (fenoterol hydrobromide 50 µg/ipratropium bromide 20 µg via Respimat® SMI or hydrofluoroalkane (HFA-MDI (randomized order on test days 1 and 2, with no inhaler technique training. The procedure was repeated on test days 3 and 4 after training. Deposition was measured by gamma scintigraphy. All 13 patients entered (9 males, mean age 62 years; FEV1 46% of predicted inhaled too fast at screening (peak inspiratory flow rate [IF]: 69–161 L/min. Whole lung deposition was higher with Respimat® SMI than with pMDI for untrained (37% of delivered dose vs 21% of metered dose and trained patients (53% of delivered vs 21% of metered dose (pSign-Test = 0.15; pANOVA< 0.05. Training also improved inhalation profiles (slower average and peak IF as well as longer breath-hold time. Drug delivery to the lungs with Respimat® SMI is more efficient than with pMDI, even with poor inhaler technique. Teaching patients to hold their breath as well as to inhale slowly and deeply increased further lung deposition using Respimat® SMI.Keywords: chronic obstructive pulmonary disease, drug delivery, inhalation, metered-dose inhaler, poor inhalation technique, training

  14. Instant velocity and consistency of emitted cloud change by the different levels of canister filling with Metered Dose Inhalers (MDIs), but not with Soft Mist Inhalers (SMIs): a bench study. (United States)

    Dal Negro, Roberto W; Longo, Pietro; Ziani, Orestepaolo Villanis; Bonadiman, Luca; Turco, Paola


    Inhalation is the preferred route for respiratory drug delivery, but several factors contribute to the variability of the respirable dose fraction. Instant velocity and the dynamic characteristics of the droplet cloud represent crucial factors. Aim was to measure and compare the instant velocity and the consistency of emitted cloud from five different MDIs (A - Salbutamol sulphate 100mcg, GSK; B - Salbutamol sulphate 100mcg, Valeas; C - Salmeterol xinafoate/Fluticasone propionate 25/125mcg, GSK; D - Formoterol fumarate/Bechlomethasone propionate 6/100mcg, Chiesi; E - Formoterol fumarate/Fluticasone dipropionate 5/125mcg, Mundipharma) and one SMI (Tiotropium bromide 5mcg, Boehringer Ingelheim), at different distance from the nozzle and canister filling. Measurements were made at 90, 50, and 10% of canister filling, and at 5, 10, and 20 cm from the nozzle, for a total of 972 puffs. A high speed video photography protocol was adopted and high speed cameras (1.200 frames/sec.) were used. Data were acquired by means of specialized softwares. Temperature, humidity, and vibrations occurrence were strictly controlled during measurements. Statistics: Anova and p 33% at 90% of emptying with all other MDIs (p cloud similarly tight (p = ns) at 10 and 20 cm from the nozzle, while it was extremely wider and constant with the SMI (p = 0-001). Also the cloud turbulence was minimized during the SMI emission. MDIs are characterized by a substantial variability in both their instant velocity and consistency of the emitted cloud at different levels of canister filling. SMI generates a much slower soft mist cloud which is constantly homogeneous and independent of canister emptying. These peculiarities assessed at bench are suggesting a higher dose consistency and a much more effective therapeutic performance also in real life.

  15. Investigation of repeated dose (90 day oral toxicity, reproductive/developmental toxicity and mutagenic potential of ‘Calebin A’

    Directory of Open Access Journals (Sweden)

    Muhammed Majeed


    Full Text Available The present work investigated repeated dose and reproductive toxicity of Calebin A in Wistar rats. A study for assessing the mutagenic potential of Calebin A through an AMES test is also described. Calebin A was orally administered to groups of 10 male and/or 10 female Wistar rats each, assigned to three dose levels (20, 50 and 100 mg/kg/body weight once daily for 90 consecutive days. None of the animals in any of the treatment/control groups exhibited any abnormal clinical signs/behavioral changes, reproductive as well as developmental parameters, or gross and microscopic changes in both male and female rats. Calebin A was also evaluated for its ability to induce reverse mutations at selected loci of Salmonella typhimurium in the presence and absence of Aroclor 1254 induced rat liver S9 cell lines. In conclusion, 100 mg/kg/d of Calebin A is not likely to produce any significant toxic effects in male and female Wistar rats and no reproductive or developmental toxicity was observed at the same dose and hence Calebin A at 100 mg/kg was determined as “No Observed Adverse Effect Level (NOAEL” under the test conditions.

  16. Repeated dose oral toxicity of inorganic mercury in wistar rats: biochemical and morphological alterations

    Directory of Open Access Journals (Sweden)

    M. D. Jegoda


    Full Text Available Aim: The study was conducted to find out the possible toxic effect of mercuric chloride (HgCl2 at the histological, biochemical, and haematological levels in the wistar rats for 28 days. Materials and Methods: The biochemical and hematological alteration were estimated in four groups of rat (each group contain ten animals, which were treated with 0 (control, 2, 4, and 8 mg/kg body weight of HgCl2 through oral gavage. At the end of study all rats were sacrificed and subjected for histopathology. Result: A significantly (P < 0.05 higher level of serum alanine amino transferase (ALT, gamma Glutamyle Transferase, and creatinine were recorded in treatment groups, while the level of alkaline phosphtase (ALP was significantly decreased as compared to the control group. The toxic effect on hematoclogical parameter was characterized by significant decrease in hemoglobin, packed cell volume, total erythrocytes count, and total leukocyte count. Gross morphological changes include congestion, severe haemorrhage, necrosis, degenerative changes in kidneys, depletion of lymphocyte in spleen, decrease in concentration of mature spermatocyte, and edema in testis. It was notable that kidney was the most affected organ. Conclusion: Mercuric chloride (HgCl caused dose-dependent toxic effects on blood parameters and kidney. [Vet World 2013; 6(8.000: 563-567

  17. Long-term dose-response studies of inhaled or injected radionuclides. Biennial report, 1 October 1991--30 September 1993

    Energy Technology Data Exchange (ETDEWEB)

    Boecker, B.B.; Muggenburg, B.A.; Miller, S.C.; Bradley, P.L. [eds.


    This report describes the scientific progress in, and current status of, life-span studies of the long-term health risks in Beagle dogs of chronic irradiation from internally deposited radionuclides or from an external source. The reporting period for this document is the 2-year period from October 1, 1991 through September 30, 1993. Studies that were initiated at three different laboratories (Inhalation Toxicology Research Institute, ITRI, University of Utah, and Argonne National Laboratory, ANL) are presented here because they are being completed at ITRI. All living dogs in the Utah-initiated studies were transferred to the ITRI facility for the remainder of their life-span observations and measurements in September 1987. This report is the fourth in a series of reports dealing with the current status and progress of both the Utah and ITRI studies. Other life-span studies involving dogs exposed to gamma radiation from an external source were initiated and conducted for many years at ANL. In 1991, the decision was made to discontinue the chronic irradiation of the remaining living dogs and to transfer all remaining dogs to ITRI for care, clinical observations, and pathological observations at death or euthanasia. This report provides the current status of these dogs. Status reports on the Utah and ITRI studies comprise most of this report. The ITRI-related section presents brief statements of project objectives, the general procedures used in these studies, and some study-specific features for each of the 19 studies being conducted with either beta- or alpha-emitting radionuclides. Dose- and effect-modifying factors being addressed in these studies include total dose, dose rate, LET, solubility, nonuniformity of dose, species, age, sex, health status, and mode of exposure. Recent additions to experimental protocols for studies in which dogs are still alive involve the collection and analysis of tumor tissues using currently available molecular biology techniques.

  18. Effects of a novel organophosphorus pesticide (RPR-V) on extra hepatic detoxifying enzymes after repeated oral doses in rats. (United States)

    Mahboob, Mohammed; Kaleem, Mohammed; Siddiqui, Javed


    The effects of a novel organophosphorous pesticide, 2-butenoic acid-3-(diethoxy phosphinothionyl) ethyl ester (RPR-V) on glutathione S-transferases (GST), UDP-glucuronyl transferases (UDPGT) and the level of glutathione (GSH) were evaluated in rats after repeated oral administration at 33 microg kg(-1)day(-1) (low), 66 microg kg(-1)day(-1) (mid) and 99 microg kg(-1)day(-1) (high) for 90 days and at 28 days (withdrawal) post-treatment. GSH level and GST in kidney; GSH level in brain decreased significantly at mid and high doses on 45th and 90th day (P RPR-V has the potential to modulate the extrahepatic detoxifying enzymes and thereby interact with other physiological processes in the exposed organisms.

  19. Toxicity evaluation of zinc aluminium levodopa nanocomposite via oral route in repeated dose study (United States)

    Kura, Aminu Umar; Cheah, Pike-See; Hussein, Mohd Zobir; Hassan, Zurina; Tengku Azmi, Tengku Ibrahim; Hussein, Nor Fuzina; Fakurazi, Sharida


    Nanotechnology, through nanomedicine, allowed drugs to be manipulated into nanoscale sizes for delivery to the different parts of the body, at the same time, retaining the valuable pharmacological properties of the drugs. However, efficient drug delivery and excellent release potential of these delivery systems may be hindered by possible untoward side effects. In this study, the sub-acute toxicity of oral zinc aluminium nanocomposite with and without levodopa was assessed using the Organization for Economic Co-operation and Development guidelines. No sign or symptom of toxicity was observed in orally treated rats with the nanocomposite at 5 and 500 mg/kg concentrations. Body weight gain, feeding, water intake, general survival and organosomatic index were not significantly different between control and treatment groups. Aspartate aminotransferase (AST) in 500 mg/kg levodopa nanocomposite (169 ± 30 U/L), 5 mg/kg levodopa nanocomposite (172 ± 49 U/L), and 500 mg/kg layered double hydroxides (LDH) nanocomposite (175 ± 25 U/L) were notably elevated compared to controls (143 ± 05 U/L); but the difference were not significant ( p > 0.05). However, the differences in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of 500 mg/kg levodopa nanocomposite (0.32 ± 0.12) and 500 mg/kg LDH nanocomposite (0.34 ± 0.12) were statistically significant ( p brain was found to be of similar morphology in both control and experimental groups. The kidneys of 500-mg/kg-treated rats with levodopa nanocomposite and LDH nanocomposite were found to have slight inflammatory changes, notably leukocyte infiltration around the glomeruli. The ultra-structure of the neurons from the substantia nigra of nanocomposite-exposed group was similar to those receiving only normal saline. The observed result has suggested possible liver and renal toxicity in orally administered levodopa intercalated nanocomposite; it is also dose-dependent that needs further assessment.

  20. Biological characterization of radiation exposure and dose estimates for inhaled uranium milling effluents. Annual progress report April 1, 1982-March 31, 1983

    Energy Technology Data Exchange (ETDEWEB)

    Eidson, A.F.


    The problems addressed are the protection of uranium mill workers from occupational exposure to uranium through routine bioassay programs and the assessment of accidental worker exposures. Comparisons of chemical properties and the biological behavior of refined uranium ore (yellowcake) are made to identify important properties that influence uranium distribution patterns among organs. These studies will facilitate calculations of organ doses for specific exposures and associated health risk estimates and will identify important bioassay procedures to improve evaluations of human exposures. A quantitative analytical method for yellowcake was developed based on the infrared absorption of ammonium diuranate and U/sub 3/O/sub 8/ mixtures in KBr. The method was applied to yellowcake samples obtained from six operating mills. The composition of yellowcake from the six mills ranged from nearly pure ammonium diuranate to nearly pure U/sub 3/O/sub 8/. The composition of yellowcake samples taken from lots from the same mill was only somewhat less variable. Because uranium mill workers might be exposed to yellowcake either by contamination of a wound or by inhalation, a study of retention and translocation of uranium after subcutaneous implantation in rats was done. The results showed that 49% of the implanted yellowcake cleared from the body with a half-time (T sub 1/2) in the body of 0.3 days, and the remainder was cleared with a T sub 1/2 of 11 to 30 days. Exposures of Beagle dogs by nose-only inhalation to aerosols of commercial yellowcake were completed. Biochemical indicators of kidney dysfunction that appeared in blood and urine 4 to 8 days after exposure to the more soluble yellowcake showed significant changes in dogs, but levels returned to normal by 16 days after exposure. No biochemical evidence of kidney dysfunction was observed in dogs exposed to the less soluble yellowcake form. 18 figures, 9 tables.

  1. Treatment with budesonide/formoterol pressurized metered-dose inhaler in patients with asthma: a focus on patient-reported outcomes

    Directory of Open Access Journals (Sweden)

    Richard D O'Connor


    Full Text Available Richard D O'ConnorSharp Rees-Stealy Medical Group, San Diego, CA, USAAbstract: In the United States, budesonide/formoterol pressurized metered-dose inhaler (pMDI is approved for treatment of asthma in patients aged ≥12 years whose asthma is not adequately controlled with an inhaled corticosteroid (ICS or whose disease severity clearly warrants treatment with an ICS and a long-acting β2-adrenergic agonist. This article reviews studies of budesonide/formoterol pMDI in patients with persistent asthma, with a particular focus on patient-reported outcomes (eg, perceived onset of effect, patient satisfaction with treatment, health-related quality of life [HRQL], global assessments, sleep quality and quantity, as these measures reflect patient perceptions of asthma control and disease burden. A search of PubMed and respiratory meetings was performed to identify relevant studies. In two pivotal budesonide/formoterol pMDI studies in adolescents and adults, greater efficacy and similar tolerability were shown with budesonide/formoterol pMDI 160/9 µg and 320/9 µg twice daily versus its monocomponents or placebo. In those studies, improvements in HRQL, patient satisfaction, global assessments of asthma control, and quality of sleep also favored budesonide/formoterol pMDI compared with one or both of its monocomponents or placebo. Budesonide/formoterol pMDI has a rapid onset of effect (within 15 minutes that patients can feel, an attribute that may have benefits for treatment adherence. In summary, budesonide/formoterol pMDI is effective and well tolerated and has additional therapeutic benefits that may be important from the patient’s perspective.Keywords: budesonide, formoterol, patient-reported outcomes, efficacy, tolerability, onset of effect

  2. Computational modeling as part of alternative testing strategies in the respiratory and cardiovascular systems: inhaled nanoparticle dose modeling based on representative aerosol measurements and corresponding toxicological analysis. (United States)

    Pilou, Marika; Mavrofrydi, Olga; Housiadas, Christos; Eleftheriadis, Kostas; Papazafiri, Panagiota


    The objectives of modeling in this work were (a) the integration of two existing numerical models in order to connect external exposure to nanoparticles (NPs) with internal dose through inhalation, and (b) to use computational fluid-particle dynamics (CFPD) to analyze the behavior of NPs in the respiratory and the cardiovascular system. Regarding the first objective, a lung transport and deposition model was combined with a lung clearance/retention model to estimate NPs dose in the different regions of the human respiratory tract and some adjacent tissues. On the other hand, CFPD was used to estimate particle transport and deposition of particles in a physiologically based bifurcation created by the third and fourth lung generations (respiratory system), as well as to predict the fate of super-paramagnetic particles suspended in a liquid under the influence of an external magnetic field (cardiovascular system). All the above studies showed that, with proper refinement, the developed computational models and methodologies may serve as an alternative testing strategy, replacing transport/deposition experiments that are expensive both in time and resources and contribute to risk assessment.

  3. Screening of repeated dose toxicity data present in SCC(NF)P/SCCS safety evaluations of cosmetic ingredients. (United States)

    Vinken, Mathieu; Pauwels, Marleen; Ates, Gamze; Vivier, Manon; Vanhaecke, Tamara; Rogiers, Vera


    Alternative methods, replacing animal testing, are urgently needed in view of the European regulatory changes in the field of cosmetic products and their ingredients. In this context, a joint research initiative called SEURAT was recently raised by the European Commission and COLIPA, representing the European cosmetics industry, with the overall goal of developing an animal-free repeated dose toxicity testing strategy for human safety assessment purposes. Although cosmetic ingredients are usually harmless for the consumer, one of the initial tasks of this research consortium included the identification of organs that could potentially be affected by cosmetic ingredients upon systemic exposure. The strategy that was followed hereof is described in the present paper and relies on the systematic evaluation, by using a self-generated electronic databank, of published reports issued by the scientific committee of DG SANCO responsible for the safety of cosmetic ingredients. By screening of the repeated dose toxicity studies present in these reports, it was found that the liver is potentially the most frequently targeted organ by cosmetic ingredients when orally administered to experimental animals, followed by the kidney and the spleen. Combined listing of altered morphological, histopathological, and biochemical parameters subsequently indicated the possible occurrence of hepatotoxicity, including steatosis and cholestasis, triggered by a limited number of cosmetic compounds. These findings are not only of relevance for the in vitro modeling efforts and choice of compounds to be tested in the SEURAT project cluster, but also demonstrate the importance of using previously generated toxicological data through an electronic databank for addressing specific questions regarding the safety evaluation of cosmetic ingredients.

  4. Influence of the adaptive iterative dose reduction 3D algorithm on the detectability of low-contrast lesions and radiation dose repeatability in abdominal computed tomography: a phantom study. (United States)

    Yoon, Jeong Hee; Lee, Jeong Min; Hur, Bo Yun; Baek, Jeehyun; Shim, Hackjoon; Han, Joon Koo; Choi, Byung Ihn


    The purpose of the study is to evaluate the influence of the adaptive iterative dose reduction (AIDR 3D) algorithm on the detectability of low-contrast focal liver lesions (FLLs) and the radiation dose repeatability of automatic tube current modulation (ATCM) in abdominal CT scans using anthropomorphic phantoms. Three different sizes of anthropomorphic phantoms, each with 4 low-contrast FLLs, were scanned on a 320-channel CT scanner using the ATCM technique and AIDR 3D, at different radiation doses: full-dose, half-dose, and quarter-dose. Scans were repeated three times and reconstructed with filtered back projection (FBP) and AIDR 3D. Radiation dose repeatability was assessed using the intraclass correlation coefficient (ICC). Image noise, quality, and lesion conspicuity were assessed by four reviewers and the number of invisible FLLs was compared among different radiation doses and reconstruction methods. ICCs of radiation dose among the three CT scans were excellent in all phantoms (0.99). Image noise, quality, and lesion conspicuity in the half-dose group were comparable with full-dose FBP after applying AIDR 3D in all phantoms. In small phantoms, the half-dose group reconstructed with AIDR 3D showed similar sensitivity in visualizing low-contrast FLLs compared to full-dose FBP (P = 0.77-0.84). In medium and large phantoms, AIDR 3D reduced the number of missing low-contrast FLLs [3.1% (9/288), 11.5% (33/288), respectively], compared to FBP [10.4% (30/288), 21.9% (63/288), respectively] in the full-dose group. By applying AIDR 3D, half-dose CT scans may be achievable in small-sized patients without hampering diagnostic performance, while it may improve diagnostic performance in medium- and large-sized patients without increasing the radiation dose.

  5. Zinc oxide nanoparticles: a 90-day repeated-dose dermal toxicity study in rats

    Directory of Open Access Journals (Sweden)

    Ryu HJ


    was dose-dependent irritation at the site of application, there were no abnormal findings related to ZnO NPs in other organs. Increased concentrations of ZnO in the liver, small intestine, large intestine, and feces were thought to result from oral ingestion of ZnO NPs via licking. Penetration of ZnO NPs through the skin seemed to be limited via the dermal route. This study demonstrates that there was no observed adverse effect of ZnO NPs up to 1,000 mg/kg body weight when they are applied dermally. Keywords: zinc oxide, nanoparticles, subchronic toxicity, dermal exposure

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

    NARCIS (Netherlands)

    Dekhuijzen, P.N.R.; Batsiou, M.; Bjermer, L.; Bosnic-Anticevich, S.; Chrystyn, H.; Papi, A.; Rodriguez-Roisin, R.; Fletcher, M.; Wood, L.; Cifra, A.; Soriano, J.B.; Price, D.B.


    BACKGROUND AND AIMS: 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. MET

  7. Asthma Control Can Be Maintained after Fixed-Dose, Budesonide/Formoterol Combination Inhaler Therapy is Stepped Down from Medium to Low Dose

    Directory of Open Access Journals (Sweden)

    Masayuki Hojo


    Conclusions: If complete control of asthma, not only of clinical symptoms but also airway inflammation, is achieved by 3-6 months of fixed-dose budesonide/formoterol 4 puffs/day, it should be possible to safely perform step-down to 2 puffs/day.

  8. Repeated Intramuscular-dose Toxicity Test of Water-soluble Carthami Flos (WCF Pharmacopuncture in Sprague-Dawley Rats

    Directory of Open Access Journals (Sweden)

    Yoo-min Choi


    Full Text Available Objectives: Water-soluble carthami flos (WCF is a new mixture of Carthami flos (CF pharmacopuncture. We conducted a 4-week toxicity test of repeated intramuscular injections of WCF in Sprague-Dawley rats. Methods: Forty male and 40 female rats were divided into 4 groups of 10 male and 10 female SD rats: The control group received 0.5 mL/animal/day of normal saline whereas the three experimental groups received WCF at doses of 0.125, 0.25, and 0.5 mL/animal/day, respectively. For 4 weeks, the solutions were injected into the femoral muscle of the rats alternating from side to side. Clinical signs, body weights, and food consumption were observed; opthalmological examinations and urinalyses were performed. On day 29, blood samples were taken for hematological and clinical chemistry analyses. Then, necropsy was conducted in all animals to observe weights and external and histopathological changes in the bodily organs. All data were tested using a statistical analysis system (SAS. Results: No deaths were observed. Temporary irregular respiration was observed in male rats of the experimental group for the first 10 days. Body weights, food consumptions, opthalmological examinations, urinalyses, clinical chemistry analyses, organ weights and necropsy produced no findings with toxicological meaning. In the hematological analysis, delay of prothrombin time (PT was observed in male rats of the 0.25- and the 0.5-mL/animal/day groups. In the histopathological test, a dose-dependent inflammatory cell infiltration into the fascia and panniculitis in perimuscular tissues was observed in all animals of the experimental groups. However, those symptoms were limited to local injection points. No toxicological meanings, except localized changes, were noted. Conclusion: WCF solution has no significant toxicological meaning, but does produce localized symptoms. No observed adverse effect level (NOAEL of WCF in male and female rats is expected for doses over 0.5 mL/animal/day.

  9. Inhaler technique

    DEFF Research Database (Denmark)

    Levy, M L; Dekhuijzen, P R N; Barnes, P J


    of this process: the use of inhalers is bewildering enough, particularly with regular introduction of new drugs, devices and ancillary equipment, without unnecessary and pointless adages. We review the evidence, or lack thereof, underlying ten items of inhaler 'lore' commonly passed on by health professionals...

  10. Automatic actuation of a dry powder inhaler into a nonelectrostatic spacer

    DEFF Research Database (Denmark)

    Bisgaard, H


    This article describes a new "automatic spacer" device, which has been developed to improve the delivery of inhaled medication to young children. In the device, a dry powder inhaler (DPI) is mechanically actuated into a nonelectrostatic spacer, producing an aerosol cloud of fine drug particles...... of the patient to the additives and propellants used in pressurized metered dose inhalers. Studies with the prototype device show a high yield of fine drug particles in the aerosol (mass median aerodynamic diameter, 2.8 microm), a high repeatability of drug delivery owing to the mechanical nature...... of the actuation (relative standard deviation, 12%), and a prolonged residence time of the fine particle aerosol (half-life of the fallout of the fine particles, 82 s). These features should prove advantageous in the treatment of young children with inhaled medication....

  11. A single whole-body low dose X-irradiation does not affect L1, B1 and IAP repeat element DNA methylation longitudinally.

    Directory of Open Access Journals (Sweden)

    Michelle R Newman

    Full Text Available The low dose radioadaptive response has been shown to be protective against high doses of radiation as well as aging-induced genomic instability. We hypothesised that a single whole-body exposure of low dose radiation would induce a radioadaptive response thereby reducing or abrogating aging-related changes in repeat element DNA methylation in mice. Following sham or 10 mGy X-irradiation, serial peripheral blood sampling was performed and differences in Long Interspersed Nucleic Element 1 (L1, B1 and Intracisternal-A-Particle (IAP repeat element methylation between samples were assessed using high resolution melt analysis of PCR amplicons. By 420 days post-irradiation, neither radiation- or aging-related changes in the methylation of peripheral blood, spleen or liver L1, B1 and IAP elements were observed. Analysis of the spleen and liver tissues of cohorts of untreated aging mice showed that the 17-19 month age group exhibited higher repeat element methylation than younger or older mice, with no overall decline in methylation detected with age. This is the first temporal analysis of the effect of low dose radiation on repeat element methylation in mouse peripheral blood and the first to examine the long term effect of this dose on repeat element methylation in a radiosensitive tissue (spleen and a tissue fundamental to the aging process (liver. Our data indicate that the methylation of murine DNA repeat elements can fluctuate with age, but unlike human studies, do not demonstrate an overall aging-related decline. Furthermore, our results indicate that a low dose of ionising radiation does not induce detectable changes to murine repeat element DNA methylation in the tissues and at the time-points examined in this study. This radiation dose is relevant to human diagnostic radiation exposures and suggests that a dose of 10 mGy X-rays, unlike high dose radiation, does not cause significant short or long term changes to repeat element or global DNA

  12. Evaluation of a repeated dose liver micronucleus assay in rats treated with two genotoxic hepatocarcinogens, dimethylnitrosamine and 2-acetylaminofluorene: the possibility of integrating micronucleus tests with multiple tissues into a repeated dose general toxicity study. (United States)

    Takashima, Rie; Takasawa, Hironao; Kawasako, Kazufumi; Ohyama, Wakako; Okada, Emiko; Narumi, Kazunori; Fujiishi, Yohei; Wako, Yumi; Yasunaga, Katsuaki; Hattori, Akiko; Kawabata, Masayoshi; Nakadate, Kiyoko; Nakagawa, Munehiro; Hamada, Shuichi


    As part of a collaborative study by the Collaborative Study Group for Micronucleus Test (CSGMT) of the Mammalian Mutagenicity Study Group (MMS) in the Japanese Environmental Mutagen Society (JEMS), the present study evaluated the effectiveness of the repeated dose liver micronucleus (RDLMN) assay. Two genotoxic hepatocarcinogens, dimethylnitrosamine (DMN) and 2-acetylaminofluorene (2-AAF), were administered orally to male rats (6 weeks old at the initial dosing) once daily for 14 and 28 days to evaluate the micronucleus (MN) inducibility in the liver. In addition, these chemicals were evaluated for MN inducibility in the bone marrow (BM) and gastrointestinal (GI) tract, i.e. glandular stomach and colon of the same animals used in the RDLMN assay. As a result, both chemicals produced positive results in the liver, although a weak positive response was given by 2-AAF. DMN gave negative results in the tissues other than the liver. 2-AAF produced positive responses in the BM and glandular stomach, and a prominent response was particularly observed in the glandular stomach, which is directly exposed to the test chemicals by gavage. The present results suggest that the RDLMN assay is a useful method for detecting genotoxic hepatocarcinogens, and that it is especially effective for evaluating test chemicals, such as DMN, undetectable by the BM and GI tract MN assay. Moreover, the results in this investigation indicate that the use of multiple tissues in the study integrating the MN tests is more effective than using a single tissue, for detection of the MN induction produced by chemical exposure to rats, and helps to determine the characteristics of the test chemicals.

  13. Radiobiological restrictions and tolerance doses of repeated single-fraction hdr-irradiation of intersecting small liver volumes for recurrent hepatic metastases

    Directory of Open Access Journals (Sweden)

    Wust Peter


    Full Text Available Abstract Background To assess radiobiological restrictions and tolerance doses as well as other toxic effects derived from repeated applications of single-fraction high dose rate irradiation of small liver volumes in clinical practice. Methods Twenty patients with liver metastases were treated repeatedly (2 - 4 times at identical or intersecting locations by CT-guided interstitial brachytherapy with varying time intervals. Magnetic resonance imaging using the hepatocyte selective contrast media Gd-BOPTA was performed before and after treatment to determine the volume of hepatocyte function loss (called pseudolesion, and the last acquired MRI data set was merged with the dose distributions of all administered brachytherapies. We calculated the BED (biologically equivalent dose for a single dose d = 2 Gy for different α/β values (2, 3, 10, 20, 100 based on the linear-quadratic model and estimated the tolerance dose for liver parenchyma D90 as the BED exposing 90% of the pseudolesion in MRI. Results The tolerance doses D90 after repeated brachytherapy sessions were found between 22 - 24 Gy and proved only slightly dependent on α/β in the clinically relevant range of α/β = 2 - 10 Gy. Variance analysis showed a significant dependency of D90 with respect to the intervals between the first irradiation and the MRI control (p 90 and the pseudolesion's volume. No symptoms of liver dysfunction or other toxic effects such as abscess formation occurred during the follow-up time, neither acute nor on the long-term. Conclusions Inactivation of liver parenchyma occurs at a BED of approx. 22 - 24 Gy corresponding to a single dose of ~10 Gy (α/β ~ 5 Gy. This tolerance dose is consistent with the large potential to treat oligotopic and/or recurrent liver metastases by CT-guided HDR brachytherapy without radiation-induced liver disease (RILD. Repeated small volume irradiation may be applied safely within the limits of this study.

  14. Upregulation of nucleoside triphosphate diphosphohydrolase-1 and ecto-5'-nucleotidase in rat hippocampus after repeated low-dose dexamethasone administration. (United States)

    Drakulić, Dunja; Stanojlović, Miloš; Nedeljković, Nadežda; Grković, Ivana; Veličković, Nataša; Guševac, Ivana; Mitrović, Nataša; Buzadžić, Ivana; Horvat, Anica


    Although dexamethasone (DEX), a synthetic glucocorticoid receptor (GR) analog with profound effects on energy metabolism, immune system, and hypothalamic-pituitary-adrenal axis, is widely used therapeutically, its impact on the brain is poorly understood. The aim of the present study was to explore the effect of repeated low-dose DEX administration on the activity and expression of the ectonucleotidase enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft. Ectonucleotidases tested were ectonucleoside triphosphate diphosphohydrolase 1-3 (NTPDase1-3) and ecto-5'-nucleotidase (eN), whereas the effects were evaluated in two brain areas that show different sensitivity to glucocorticoid action, hippocampus, and cerebral cortex. In the hippocampus, but not in cerebral cortex, modest level of neurodegenerative changes as well as increase in ATP, ADP, and AMP hydrolysis and upregulation of NTPDase1 and eN mRNA expression ensued under the influence of DEX. The observed pattern of ectonucleotidase activation, which creates tissue volume with enhanced capacity for adenosine formation, is the hallmark of the response after different insults to the brain.

  15. Twelve-week efficacy and safety study of mometasone furoate/formoterol 200/10 microg and 400/10 microg combination treatments in patients with persistent asthma previously receiving high-dose inhaled corticosteroids

    DEFF Research Database (Denmark)

    Weinstein, Steven F; Corren, Jonathan; Murphy, Kevin


    with asthma uncontrolled on high-dose inhaled corticosteroids (ICS). In a 12-week, randomized, multicenter, double-blind, parallel-group study, patients (>or=12 years of age) were randomized to MF/F 200/10 microg, MF/F 400/10 microg, or MF 400 microg, b.i.d. after a 2- to 3-week open-label run in with MF 400...

  16. Assessment of inhalation and ingestion doses from exposure to radon gas using passive and active detecting techniques

    Energy Technology Data Exchange (ETDEWEB)

    Ismail, A. H.; Jafaar, M. S. [Universiti Sains Malaysia, 11800 USM, Penang (Malaysia)


    The aim of this study was to assess an environmental hazard of radon exhalation rate from the samples of soil and drinking water in selected locations in Iraqi Kurdistan, passive (CR-39NTDs) and active (RAD7) detecting techniques has been employed. Long and short term measurements of emitted radon concentrations were estimated for 124 houses. High and lower radon concentration in soil samples was in the cities of Hajyawa and Er. Tyrawa, respectively. Moreover, for drinking water, high and low radon concentration was in the cities of Similan and Kelak, respectively. A comparison between our results with that mentioned in international reports had been done. Average annual dose equivalent to the bronchial epithelium, stomach and whole body in the cities of Kelak and Similan are estimated, and it was varied from 0.04{+-}0.01 mSv to 0.547{+-}0.018 mSv, (2.832{+-}0.22)x10{sup -5} to (11.972{+-}2.09)x10{sup -5} mSv, and (0.056 {+-}0.01) x10{sup -5} to (0.239{+-}0.01)x10{sup -5} mSv, respectively. This indicated that the effects of dissolved radon on the bronchial epithelium are much than on the stomach and whole body. (authors)

  17. Iloprost inhalation in mild asthma. (United States)

    Majeski, Elizabeth; Hoskins, Aimee; Dworski, Ryszard; Sheller, James R


    To determine the feasibility of administering iloprost by inhalation in patients with mild atopic asthma. Volunteers underwent supervised inhalation of iloprost in the clinic with measurement of spirometry and blood pressure for 2 hours. The volunteers then inhaled iloprost four times daily at a dose of 2.5 or 5 μg for 14 days. Spirometry, asthma questionnaires, peak flow diaries, measurement of methacholine responsiveness, and exhaled nitric oxide concentrations were obtained prior to and after the treatment period. Chronic inhalation of iloprost (2.5-5 μg) did not alter spirometry or methacholine responsiveness. Inhaled iloprost in carefully selected volunteers with mild asthma appears to be a suitable intervention to explore the effects of prostacyclin in human asthma.

  18. Study on Effectiveness of Low Dose Theophylline as Add-on to Inhaled Corticosteroid for Patients with Sulfur Mustard Induced Bronchiolitis

    Directory of Open Access Journals (Sweden)

    Yunes Panahi


    , Saburi A, Shohrati M, Ghanei M. Study on Effectiveness of Low Dose Theophylline as Add-on to Inhaled Corticosteroid for Patients with Sulfur Mustard Induced Bronchiolitis. Asia Pac J Med Toxicol 2013;2:126-130.

  19. Inhalation delivery of asthma drugs. (United States)

    Matthys, H


    In the immediate future, metered-dose inhalers (MDIs) with spacers remain the aerosol application of choice for topical steroids, mainly to reduce side effects. For beta 2-agonist, anticholinergics and prophylactic drugs, MDI (with or without demand valve), dry powder inhalers (multidose inhalers), ultrasonic or jet aerosol generators (with or without mechanical breathing assistance [IPPB]) are chosen according to the preference or the ability of the patients to perform the necessary breathing maneuvers as well as the availability of different products in different countries.

  20. SULT 1A3 single-nucleotide polymorphism and the single dose pharmacokinetics of inhaled salbutamol enantiomers: are some athletes at risk of higher urine levels? (United States)

    Jacobson, Glenn A; Yee, Kwang Choon; Wood-Baker, Richard; Walters, E Haydn


    The study was designed to investigate the effect of a common genetic variation of the main salbutamol metabolizing enzyme SULT1A3 (single nucleotide polymorphism 105A>G, rs1975350) on the stereoselective pharmacokinetics of salbutamol. Subjects were administered a 400 µg dose of inhaled salbutamol via a large volume spacer and blood samples were collected over 4 h. Plasma levels of (R)- and (S)-salbutamol were determined by an enantioselective liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. Twenty-five subjects with asthma were recruited and underwent SULT1A3 genotyping, from which four SNP homozygote (GG) subjects and nine wild-type (AA) subjects were selected to participated in the pharmacokinetic investigation. There were no differences in pharmacokinetic parameters (t1/2 , Cmax , AUC0-4h ) between SNP and wild-type genotypes for either the R- or S-enantiomer. Observed Cmax of R- and S-salbutamol [mean (SD)] was 0.64 (0.30) ng/mL and 1.32 (0.98) ng/mL, respectively. The mean t1/2 of R- and S-salbutamol was estimated at 2.94 (1.17) h and 7.86 (6.14) h respectively. The AUC0-4h of R- and S-salbutamol was 14.0 (6.8) and 38.3 (19.5) ng/mL.h respectively. In conclusion, the common SULT1A3 SNP 105A>G is not an important determinant of salbutamol enantiomer pharmacokinetics under normal clinical use and does not place some individuals at greater risk of accumulation in the body.

  1. The efficacy of single-high dose inhaled corticosteroid versus oral prednisone treatment on exhaled leukotriene and 8-isoprostane levels in mild to moderate asthmatic children with asthma exacerbation. (United States)

    Keskin, O; Uluca, U; Keskin, M; Gogebakan, B; Kucukosmanoglu, E; Ozkars, M Y; Kul, S; Bayram, H; Coskun, Y


    The anti-inflammatory effect of high-dose inhaled corticosteroids (ICS) in children with asthma exacerbation is unknown. We aimed to investigate the efficacy of single-high dose ICS versus oral prednisone treatment followed by a course of six day high-dose ICS or oral prednisone (P) treatment on the concentrations of Cys-LTs and 8-isoprostane levels in the exhaled breath condensate (EBC) of children with asthma exacerbation. Ninety-four children with moderate-severe asthma exacerbation were evaluated with asthma scores, peak expiratory flow rate (PEF), forced expiratory volume in first second (FEV1) and exhaled Cys-LT and 8-isoprostane levels before and after treatment. EBC was collected from 52 patients before and four hours after treatment with inhaled fluticasone propionate (FP) (4000 μg) or P and after six days of treatment with FP-1000 μg/day or P. Cys-LTs and 8-isoprostane concentrations were determined using a specific immunoassay kit. Both single high-dose FP (n=59) and p (n=35) treatment resulted in a significant improvement in asthma score (pchildren with asthma exacerbation. High-dose ICS treatment may be useful in the treatment of children with asthma exacerbation. The effects start as early as after four hours. The suppression of Cys-LTs production contributes to the early effects. Suppression of both Cys-LTs and oxidants may favourably contribute to the effects observed later. Copyright © 2015 SEICAP. Published by Elsevier Espana. All rights reserved.

  2. Activity and Safety of Inhaled Itraconazole Nanosuspension in a Model Pulmonary Aspergillus fumigatus Infection in Inoculated Young Quails. (United States)

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


    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.

  3. Comparable long-term safety and efficacy of a novel budesonide/formoterol pressurized metered-dose inhaler versus budesonide/formoterol Turbuhaler in adolescents and adults with asthma. (United States)

    Morice, Alyn H; Hochmuth, Ludĕk; Ekelund, Jan; Thorén, Anders; Puterman, Allan S


    Budesonide/formoterol in one inhaler is an established therapy for asthma and chronic obstructive pulmonary disease. The long-term safety and efficacy profile of a novel hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) formulation of budesonide/formoterol was compared with that of budesonide/formoterol in a dry powder inhaler (DPI; Turbuhaler). This multinational, 52-week, randomized, open, parallel-group study included patients aged > or = 12 years with asthma who had a forced expiratory volume in 1s (FEV1)> or = 50% of predicted normal; all patients used inhaled corticosteroids (400-1200 microg/day) and needed additional short-acting beta 2-agonist therapy. Patients were randomized to receive budesonide/formoterol pMDI or DPI 160/4.5 microg, two inhalations twice daily. Safety endpoints included assessment of adverse events and laboratory parameters. Efficacy endpoints included change from baseline in FEV1 and time to first severe asthma exacerbation. Overall, 673 patients (446pMDI, 227DPI) were included. There were no clinically significant differences between treatment groups in the nature, incidence or severity of adverse events or laboratory parameters. The number of patients experiencing adverse events was comparable in the pMDI (332/446 [74%]) and DPI (175/227 [77%]) groups; the most commonly reported adverse event was upper respiratory tract infection. The proportion of patients discontinuing as a result of adverse events was low in both groups (pMDI 12/446 [3%], DPI 2/227 [1%]). Lung function was improved to a similar extent in both groups and there was no detectable difference in time to first severe asthma exacerbation. The novel HFA pMDI formulation of budesonide/formoterol is an equally well tolerated and effective treatment for adults and adolescents with asthma as the budesonide/formoterol DPI.

  4. Inhaler device preferences in older adults with chronic lung disease

    Directory of Open Access Journals (Sweden)

    Ghazala L


    Full Text Available Introduction: Patient preferences are important for medication adherence and patient satisfaction, but little is known about older adult preferences for inhaler devices. Methods: We developed a 25-item written self-administered questionnaire assessing experience with inhalers, prior inhaler education, and preferences with respect to inhaler device features and inhaler device teaching. We then conducted a cross-sectional survey of patients at least 65 years of age with chronic lung disease who had experience using inhaler devices for at least six months in the ambulatory setting. Results: Fifty participants completed the questionnaire. The majority of participants (80% reported prior experience with a metered dose inhaler (MDI, but only 26% used an MDI with a spacer. Most patients (76% had received formal instruction regarding proper use of the inhaler, but only 34% had ever been asked to demonstrate their inhaler technique. Physician recommendation for an inhaler, cost of the inhaler device, and inhaler features related to convenience were important with respect to patient preferences. With regard to inhaler education, participants prefer verbal instruction and/or hands-on demonstration at the time a new inhaler is prescribed in the setting of the prescribing provider’s office. Conclusion: Patient preferences for inhaler devices and inhaler education among older adults indicate physician recommendation, cost, and convenience are important. The impact of patient preferences on inhaler adherence and clinical outcomes remains unknown.

  5. Effects of roflumilast in COPD patients receiving inhaled corticosteroid/long-acting β2-agonist fixed-dose combination: RE2SPOND rationale and study design

    Directory of Open Access Journals (Sweden)

    Rennard SI


    Full Text Available Stephen I Rennard,1,2 Fernando J Martinez,3,4 Klaus F Rabe,5–7 Sanjay Sethi,8 Emilio Pizzichini,9 Andrew McIvor,10 Shahid Siddiqui,11 Antonio Anzueto,12 Haiyuan Zhu13 1Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 2AstraZeneca, Cambridge, UK; 3Joan and Sanford I Weill Department of Medicine, Weill Cornell University, New York, NY, 4Department of Internal Medicine, Michigan Health System, Ann Arbor, MI, USA; 5LungenClinic Grosshansdorf, Großhansdorf, 6Department of Medicine, University Kiel, Kiel, 7Airway Research Center North, German Center for Lung Research, Großhansdorf, Germany; 8Department of Medicine, University at Buffalo, State University of New York, Buffalo, NY, USA; 9Department of Medicine, Universidade Federal de Santa Catarina, Santa Catarina, Brazil; 10Firestone Institute of Respiratory Health, St Joseph’s Healthcare, McMaster University, Hamilton, ON, Canada; 11AstraZeneca, Gaithersburg, MD, 12South Texas Veterans Health Care System at San Antonio, University of Texas Health Science Center, San Antonio, TX, 13Allergan plc, Jersey City, NJ, USA Background: Roflumilast, a once-daily, selective phosphodiesterase-4 inhibitor, reduces the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. The RE2SPOND study is examining whether roflumilast, when added to an inhaled corticosteroid/long-acting β2-agonist (ICS/LABA fixed-dose combination (FDC, further reduces exacerbations. The methodology is described herein. Methods: In this Phase IV, multicenter, double-blind, placebo-controlled, parallel-group trial, participants were randomized 1:1 (stratified by long-acting muscarinic antagonist use to receive roflumilast or placebo, plus ICS/LABA FDC, for 52 weeks. Eligible participants had severe COPD associated with chronic bronchitis, had two or more moderate–severe exacerbations within 12 months, and were receiving ICS

  6. Detection of the effects of repeated dose combined propoxur and heavy metal exposure by measurement of certain toxicological, haematological and immune function parameters in rats. (United States)

    Institóris, L; Siroki, O; Undeger, U; Basaran, N; Banerjee, B D; Dési, I


    In the present study, an immunotoxicity test system, containing general toxicological (body weight gain, organ weights), haematological (WBC,RBC, Ht, mean cell volume of the RBCs, cell content of the femoral bone marrow), and immune function (PFC assay, DTH reaction) investigations, was used for detection the effects of a 4 weeks repeated low dose combined oral exposure of male Wistar rats with propoxur and the heavy metals arsenic or mercury. Two doses of the compounds were used: a higher one (the lowest dose which resulted in significant change of at least one parameter examined in previous dose-effect experiments), and a lower one (the highest dose which proved to be non-effective). The applied doses were: 8.51 and 0.851 mg kg(-1) of propoxur, 13.3 and 3.33 mg kg(-1) of NaAsO(2), and 3.20 and 0.40 mg kg(-1) of HgCl(2). In the combination treatment, the high dose of propoxur was combined with the low dose of arsenic or mercury, and the high doses of each heavy metals were combined with the low dose of propoxur. The main finding of this study was that some of the combinations significantly altered the relative weight of liver, adrenals and kidneys, related to both the untreated and the high dose internal control. Among the immune functions examined, only the PFC content of the spleen showed a trend of changes in certain combinations versus the corresponding high dose control. According to the present results, combined exposure with propoxur and the heavy metals examined can modify the detection limit of the single compounds and/or may alter their toxic effects.

  7. Adhesive mixtures for inhalation : the cohesion between formulation variables, inhalation variables and dispersion performance

    NARCIS (Netherlands)

    Grasmeijer, Floris


    Powdery drugs for inhalation to treat asthma and COPD are often mixed with lactose to enable their accurate dosing. However, because the drug particles adhere strongly to the lactose particles, they are difficult to disperse with the aid of a dry powder inhaler. As a result, over half the dose usual

  8. Collaborative work on evaluation of ovarian toxicity. 2) Two- or four-week repeated dose studies and fertility study of mifepristone in female rats. (United States)

    Tamura, Toru; Yokoi, Ryohei; Okuhara, Yuji; Harada, Chiho; Terashima, Yukari; Hayashi, Morimichi; Nagasawa, Tatsuya; Onozato, Tomoya; Kobayashi, Kazuo; Kuroda, Junji; Kusama, Hiroshi


    In order to assess ovarian pathological changes and their relationship to changes in female fertility parameters, mifepristone, a progesterone receptor antagonist, was selected as the test article and was administered orally to female rats at dose levels of 0, 0.8, 4, 20 and 100 mg/kg for 2 or 4 weeks in repeated dose-toxicity studies and in a female fertility study at dose levels of 0, 0.8, 4 and 20 mg/kg from > 2 weeks before copulation to postcoital day 7. In the repeated dose toxicity studies, persistent estrus was seen in the vaginal smears, and multiple cysts in the ovaries at necropsy, increases in luteinized cysts and hypertrophy of previously formed corpora lutea were observed in the histopathological examination of ovaries in rats receiving 20 mg/kg or more for 2 or 4 weeks. In female fertility studies, persistent vaginal cornification was also observed at 20 mg/kg and the precoital interval was significantly shortened. All of the animals were completely infertile when dosed with 20 mg/kg during the post-coital period. An increase in pre-implantation losses was observed in the animals treated with 20 mg/kg during the pre-coital phase, while treatment with 4 mg/kg mifepristone during the post-coital phase induced an increase in post-implantation losses. These results suggested that a 2-week administration period would be sufficient to detect the ovarian toxicity of mifepristone in repeated dose toxicity study and the pathological findings in the ovaries would reflect the alterations in female reproductive endpoints in the female fertility study.

  9. Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: implications for treatment in Alzheimer's disease. (United States)

    Ferruzzi, Mario G; Lobo, Jessica K; Janle, Elsa M; Cooper, Bruce; Simon, James E; Wu, Qing-Li; Welch, Cara; Ho, Lap; Weaver, Connie; Pasinetti, Giulio M


    The present study explored the bioavailability and brain deposition of a grape seed polyphenolic extract (GSPE) previously found to attenuate cognitive deterioration in a mouse model of Alzheimer's disease (AD). Plasma pharmacokinetic response of major GSPE phenolic components was measured following intragastric gavage of 50, 100, and 150 mg GSPE per kg body weight. Liquid chromatography-mass spectrometry (LC-MS) analysis identified gallic acid (GA), catechin (C), and epicatechin (EC) in plasma of rats gavaged acutely with GSPE. Additionally, 4-methylgallic acid (4-OMeGA), 3'-methylcatechin (3'-OMeC), and 3'-methylepicatechin (3'-OMeEC) were identified as circulating metabolites of GSPE phenolic constituents. Cmax for individual GSPE constituents and their metabolites increased in a dose-dependent fashion (with increasing GSPE oral dose). Repeated daily exposure to GSPE was found to significantly increase bioavailability (defined as plasma AUC0-8h) of GA, C, and EC by 198, 253, and 282% relative to animals receiving only a single acute GSPE dose. EC and C were not detectable in brain tissues of rats receiving a single GSPE dose but reached levels of 290.7 +/-45.9 and 576.7 +/- 227.7 pg/g in brain tissues from rats administered GSPE for 10 days. This study suggests that brain deposition of GA, C, and EC is affected by repeated dosing of GSPE.

  10. Broncodilatadores en la crisis asmática: ¿Aerosol o nebulización? Bronchodilators in acute asthma: metered dose inhalers or wet nebulizations?

    Directory of Open Access Journals (Sweden)

    Dora M. Lombardi


    Full Text Available El número de consultas por asma aguda en el Hospital María Ferrer ha aumentado de 3300 consultas anuales en 1980 a 15364 en 2002. Los broncodilatadores de acción corta (salbutamol-ipratropio en nebulizaciones, procedimiento que consume tiempo y recursos humanos, eran el tratamiento inicial en 2002. Para tratar de mejorar el cumplimiento del tratamiento frente al aumento de la demanda, se reemplazaron las nebulizaciones por aerosoles dosificadores. El objetivo de este estudio es evaluar el impacto de este cambio. Comparamos 90 pacientes con crisis asmática tratados con aerosoles en diciembre del 2003 con igual número tratados con nebulizaciones en diciembre del 2002 pareados por sexo, edad, altura, VEF1 teórico y de ingreso. Con aerosoles se observó una reducción significativa del tiempo de permanencia en el Departamento de Emergencia (mediana 3 h (2-4.75 versus 4 h (1-6 p=0.01 y un número mayor de altas en las primeras 2 horas (48% vs. 31% p=0.03. Los pacientes tratados con aerosol recibieron el 87% de las dosis prescriptas, mientras que el otro grupo recibió sólo el 38%. El VEF1 mostró una tendencia a ser mayor al egreso en el grupo que recibió aerosoles, pero la diferencia no fue estadísticamente significativa (78% ± 17% vs. 73% ± 17% p=0.09. El porcentaje de alta final fue similar en los dos grupos (96% vs. 93%. El tratamiento con aerosoles produjo una mejoría más rápida y mejor cumplimiento de las normas de tratamiento indicadas.The number of patients attending our Emergency Department (ED with acute asthma has increased from 3300 patient/year in 1980 to 15364 in 2003. Short acting bronchodilators (albuterol/ipratropium administered in wet nebulizations, a resource consuming procedure, were our main initial treatment in 2002. To improve treatment goals, we switched the method of bronchodilator delivery to metered dose inhalers (MDI in 2003. The purpose of this study is to evaluate the impact of this change in the

  11. Effect of repeated inhalation of sevoflurane on cognitive function in infantile rats%反复吸入七氟烷对幼年大鼠认知功能的影响

    Institute of Scientific and Technical Information of China (English)

    王志萍; 谢蕾; 江山; 曾因明


    Objective To investigate the effects of repeated inhalation of sevoflurane on cognitive function in infantile rats.MethodsOne hundred and eisht 25-35 day old infantile SD rats weighing 90-100 g were randomly divided into 6 groups(n=18 each):group C1,C2,C3 and group S1,S2,S3.Group C1,C2 and C3 inhaled pure oxygen(0.5 L/min)1 h/d for 1,3 and 5 d respectively,while group S1,S2 and S3 inhaled 2.3% sevoflurane in O2(0.5 L/min)1 h/d for 1,3 and 5 d respectively.Seven days after the last inhalation,learning and memory function were assessed using Moms Water Maze(MWM)test in 10 animals in each group;another 8 animals were decapitated under ether anesthesia.Brains were removed and hippocampal slices were prepared and long-term potentiation(LTP)was induced according to the technique described by Lynch.Results There were no significant differences in the number of exercises required for the rats to reach the safe platform,the latency of escaping and the number of times the rats entered the dead end between the corresponding group C and S.The Success rats of LTP induction was significantly lower in group S3 than in group C3.There was no significant difference in the success rate of LTP induction between group C1 and S1 and group C2 and S2.Conclusion Although repeated inhalation of sevoflurflne can depress the formation of LTP,the degree of depression is tOO low to influence the cognitive function in infantile rats.%目的 评价反复吸入七氟烷对幼年大鼠认知功能的影响.方法 健康雄性SD大鼠108只,25~35日龄,体重90~100 g,随机分为6组(n=18),C1组、C2组和C3组每天同一时间吸入纯氧0.5 L/min,1 h/次,分别吸入1、3、5 d;S1组、S2组和S3组每天同一时间吸入2.3%七氟烷及纯氧0.5 L/min,1 h/次,分别吸1、3、5 d.干预结束后7 d,各组随机取10只大鼠进行水迷宫实验,记录达标所需训练次数、逃避潜伏期及进入盲端次数;其余8只记录神经电生理强直刺激后群峰电位(PS)振幅,计算

  12. Genotoxic and inflammatory effects of depleted uranium particles inhaled by rats. (United States)

    Monleau, Marjorie; De Méo, Michel; Paquet, François; Chazel, Valérie; Duménil, Gérard; Donnadieu-Claraz, Marie


    Depleted uranium (DU) is a radioactive heavy metal coming from the nuclear industry and used in numerous military applications. Uranium inhalation can lead to the development of fibrosis and neoplasia in the lungs. As little is known concerning the molecular processes leading to these pathological effects, some of the events in terms of genotoxicity and inflammation were investigated in rats exposed to DU by inhalation. Our results show that exposure to DU by inhalation resulted in DNA strand breaks in broncho-alveolar lavage (BAL) cells and in increase of inflammatory cytokine expression and production of hydroperoxides in lung tissue suggesting that the DNA damage was in part a consequence of the inflammatory processes and oxidative stress. The effects seemed to be linked to the doses, were independent of the solubility of uranium compounds and correlating with the type of inhalation. Repeated inhalations seemed to induce an effect of potentiation in BAL cells and also in kidney cells. Comet assay in neutral conditions revealed that DNA damage in BAL cells was composed partly by double strands breaks suggesting that radiation could contribute to DU genotoxic effects in vivo. All these in vivo results contribute to a better understanding of the pathological effect of DU inhalation.

  13. Comparative Study for Clinical Effect on Bronchial Asthma between Single - dose Inhalation of Salmeterol and Fluticas and Double - dose Inhalation of Flonase%单剂量沙美特罗替卡松与双倍剂量替卡松吸入治疗支气管哮喘临床疗效的比较研究

    Institute of Scientific and Technical Information of China (English)



    目的:比较单剂量沙美特罗替卡松与双倍剂量替卡松吸入治疗支气管哮喘的临床疗效。方法选取2014年6月—2015年4月重庆北部新区第一人民医院呼吸科收治的支气管哮喘患者78例,按照住院单双号分为单剂量组36例和双倍剂量组42例。单剂量组患者给予沙美特罗替卡松粉吸入剂(规格:50μg/250μg)吸入治疗,1吸/次,2次/ d;双倍剂量组患者给予丙酸氟替卡松吸入气雾剂(规格:125μg/揿)吸入治疗,4揿/次,2次/ d。比较两组患者治疗前及治疗2个月日间症状评分和夜间症状评分、肺功能指标〔第一秒用力呼气容积(FEV1)、用力肺活量(FVC)、呼气峰流速(PEF)〕,痰中嗜酸粒细胞分数(EOS)、中性粒细胞分数(NEU)、淋巴细胞分数(LYM)、巨噬细胞分数(MAC)、上皮细胞分数(EE)及白介素5(IL -5)水平,血浆皮质醇水平。结果两组患者治疗前及治疗2个月日间症状评分和夜间症状评分及 FEV1、FVC、PEF 比较,差异无统计学意义(P ﹥0.05);两组患者治疗2个月日间症状评分和夜间症状评分均低于治疗前,FEV1、PEF 均高于治疗前(P ﹤0.05)。两组患者治疗前及治疗2个月痰中 EOS、NEU、LYM、MAC、EE 及 IL -5水平比较,差异无统计学意义(P ﹥0.05);两组患者治疗2个月痰中 EOS及 IL -5水平低于治疗前(P ﹤0.05)。两组患者治疗前及治疗2个月血浆皮质醇水平比较,差异无统计学意义(P ﹥0.05)。结论单剂量沙美特罗替卡松吸入治疗支气管哮喘的临床疗效及对气道炎症的控制效果与双倍剂量替卡松相似,但激素用量更小,不良反应发生风险更低。%Objective To compare the clinical effect on bronchial asthma between single - dose inhalation of salmeterol and fluticas and double - dose inhalation of flonase. Methods A total of 78 patients with bronchial asthma were

  14. Hemodynamic effects of combination therapy with inhaled nitric oxide and iloprost in patients with pulmonary hypertension and right ventricular dysfunction after high-risk cardiac surgery. (United States)

    Antoniou, Theofani; Koletsis, Efstratios N; Prokakis, Christos; Rellia, Panagiota; Thanopoulos, Apostolos; Theodoraki, Kassiani; Zarkalis, Dimitrios; Sfyrakis, Petros


    The purpose of this study was to evaluate the hemodynamic effects of inhaled nitric oxide (NO) plus aerosolized iloprost in patients with pulmonary hypertension/right ventricular dysfunction after cardiac surgery. A retrospective study. A single center. Eight consecutive patients with valve disease and postextracorporeal circulation (ECC) pulmonary hypertension/right ventricular dysfunction. The continuous inhalation of nitric oxide (10 ppm) and iloprost, 10 μg, in repeated doses. The hemodynamic profile was obtained before inhalation, during the administration of inhaled NO alone (prior and after iloprost), and after the first 2 doses of iloprost. Tricuspid annular velocity and tricuspid annular plane systolic excursion were estimated at baseline and before and after adding iloprost. At the end of the protocol, there were significant decreases in pulmonary vascular resistance (p iloprost dose was associated with further decreases in pulmonary vascular resistances/pressure. By comparing data at the beginning of inhaled NO with those after the second dose of iloprost, the authors noticed decreases in pulmonary vascular resistances (p = 0.004) and the mean pulmonary artery pressure (p = 0.017) and rises in tricuspid annular velocity (p iloprost significantly reduced pulmonary hypertension and contributed to the improvement in right ventricular function. Inhaled NO and iloprost have additive effects on pulmonary vasculature. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. The abbreviated impactor measurement (AIM) concept: part 1--Influence of particle bounce and re-entrainment-evaluation with a "dry" pressurized metered dose inhaler (pMDI)-based formulation. (United States)

    Mitchell, J P; Nagel, M W; Avvakoumova, V; MacKay, H; Ali, R


    The abbreviated impactor measurement concept is a potential improvement to the labor-intensive full-resolution cascade impactor methodology for inhaler aerosol aerodynamic particle size distribution (APSD) measurement by virtue of being simpler and therefore quicker to execute. At the same time, improved measurement precision should be possible by eliminating stages upon which little or no drug mass is collected. Although several designs of abbreviated impactor systems have been developed in recent years, experimental work is lacking to validate the technique with aerosols produced by currently available inhalers. In part 1 of this two-part article that focuses on aerosols produced by pressurized metered dose inhalers (pMDIs), the evaluation of two abbreviated impactor systems (Copley fast screening Andersen impactor and Trudell fast screening Andersen impactor), based on the full-resolution eight-stage Andersen nonviable cascade impactor (ACI) operating principle, is reported with a formulation producing dry particles. The purpose was to investigate the potential for non-ideal collection behavior associated with particle bounce in relation to internal losses to surfaces from which particles containing active pharmaceutical ingredient are not normally recovered. Both abbreviated impactors were found to be substantially equivalent to the full-resolution ACI in terms of extra-fine and fine particle and coarse mass fractions used as metrics to characterize the APSD of these pMDI-produced aerosols when sampled at 28.3 L/min, provided that precautions are taken to coat collection plates to minimize bounce and entrainment.

  16. Twenty-six-week efficacy and safety study of mometasone furoate/formoterol 200/10 microg combination treatment in patients with persistent asthma previously receiving medium-dose inhaled corticosteroids

    DEFF Research Database (Denmark)

    Nathan, Robert A; Nolte, Hendrik; Pearlman, David S


    deteriorations and pulmonary function in patients with asthma uncontrolled on medium-dose inhaled corticosteroid (ICS). After 2- to 3-week open-label run-in with MF 200 microg b.i.d., patients (>or=12 years) were randomized to 26 weeks of treatment with MF/F 200/10 microg, MF 200 microg, F 10 microg, or placebo...... with MF/F 200/10 microg reduced asthma deteriorations and clinically judged deteriorations (i.e., deterioration resulting in emergency treatment, hospitalization, or treatment with additional excluded asthma medication [i.e., systemic corticosteroids]). The proportion of patients experiencing asthma...

  17. Cost-effectiveness of fluticasone propionate administered via metered-dose inhaler plus babyhaler spacer in the treatment of asthma in preschool-aged children

    DEFF Research Database (Denmark)

    Bisgaard, H; Price, M J; Maden, Christian Nicolai;


    STUDY OBJECTIVES: To evaluate the cost-effectiveness of inhaled fluticasone propionate (FP) in children aged 12 to 47 months with asthma symptoms. DESIGN: A retrospective economic analysis conducted from the perspective of the Danish health-care system, based on clinical data from a 12-week study...

  18. Terbutaline: level the playing field for inhaled β2-agonists by introducing a dosing and urine threshold

    DEFF Research Database (Denmark)

    Jacobson, Glenn A; Hostrup, Morten


    Terbutaline, a short-acting β2-agonist similar to salbutamol, is widely used in Europe in the treatment of asthma and exercise-induced bronchoconstriction. Unlike salbutamol, terbutaline requires therapeutic use exemption (TUE) for therapeutic inhaled use in competitive sport. There is now...

  19. Use of inhaled corticosteroids in pediatric asthma

    DEFF Research Database (Denmark)

    Bisgaard, H


    Inhaled corticosteroids reduce asthma symptoms and exacerbations, improve lung function, and reduce airway inflammation and bronchial hyperreactivity more effectively than other treatments. However, inhaled corticosteroids may be unable to return lung function and bronchial hyperreactivity...... of the disease. Therefore, a change in treatment strategy toward earlier introduction of corticosteroids may impede airway remodeling, bronchial hyperreactivity, and airway damage. No other treatment has been found to affect the course of the disease. Systemic side-effects, particularly inhibition of growth...... in asthmatic children using inhaled corticosteroids, do not seem to be cause for concern. Growth retardation has not been reported when inhaled corticosteroid doses of

  20. Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 22). Effects of 2- and 4-week administration of theobromine on the testis. (United States)

    Funabashi, H; Fujioka, M; Kohchi, M; Tateishi, Y; Matsuoka, N


    The effects of theobromine, a xanthine derivative, on the testis were compared between rats dosed for 2 and 4 weeks to determine whether a 2-week dosing period is long enough to detect toxicity. Theobromine was administered orally to male Sprague-Dawley rats at dose levels of 250 and 500 mg/kg for 2 weeks starting at the age of 6 or 8 weeks, and for 4 weeks from the age of 6 weeks. Histopathological examination of reproductive organs revealed toxic findings in the testis at 500 mg/kg after 2 weeks of dosing at both ages, and at 250 and 500 mg/kg after 4 weeks of dosing. The primary findings were degeneration/necrosis and desquamation of spermatids and spermatocytes, vacuolization of seminiferous tubules, and multinucleated giant cell formation. These findings were present mainly in stages I-VI and XII-XIV. From these results, it is concluded that the toxic effects of theobromine on the testis can be detected by repeated dosing for 2 weeks as well as for 4 weeks.

  1. Collaborative work on evaluation of ovarian toxicity. 17) Two- or four-week repeated-dose studies and fertility study of sulpiride in female rats. (United States)

    Ishii, Shun-ichiro; Ube, Masayuki; Okada, Miyoko; Adachi, Tamiko; Sugimoto, Jiro; Inoue, Yoshimi; Uno, Yoshifumi; Mutai, Mamoru


    To find the appropriate dosing period to detect ovarian toxicity, sulpiride, a D2 antagonist was orally dosed to female rats at dose levels of 1, 10, and 100 mg/kg/day daily for 2 or 4 weeks in repeated-dose toxicity studies. In addition, sulpiride at the same dose levels was given to female rats daily during the pre-mating period, mating period, and Days 0-7 of gestation to assess its effect on fertility. In ovarian histology in the 2-week study, increases in atretic follicle were seen at 1 mg/kg or more and increases in follicular cysts at 10 mg/kg or more. In the 4-week study, these findings were seen at 1 mg/kg or more, and a decrease in large follicles was seen at 10 mg/kg or more. Increased body weight gain was observed at 10 mg/kg or more in the 2- and 4-week studies. The females in these groups exhibited development of mammary alveolus by sulpiride-induced hyperprolactinemia. In the fertility study, sulpiride-treated females showing persistent diestrus resulted in successful mating, and almost all females got pregnant. However, increased implantation loss was observed at 10 mg/kg or more, which was considered to be caused by the adverse effect of sulpiride on oocyte development. From these results, sulpiride-induced ovarian toxicity was seen at 1 mg/kg or more in the 2- and 4-week repeated-dose toxicity studies, and the observed ovarian changes were considered to be related to adverse effects on female fertility.

  2. Development of sensitisation or tolerance following repeated OVA inhalation in BALB/cJ mice. Dose-dependency and modulation by the Al(OH)3 adjuvant

    DEFF Research Database (Denmark)

    Clausen, Susanne Knoth; Bergqvist, Mette; Poulsen, Lars K.


    Anthropogenically induced exposures may, due to their adjuvant effect, promote development of sensitisation to commonly occurring aeroallergens. No generally accepted model exists for determination of adjuvant effect of airborne substances. Therefore, BALB/cJ mice were exposed for 10 consecutive ...

  3. Know How to Use Your Asthma Inhaler

    Medline Plus

    Full Text Available ... On: Walking Through the Steps and Standards 2. Getting Started 3. Describing and Focusing 3A. Focus On: ... a video to follow along with the correct way to use your metered dose inhaler. Print the ...

  4. Know How to Use Your Asthma Inhaler

    Medline Plus

    Full Text Available ... things that can cause an attack. Watch a video to follow along with the correct way to use your metered dose inhaler. Print the step-by-step instructions and keep them with your Asthma Action Plan. ...

  5. Know How to Use Your Asthma Inhaler

    Medline Plus

    Full Text Available ... Quick Links Asthma Action Plan America Breathing Easier [PDF – 1.1 MB] ASL Asthma Film Asthma Clinical ... Using a metered dose inhaler with a spacer [ PDF - 377 KB] Your browser does not support iframes ...

  6. Know How to Use Your Asthma Inhaler

    Medline Plus

    Full Text Available ... avoid an attack by taking your medicine exactly as your doctor or other medical professional tells you ... keep them with your Asthma Action Plan. Using a metered dose inhaler with a spacer Your browser ...

  7. Know How to Use Your Asthma Inhaler

    Medline Plus

    Full Text Available ... avoid an attack by taking your medicine exactly as your doctor or other medical professional tells you ... keep them with your Asthma Action Plan. Using a metered dose inhaler with a spacer Your browser ...

  8. A comparative study to evaluate the role of inhaled steroid versus low-dose oral steroid in patients of chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Surya Kant


    Conclusion: The use of steroids has ever been a subject of divergence of views ever since its role in the treatment of COPD was first described. Although, overall steroid in any form is beneficial in symptomatic/subjective and objective improvements in COPD, oral steroids stand a better chance as compared to inhaled steroids. [Int J Basic Clin Pharmacol 2015; 4(2.000: 240-244

  9. Needle migration and dosimetric impact in high-dose-rate brachytherapy for prostate cancer evaluated by repeated MRI. (United States)

    Buus, Simon; Lizondo, Maria; Hokland, Steffen; Rylander, Susanne; Pedersen, Erik M; Tanderup, Kari; Bentzen, Lise


    To quantify needle migration and dosimetric impact in high-dose-rate brachytherapy for prostate cancer and propose a threshold for needle migration. Twenty-four high-risk prostate cancer patients treated with an HDR boost of 2 × 8.5 Gy were included. Patients received an MRI for planning (MRI1), before (MRI2), and after treatment (MRI3). Time from needle insertion to MRI3 was ∼3 hours. Needle migration was evaluated from coregistered images: MRI1-MRI2 and MRI1-MRI3. Dose volume histogram parameters from the treatment plan based on MRI1 were related to parameters based on needle positions in MRI2 or MRI3. Regression was used to model the average needle migration per implant and change in D90 clinical target volume, CTVprostate+3mm. The model fit was used for estimating the dosimetric impact in equivalent dose in 2 Gy fractions for dose levels of 6, 8.5, 10, 15, and 19 Gy. Needle migration was on average 2.2 ± 1.8 mm SD from MRI1-MRI2 and 5.0 ± 3.0 mm SD from MRI1-MRI3. D90 CTVprostate+3mm was robust toward average needle migration ≤3 mm, whereas for migration >3 mm D90 decreased by 4.5% per mm. A 3 mm of needle migration resulted in a decrease of 0.9, 1.7, 2.3, 4.8, and 7.6 equivalent dose in 2 Gy fractions for dose levels of 6, 8.5, 10, 15, and 19 Gy, respectively. Substantial needle migration in high-dose-rate brachytherapy occurs frequently in 1-3 hours following needle insertion. A 3-mm threshold of needle migration is proposed, but 2 mm may be considered for dose levels ≥15 Gy. Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  10. Development of QSAR models using artificial neural network analysis for risk assessment of repeated-dose, reproductive, and developmental toxicities of cosmetic ingredients. (United States)

    Hisaki, Tomoka; Aiba Née Kaneko, Maki; Yamaguchi, Masahiko; Sasa, Hitoshi; Kouzuki, Hirokazu


    Use of laboratory animals for systemic toxicity testing is subject to strong ethical and regulatory constraints, but few alternatives are yet available. One possible approach to predict systemic toxicity of chemicals in the absence of experimental data is quantitative structure-activity relationship (QSAR) analysis. Here, we present QSAR models for prediction of maximum "no observed effect level" (NOEL) for repeated-dose, developmental and reproductive toxicities. NOEL values of 421 chemicals for repeated-dose toxicity, 315 for reproductive toxicity, and 156 for developmental toxicity were collected from Japan Existing Chemical Data Base (JECDB). Descriptors to predict toxicity were selected based on molecular orbital (MO) calculations, and QSAR models employing multiple independent descriptors as the input layer of an artificial neural network (ANN) were constructed to predict NOEL values. Robustness of the models was indicated by the root-mean-square (RMS) errors after 10-fold cross-validation (0.529 for repeated-dose, 0.508 for reproductive, and 0.558 for developmental toxicity). Evaluation of the models in terms of the percentages of predicted NOELs falling within factors of 2, 5 and 10 of the in-vivo-determined NOELs suggested that the model is applicable to both general chemicals and the subset of chemicals listed in International Nomenclature of Cosmetic Ingredients (INCI). Our results indicate that ANN models using in silico parameters have useful predictive performance, and should contribute to integrated risk assessment of systemic toxicity using a weight-of-evidence approach. Availability of predicted NOELs will allow calculation of the margin of safety, as recommended by the Scientific Committee on Consumer Safety (SCCS).

  11. Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice (United States)

    Guo, RX; Anaclet, C; Roberts, JC; Parmentier, R; Zhang, M; Guidon, G; Buda, C; Sastre, JP; Feng, JQ; Franco, P; Brown, SH; Upton, N; Medhurst, AD; Lin, JS


    Background and purpose: Histamine H3 receptor antagonists are currently being evaluated in clinical trials for a number of central nervous system disorders including narcolepsy. These agents can increase wakefulness (W) in cats and rodents following acute administration, but their effects after repeat dosing have not been reported previously. Experimental approach: EEG and EMG recordings were used to investigate the effects of acute and repeat administration of the novel H3 antagonist GSK189254 on the sleep–wake cycle in wild-type (Ox+/+) and orexin knockout (Ox−/−) mice, the latter being genetically susceptible to narcoleptic episodes. In addition, we investigated H3 and H1 receptor expression in this model using radioligand binding and autoradiography. Key results: In Ox+/+ and Ox−/− mice, acute administration of GSK189254 (3 and 10 mg·kg−1 p.o.) increased W and decreased slow wave and paradoxical sleep to a similar degree to modafinil (64 mg·kg−1), while it reduced narcoleptic episodes in Ox−/− mice. After twice daily dosing for 8 days, the effect of GSK189254 (10 mg·kg−1) on W in both Ox+/+ and Ox−/− mice was significantly reduced, while the effect on narcoleptic episodes in Ox−/− mice was significantly increased. Binding studies revealed no significant differences in H3 or H1 receptor expression between Ox+/+ and Ox−/− mice. Conclusions and implications: These studies provide further evidence to support the potential use of H3 antagonists in the treatment of narcolepsy and excessive daytime sleepiness. Moreover, the differential effects observed on W and narcoleptic episodes following repeat dosing could have important implications in clinical studies. PMID:19413575

  12. Efficacy and safety of fixed-dose artesunate-amodiaquine vs. artemether-lumefantrine for repeated treatment of uncomplicated malaria in Ugandan children.

    Directory of Open Access Journals (Sweden)

    Adoke Yeka

    Full Text Available The safety and efficacy of the two most widely used fixed-dose artemisinin-based combination therapies (ACT, artesunate-amodiaquine (ASAQ and artemether-lumefantrine (AL are well established for single episodes of uncomplicated Plasmodium falciparum malaria, but the effects of repeated, long-term use are not well documented. We conducted a 2-year randomized, open-label, longitudinal, phase IV clinical trial comparing the efficacy and safety of fixed-dose ASAQ and AL for repeated treatment of uncomplicated malaria in children under 5 years at Nagongera Health Centre, Uganda. Participants were randomized to ASAQ or AL and all subsequent malaria episodes were treated with the same regimen. 413 children were enrolled and experienced a total of 6027 malaria episodes (mean 15; range, 1-26. For the first malaria episode, the PCR-corrected-cure rate for ASAQ (97.5% was non-inferior to that for AL (97.0%; 95% CI [-0.028; 0.037]. PCR-corrected cure rates for subsequent malaria episodes that had over 100 cases (episodes 2-18, ranged from 88.1% to 98.9% per episode, with no clear difference between the treatment arms. Parasites were completely cleared by day 3 for all malaria episodes and gametocyte carriage was less than 1% by day 21. Fever clearance was faster in the ASAQ group for the first episode. Treatment compliance for subsequent episodes (only first dose administration observed was close to 100%. Adverse events though common were similar between treatment arms and mostly related to the disease. Serious adverse events were uncommon, comparable between treatment arms and resolved spontaneously. Anemia and neutropenia occurred in <0.5% of cases per episode, abnormal liver function tests occurred in 0.3% to 1.4% of cases. Both regimens were safe and effective for repeated treatment of malaria.Current Controlled Trials NCT00699920.

  13. Repeated exposure of male mice to low doses of lipopolysaccharide: dose and time dependent development of behavioral sensitization and tolerance in an automated light-dark anxiety test. (United States)

    Banasikowski, Tomek J; Cloutier, Caylen J; Ossenkopp, Klaus-Peter; Kavaliers, Martin


    Although lipopolysaccharide (LPS) is widely used to examine immune behavior relationships there has been little consideration of the effects of low doses and the roles of sensitization and, or tolerance. Here low doses of LPS (1.0, 5.0 and 25.0 μg/kg) were peripherally administered to male mice on Days 1, 4, 28 and 32 after a baseline recording of anxiety-like behaviors in an automated light-dark apparatus (total time in the light chamber, number of light-dark transitions, nose pokes into the light chamber). LPS at 1.0 μg/kg, while having no significant effects on anxiety-like behaviors in the light-dark test on Days 1 and 4, displayed sensitization with the mice exhibiting significantly enhanced anxiety-like responses on Days 28 and 32. LPS at 5.0 μg/kg had no consistent significant effects on anxiety-like behavior on Days 1 and 4, with sensitization and enhanced anxiety-like behaviors on Day 28 followed by tolerance on Day 32. LPS at 25 μg/kg significantly enhanced anxiety-like behaviors on Day 1, followed by tolerance on Day 4, which was not evident by Day 28 and re-emerged on Day 32. There was a similar overall pattern of sensitization and tolerance for LPS-induced decreases in locomotor activity in the safe dark chamber, without, however, any significant effects on activity in the riskier light chamber. This shows that low doses of LPS induce anxiety-like behavior and these effects are subject to sensitization and tolerance in a dose, context, and time related manner.

  14. Distribution and antitumor activity of adriamycin given in a high-dose and a repeated low-dose schedule to mice. (United States)

    Pacciarini, M A; Barbieri, B; Colombo, T; Broggini, M; Garattini, S; Donelli, M G


    Experimental studies on the distribution of adriamycin (AM) under different treatment conditions and possible correlations between tissue and plasma levels and chemotherapeutic activity are discussed. C57BL/6J mice bearing im Lewis lung carcinoma and (C3H x O2O)F1 mice bearing mammary carcinoma were injected iv with AM at a single dose of 15 mg/kg or with the same total amount of drug administered in spaced doses of 3.75 mg/kg for 4 consecutive days. In the two experimental systems studied, the drug reached approximately the same value in the tumor and spleen with both types of treatment, but with the 3.75-mg/kg x 4 schedule much lower AM concentrations were observed in the heart than with the single high-dose treatment. The therapeutic activity of the two treatments also differed: the antitumor and antimetastatic effect was the same in the two tumor systems, but with the 3.75-mg/kg x 4 schedule, increased survival and somewhat lower toxicity were observed. Daunorubicin, tested in the mammary carcinoma system with the two schedules of treatment, behaves very similarly to AM in terms of both distribution and chemotherapeutic effect.

  15. Evaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult subjects. (United States)

    Winter, Helen; Egizi, Erica; Murray, Stephen; Erondu, Ngozi; Ginsberg, Ann; Rouse, Doris J; Severynse-Stevens, Diana; Pauli, Elliott


    This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0-t), and AUC extrapolated to infinity (AUC0-inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0-t, and AUC0-inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0-t, and AUC0-inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at under identifier NCT02216331.).

  16. Variation in target and rectum dose due to prostate deformation: an assessment by repeated MR imaging and treatment planning

    Energy Technology Data Exchange (ETDEWEB)

    Kerkhof, E M; Put, R W van der; Raaymakers, B W; Heide, U A van der; Vulpen, M van; Lagendijk, J J W [Department of Radiotherapy, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht (Netherlands)], E-mail:


    In daily clinical practice, implanted fiducial markers are used to correct for prostate motion, but not for prostate deformation. The aim of this study is to investigate the variation in target and rectum dose due to the deformation of the prostate gland (without seminal vesicles). Therefore, we performed five to six MRI scans of eight healthy volunteers that exhibited large variation in rectal volume and thus prostate deformation. Prostate motion was corrected by a mask-based rigid registration which uses the delineation as well as the internal structures of the prostate gland. Per MRI scan, one IMRT plan with a PTV margin of 4 mm was created, resulting in 41 IMRT plans. The dose distribution of the IMRT plan based on the MRI scan with the minimum rectal volume was applied to the other rigidly registered MRI scans to evaluate the impact of prostate deformation. In conclusion, pre-treatment planning on the minimum rectal volume can cause a fraction dose increase (up to 15%) to the rectum due to prostate deformation. The impact on the total dose increase to the rectum depends on the intrapatient rectum variation during treatment, but is negligible with the currently used PTV margins in a fractionated treatment.

  17. Variation in target and rectum dose due to prostate deformation: an assessment by repeated MR imaging and treatment planning (United States)

    Kerkhof, E. M.; van der Put, R. W.; Raaymakers, B. W.; van der Heide, U. A.; van Vulpen, M.; Lagendijk, J. J. W.


    In daily clinical practice, implanted fiducial markers are used to correct for prostate motion, but not for prostate deformation. The aim of this study is to investigate the variation in target and rectum dose due to the deformation of the prostate gland (without seminal vesicles). Therefore, we performed five to six MRI scans of eight healthy volunteers that exhibited large variation in rectal volume and thus prostate deformation. Prostate motion was corrected by a mask-based rigid registration which uses the delineation as well as the internal structures of the prostate gland. Per MRI scan, one IMRT plan with a PTV margin of 4 mm was created, resulting in 41 IMRT plans. The dose distribution of the IMRT plan based on the MRI scan with the minimum rectal volume was applied to the other rigidly registered MRI scans to evaluate the impact of prostate deformation. In conclusion, pre-treatment planning on the minimum rectal volume can cause a fraction dose increase (up to 15%) to the rectum due to prostate deformation. The impact on the total dose increase to the rectum depends on the intrapatient rectum variation during treatment, but is negligible with the currently used PTV margins in a fractionated treatment.

  18. Variation in target and rectum dose due to prostate deformation: an assessment by repeated MR imaging and treatment planning. (United States)

    Kerkhof, E M; van der Put, R W; Raaymakers, B W; van der Heide, U A; van Vulpen, M; Lagendijk, J J W


    In daily clinical practice, implanted fiducial markers are used to correct for prostate motion, but not for prostate deformation. The aim of this study is to investigate the variation in target and rectum dose due to the deformation of the prostate gland (without seminal vesicles). Therefore, we performed five to six MRI scans of eight healthy volunteers that exhibited large variation in rectal volume and thus prostate deformation. Prostate motion was corrected by a mask-based rigid registration which uses the delineation as well as the internal structures of the prostate gland. Per MRI scan, one IMRT plan with a PTV margin of 4 mm was created, resulting in 41 IMRT plans. The dose distribution of the IMRT plan based on the MRI scan with the minimum rectal volume was applied to the other rigidly registered MRI scans to evaluate the impact of prostate deformation. In conclusion, pre-treatment planning on the minimum rectal volume can cause a fraction dose increase (up to 15%) to the rectum due to prostate deformation. The impact on the total dose increase to the rectum depends on the intrapatient rectum variation during treatment, but is negligible with the currently used PTV margins in a fractionated treatment.

  19. Conference report: 2nd Medicon Valley Inhalation Symposium. (United States)

    Lastow, Orest


    2nd Medicon Valley Inhalation Symposium 16 October 2013, Lund, Sweden The 2nd Medicon Valley Inhalation Symposium was arranged by the Medicon Valley Inhalation Consortium. It was held at the Medicon Village, which is the former AstraZeneca site in Lund, Sweden. It was a 1 day symposium focused on inhaled drug delivery and inhalation product development. 120 delegates listened to 11 speakers. The program was organized to follow the value chain of an inhalation product development. This year there was a focus on inhaled biomolecules. The inhaled delivery of insulin was covered by two presentations and a panel discussion. The future of inhaled drug delivery was discussed together with an overview of the current market situation. Two of the inhalation platforms, capsule inhalers and metered-dose inhalers, were discussed in terms of the present situation and the future opportunities. Much focus was on the regulatory and intellectual aspects of developing inhalation products. The manufacturing of a dry powder inhaler requires precision filling of powder, and the various techniques were presented. The benefits of nebulization and nasal delivery were illustrated with some case studies and examples. The eternal challenge of poor compliance was addressed from an industrial design perspective and some new approaches were introduced.

  20. Compared efficacy of repeated annual and semi-annual doses of ivermectin and diethylcarbamazine for prevention of Wuchereria bancrofti filariasis in French Polynesia. Final evaluation. (United States)

    Cartel, J L; Spiegel, A; Nguyen Ngnoc, L; Cardines, R; Plichart, R; Martin, P M; Roux, J F; Moulia-Pelat, J P


    In October 1989, 58 apparently healthy Polynesian Wuchereria bancrofti carriers, in whom microfilarial (mf) density was greater than or equal to 100 mf/ml, were randomly allocated to treatment groups receiving single doses of either ivermectin at 100 mcg/kg or diethylcarbamazine (DEC) at 3 and 6 mg/kg. Six months later, half of the carriers initially treated with ivermectin 100 mcg/kg or DEC 3 mg/kg were given a second similar dose while the rest were given a placebo. Six months later again, all of the carriers received a last treatment dose similar to the initial one. The results observed during the 12-month period which followed this last treatment have confirmed that (i) in terms of immediate clearance or complete negativation of microfilaremia, the efficacy of ivermectin is higher than that of DEC (at dosage of 3 or 6 mg/kg), (ii) DEC is more effective than ivermectin in sustaining the reduction of microfilaremia over a longer period of time and (iii) the efficacy of repeated single doses of either DEC 3 mg/kg or ivermectin 100 mcg/kg is much higher when given semi-annually than annually.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Repeated dose 28-days oral toxicity study of Carica papaya L. leaf extract in Sprague Dawley rats. (United States)

    Afzan, Adlin; Abdullah, Noor Rain; Halim, Siti Zaleha; Rashid, Badrul Amini; Semail, Raja Hazlini Raja; Abdullah, Noordini; Jantan, Ibrahim; Muhammad, Hussin; Ismail, Zakiah


    Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent.

  2. Repeated high-dose (5 × 10(8) TCID50) toxicity study of a third generation smallpox vaccine (IMVAMUNE) in New Zealand white rabbits. (United States)

    Tree, Julia A; Hall, Graham; Rees, Peter; Vipond, Julia; Funnell, Simon G P; Roberts, Allen D


    Concern over the release of variola virus as an agent of bioterrorism remains high and a rapid vaccination regimen is desirable for use in the event of a confirmed release of virus. A single, high-dose (5×10(8) TCID50) of Bavarian Nordic's IMVAMUNE was tested in a Phase-II clinical trial, in humans, as a substitute for the standard (1×10(8) TCID50), using a 2-dose, 28-days apart regimen. Prior to this clinical trial taking place a Good Laboratory Practice, repeated high-dose, toxicology study was performed using IMVAMUNE, in New Zealand white rabbits and the results are reported here. Male and female rabbits were dosed twice, subcutaneously, with 5×10(8) TCID50 of IMVAMUNE (test) or saline (control), 7-days apart. The clinical condition, body-weight, food consumption, haematology, blood chemistry, immunogenicity, organ-weight, and macroscopic and microscopic pathology were investigated. Haematological investigations indicated changes within the white blood cell profile that were attributed to treatment with IMVAMUNE; these comprised slight increases in neutrophil and monocyte numbers, on study days 1-3 and a marginal increase in lymphocyte numbers on day 10. Macroscopic pathology revealed reddening at the sites of administration and thickened skin in IMVAMUNE, treated animals. After the second dose of IMVAMUNE 9/10 rabbits seroconverted, as detected by antibody ELISA on day 10, by day 21, 10/10 rabbits seroconverted. Treatment-related changes were not detected in other parameters. In conclusion, the subcutaneous injection of 2 high-doses of IMVAMUNE, to rabbits, was well tolerated producing only minor changes at the site of administration. Vaccinia-specific antibodies were raised in IMVAMUNE-vaccinated rabbits only.

  3. Repeat spinal anesthesia in cesarean section: A comparison between 10 mg and 12 mg doses of intrathecal hyperbaric (0.05%) bupivacaine repeated after failed spinal anesthesia: A prospective, parallel group study. (United States)

    Bhar, Debasish; RoyBasunia, Sandip; Das, Anjan; Chhaule, Subinay; Mondal, Sudipta Kumar; Bisai, Subrata; Chattopadhyay, Surajit; Mandal, Subrata Kumar


    Spinal anesthesia for cesarean section is not a 100% successful technique. At times, despite straightforward insertion and drug administration, intrathecal anesthesia for cesarean section fails to obtain any sensory or motor block. Very few studies and literature are available regarding repeat administration of spinal anesthesia and its drug dosage, especially after first spinal failure in cesarean section lower segment cesarean section (LSCS) due to fear of the excessive spread of drug. The aim of our study is to compare the outcome between two different doses of 0.5% hyperbaric bupivacaine repeated intrathecally after failed spinal. After taking informed consent and Ethical Committee approval this prospective, randomized single-blinded study was conducted in 100 parturients of American Society of Anesthesiologists I-II who were posted for elective LSCS and had Bromage score 0 and no sensory block even at L4 dermatome after 10 min of first spinal anesthesia; were included in the study. Group A (n = 50) patients received 2.4 ml and Group B (n = 50) patients received 2 ml of 0.5% hyperbaric bupivacaine respectively for administering repeat spinal anesthesia. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), oxygen saturation, respiratory rate and electrocardiogram were monitored both intra- and post-operatively and complications were recorded. Incidence of high spinal, bradycardia, hypotension, respiratory complications, and nausea vomiting are significantly higher in Group A compared to Group B (P cesarean section with 10 mg of 0.5% hyperbaric bupivacaine provided after first spinal anesthesia, the level of sensory block is below L4 and motor power in Bromage scale is 0.

  4. Measurement of activity concentrations of {sup 40}K, 2{sup 32T}h and {sup 238}U in TSP aerosols and the associated inhalation annual effective radiation dose to the public in Gosan site, Jeju

    Energy Technology Data Exchange (ETDEWEB)

    Han, Chung Hun; Park, Youn Hyun; Park, Jae Woo [Jeju National University, Jeju (Korea, Republic of)


    Gamma radiation emitted from naturally occurring radioisotopes, such as 40K and the radionuclides from the {sup 232}Th and {sup 238}U series and their decay products, which exist at trace levels in all ground formations, represents the main external source of irradiation to the human body. The objective of the current study is to determine the activity concentrations of 40K, {sup 232}Th and {sup 238}U in airborne TSP and the associated internal radiation dose to the public due to inhalation in Gosan site, Jeju Island, Korea. The atmospheric total suspended particulates (TSP) aerosols were collected at Gosan site of Jeju Island, which is one of the background sites of Korea, during January to April 2013. This study analyzed using ICP-DRC-MS the concentrations of potassium, uranium and thorium, and evaluated the annual effective dose by breathing from the results. The correlations between the studied natural isotopes is a good positive correlation between {sup 232}Th and {sup 238}U, supporting the conclusion that they originated from the same source, mostly the crust. The backward trajectory analysis has confirmed that the 40K, {sup 238}U and {sup 232}Th are delivered as the air masses have moved from the China continent. The inhalation annual effective radiation dose (default mode F) to the public due to natural isotopes of the airborne TSP was in the range 16.195 - 77.051 nSv/y, depending on the age group. Jeju Island with less pollution source and low population density is also one of the best places as a background area in Asia.

  5. Influence of Food on the Bioavailability of an Enteric-Coated Tablet Formulation of Omeprazole 20 mg Under Repeated Dose Conditions

    Directory of Open Access Journals (Sweden)

    ABR Thomson


    Full Text Available The objective of this study was to investigate the influence of food on the bioavailability of omeprazole (20 mg given as an enteric-coated tablet under repeated dose conditions. This open randomized crossover study consisted of three seven-day treatment periods, each separated by a drug-free period. During each treatment period an enteric-coated tablet of omeprazole was taken once daily either under fasting conditions, or immediately before or after a standardized breakfast. On the last day of each treatment period, blood samples for the determination of plasma omeprazole concentrations were collected at baseline and at predetermined intervals over the 24 h period following drug administration. Fifty-seven male and female subjects, aged 18 to 52 years, completed the study according to the protocol. No statistically significant differences were found when comparing either the before breakfast or after breakfast treatment regimens with the fasting regimen for the estimated mean area under the plasma concentration-time curve (AUC. The maximum plasma concentration was not found to differ significantly among any of the treatment regimens. However, the lower limit of the CI for the comparison of fasting/before breakfast was not contained within the limits of bioequivalence. The time to reach maximum plasma concentration was significantly different when fasting and after breakfast regimens were compared. Thus, under repeated dose conditions, food has no influence on the bioavailability (expressed as AUC of omeprazole given as the enteric-coated tablet formulation.

  6. Substance use -- inhalants (United States)

    ... rags or toilet paper soaked with the chemical. Effects of Inhalants on the Brain When inhaled, the chemicals are absorbed by the ... to replace the ones that involved inhalant use. Exercise and eat healthy ... the harmful effects of inhalants. Avoid triggers. These triggers can be ...

  7. The influence of exercise and dehydration on the urine concentrations of salbutamol after inhaled administration of 1600 µg salbutamol as a single dose in relation to doping analysis. (United States)

    Haase, Christoffer Bjerre; Backer, Vibeke; Kalsen, Anders; Rzeppa, Sebastian; Hemmersbach, Peter; Hostrup, Morten


    The present study investigated the influence of exercise and dehydration on the urine concentrations of salbutamol after inhalation of that maximal permitted (1600 µg) on the 2015 World Anti-Doping Agency (WADA) prohibited list. Thirteen healthy males participated in the study. Urine concentrations of salbutamol were measured during three conditions: exercise (EX), exercise+dehydration (EXD), and rest (R). Exercise consisted of 75 min cycling at 60% of VO2max and a 20-km time-trial. Fluid intake was 2300, 270, and 1100 mL during EX, EXD, and R, respectively. Urine samples of salbutamol were collected 0-24 h after drug administration. Adjustment of urine concentrations of salbutamol to a specific gravity (USG) of 1.020 g/mL was compared with no adjustment. The 2015 WADA decision limit (1200 ng/mL) for salbutamol was exceeded in 23, 31, and 10% of the urine samples during EX, EXD, and R, respectively, when unadjusted for USG. When adjusted for USG, the corresponding percentages fell to 21, 15, and 8%. During EXD, mean urine concentrations of salbutamol exceeded (1325±599 ng/mL) the decision limit 4 h after administration when unadjusted for USG. Serum salbutamol Cmax was lower (Psalbutamol and increase the risk of Adverse Analytical Findings in samples collected after inhalation of that maximal permitted (1600 µg) for salbutamol. This should be taken into account when evaluating doping cases of salbutamol. Copyright © 2015 John Wiley & Sons, Ltd.

  8. Capsaicin inhalation in man and the effects of sodium cromoglycate. (United States)

    Collier, J. G.; Fuller, R. W.


    The inhalation of capsaicin for 1 min, delivered as an aerosol by nebulising solutions of capsaicin at concentrations of 2-65 mumol 1(-1), caused dose-dependent coughing in normal volunteers and subjects with mild asthma. Capsaicin did not cause a feeling of breathlessness, and had no effect on forced expiratory volume in 1 s (FEV1) measured at the 1st, 5th and 9th min after the challenge was completed. Coughing started within seconds of applying the face mask, continued throughout the minute of capsaicin inhalation, and stopped within seconds of the mask being removed. In any one subject the number of coughs was reproducible when repeated on the same day or after an interval of several days. Experiments using local anaesthesia applied to the buccal mucosa or larynx indicated that the cough was caused by the stimulation of capsaicin-sensitive nerve terminals situated in the larynx. Cough response was not altered by the prior inhalation of sodium cromoglycate. PMID:6423016

  9. Influence of Two Depuration Periods on the Activity and Transcription of Antioxidant Enzymes in Tilapia Exposed to Repeated Doses of Cylindrospermopsin under Laboratory Conditions

    Directory of Open Access Journals (Sweden)

    Victoria Ríos


    Full Text Available The cyanobacterial toxin Cylindrospermopsin (CYN, a potent protein synthesis inhibitor, is increasingly being found in freshwater bodies infested by cyanobacterial blooms worldwide. Moreover, it has been reported to be implicated in human intoxications and animal mortality. Recently, the alteration of the activity and gene expression of some glutathione related enzymes in tilapias (Oreochromis niloticus exposed to a single dose of CYN has been reported. However, little is known about the effects induced by repeated doses of this toxin in tilapias exposed by immersion and the potential reversion of these biochemical alterations after two different depuration periods (3 or 7 days. In the present study, tilapias were exposed by immersion to repeated doses of a CYN-containing culture of Aphanizomenon ovalisporum during 14 days, and then were subjected to depuration periods (3 or 7 days in clean water in order to examine the potential reversion of the effects observed. The activity and relative mRNA expression by real-time polymerase chain reaction (PCR of the antioxidant enzymes glutathione peroxidase (GPx and soluble glutathione-S-transferases (sGST, and also the sGST protein abundance by Western blot analysis were evaluated in liver and kidney of fish. Results showed significant alterations in most of the parameters evaluated and their recovery after 3 days (GPx activity, sGST relative abundance or 7 days (GPx gene expression, sGST activity. These findings not only confirm the oxidative stress effects produced in fish by cyanobacterial cells containing CYN, but also show the effectiveness of depuration processes in mitigating the CYN-containing culture toxic effects.

  10. Effects of repeated low-dose exposure of the nerve agent VX on monoamine levels in different brain structures in mice. (United States)

    Graziani, S; Christin, D; Daulon, S; Breton, P; Perrier, N; Taysse, L


    In a previous report, alterations of the serotonin metabolism were previously reported in mice intoxicated with repeated low doses of soman. In order to better understand the effects induced by repeated low-dose exposure to organophosphorus compounds on physiological and behavioural functions, the levels of endogenous monoamines (serotonin and dopamine) in different brain areas in mice intoxicated with sublethal dose of (O-ethyl-S-[2(di-isopropylamino) ethyl] methyl phosphonothioate) (VX) were analysed by HPLC method with electrochemical detection. Animals were injected once a day for three consecutive days with 0.10 LD50 of VX (5 μg/kg, i.p). Neither severe signs of cholinergic toxicity nor pathological changes in brain tissue of exposed animals were observed. Cholinesterase (ChE) activity was only inhibited in plasma (a maximum of 30% inhibition 24 h after the last injection of VX), but remained unchanged in the brain. Serotonin and dopamine (DA) metabolism appeared significantly modified. During the entire period of investigation, at least one of the three parameters investigated (i.e. DA and DOPAC levels and DOPAC/DA ratio) was modified. During the toxic challenge, an increase of the serotonin metabolism was noted in hippocampus (HPC), hypothalamus/thalamus, pons medulla and cerebellum (CER). This increase was maintained 4 weeks after exposure in HPC, pons medulla and CER whereas a decrease in cortex 3 weeks after the toxic challenge was observed. The lack of correlation between brain ChE activity and neurochemical outcomes points out to independent mechanisms. The involvement in possibly long-lasting behavioural disorders is discussed.

  11. Technological and practical challenges of dry powder inhalers and formulations

    NARCIS (Netherlands)

    Hoppentocht, M.; Hagedoorn, P.; Frijlink, H.W.; de Boer, A.H.


    In the 50 years following the introduction of the first dry powder inhaler to the market, several developments have occurred. Multiple-unit dose and multi-dose devices have been introduced, but first generation capsule inhalers are still widely used for new formulations. Many new particle engineerin

  12. Species- and dose-specific pancreatic responses and progression in single- and repeat-dose studies with GI181771X: a novel cholecystokinin 1 receptor agonist in mice, rats, and monkeys. (United States)

    Myer, James R; Romach, Elizabeth H; Elangbam, Chandikumar S


    Compound-induced pancreatic injury is a serious liability in preclinical toxicity studies. However, its relevance to humans should be cautiously evaluated because of interspecies variations. To highlight such variations, we evaluated the species- and dose-specific pancreatic responses and progression caused by GI181771X, a novel cholecystokinin 1 receptor agonist investigated by GlaxoSmithKline for the treatment of obesity. Acute (up to 2,000 mg/kg GI181771X, as single dose) and repeat-dose studies in mice and/or rats (0.25-250 mg/kg/day for 7 days to 26 weeks) showed wide-ranging morphological changes in the pancreas that were dose and duration dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation. In contrast to rodents, pancreatic changes were not observed in cynomolgus monkeys given GI181771X (1-500 mg/kg/day with higher systemic exposure than rats) for up to 52 weeks. Similarly, no GI181771X treatment-associated abnormalities in pancreatic structure were noted in a 24-week clinical trial with obese patients (body mass index >30 or >27 kg/m(2)) as assessed by abdominal ultrasound or by magnetic resonance imaging. Mechanisms for interspecies variations in the pancreatic response to CCK among rodents, monkeys, and humans and their relevance to human risk are discussed.

  13. Prospective evaluation of potential toxicity of repeated doses of Thymus vulgaris L. extracts in rats by means of clinical chemistry, histopathology and NMR-based metabonomic approach. (United States)

    Benourad, Fouzia; Kahvecioglu, Zehra; Youcef-Benkada, Mokhtar; Colet, Jean-Marie


    In the field of natural extracts, research generally focuses on the study of their biological activities for food, cosmetic, or pharmacological purposes. The evaluation of their adverse effects is often overlooked. In this study, the extracts of Thymus vulgaris L. were obtained by two different extraction methods. Intraperitoneal injections of both extracts were given daily for four days to male Wistar Han rats, at two different doses for each extract. The evaluation of the potential toxic effects included histopathological examination of liver, kidney, and lung tissues, as well as serum biochemistry of liver and kidney parameters, and (1)H-NMR-based metabonomic profiles of urine. The results showed that no histopathological changes were observed in the liver and kidney in rats treated with both extracts of thyme. Serum biochemical investigations revealed significant increases in blood urea nitrogen, creatinine, and uric acid in animals treated with polyphenolic extract at both doses. In these latter groups, metabonomic analysis revealed alterations in a number of urine metabolites involved in the energy metabolism in liver mitochondria. Indeed, the results showed alterations of glycolysis, Krebs cycle, and β-oxidative pathways as evidenced by increases in lactate and ketone bodies, and decreases in citrate, α-ketoglutarate, creatinine, hippurate, dimethylglycine, and dimethyalanine. In conclusion, this work showed that i.p. injection of repeated doses of thyme extracts causes some disturbances of intermediary metabolism in rats. The metabonomic study revealed interesting data which could be further used to determine the cellular pathways affected by such treatments.

  14. Additional notes on clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance. (United States)

    Takaai, Mari; Kayano, Yuichiro; Shimizu, Takako; Taguchi, Masato; Hashimoto, Yukiya


    In the previous study, we performed a simulation of a clinical pharmacokinetic trial, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral administration at the dose, D, and dosing interval, tau. The approximate oral clearance (CL/F(approx)), estimated as 2 x D/(C(peak) x tau+C(trough) x tau), is accurate for drugs with an elimination half-life comparative to or longer than tau; however, it was suggested that we might not use CL/F(approx) for drugs with a considerably short elimination half-life relative to tau. In the present study, we evaluated the accuracy of the alternative oral clearance (CL/F(exp)) estimated by the simple monoexponential model. In contrast to CL/F(approx), CL/F(exp) was accurate for drugs with a short elimination half-life relative to tau. The present finding in conjunction with our previous study suggested that the peak-and-trough sampling design is promising for the clinical repeated-dose pharmacokinetic trial for drugs with not only slow but also rapid elimination from the body. We think that the accuracy and precision of the two analysis methods to estimate oral clearance (CL/F(approx) and CL/F(exp)) for a target drug should be evaluated carefully before and after a real clinical trial.

  15. 26-week repeated oral dose toxicity study of UP446, a combination of defined extracts of Scutellaria baicalensis and Acacia catechu, in beagle dogs. (United States)

    Yimam, Mesfin; Lee, Young Chul; Jia, Qi


    The needs for relatively safe botanical alternatives to relieve symptoms associated to arthritis have continued to grow in parallel with the ageing population. UP446, a standardized bioflavonoid composition from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu, has been used as over the counter joint care dietary supplements and a prescription medical food. Significant safety data have been documented in rodents and human for this composition. Here we evaluated the potential adverse effects of orally administered UP446 in beagle dogs following a 26-week repeated oral dose toxicity study. UP446 at doses of 250, 500 and 1000 mg/kg/day were administered orally to beagle dogs for 26 weeks. A 4-week recovery group from the high dose (1000 mg/kg) and vehicle treated groups were included. No morbidity or mortality was observed for the duration of the study. No significant differences between groups in body weights, food consumption, ophthalmological examinations, electrocardiograms, urinalysis, hematology, clinical chemistry, organ weights, gross pathology and histopathology were documented. Emesis, loose feces and diarrhea were noted in both genders at the 1000 mg/kg treatment groups. These clinical signs were considered to be reversible as they were not evident in the recovery period. In conclusion, the no-observed-adverse-effect-level (NOAEL) of UP446 was considered to be 500 mg/kg/day both in male and female beagle dogs.

  16. The influence of exercise and dehydration on the urine concentrations of salbutamol after inhaled administration of 1600 µg salbutamol as a single dose in relation to doping analysis

    DEFF Research Database (Denmark)

    Haase, Christoffer Bjerre; Backer, Vibeke; Kalsen, Anders


    The present study investigated the influence of exercise and dehydration on the urine concentrations of salbutamol after inhalation of that maximal permitted (1600 µg) on the 2015 World Anti-Doping Agency (WADA) prohibited list. Thirteen healthy males participated in the study. Urine concentrations......-24 h after drug administration. Adjustment of urine concentrations of salbutamol to a specific gravity (USG) of 1.020 g/mL was compared with no adjustment. The 2015 WADA decision limit (1200 ng/mL) for salbutamol was exceeded in 23, 31, and 10% of the urine samples during EX, EXD, and R, respectively......, when unadjusted for USG. When adjusted for USG, the corresponding percentages fell to 21, 15, and 8%. During EXD, mean urine concentrations of salbutamol exceeded (1325±599 ng/mL) the decision limit 4 h after administration when unadjusted for USG. Serum salbutamol Cmax was lower (P

  17. A method for determining an indicator of effective dose calculation due to inhalation of Radon and its progeny from in vivo measurements; Um metodo para determinar um indicador para calcular dose efetiva devida a inalacao de Radonio e seus descendentes utilizando medicoes in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Estrada, Julio Jose da Silva


    Direct measurement of the absolved dose to lung tissue from inhalation of radon and its progeny is not possible and must be calculated using dosimetric models, taking into consideration the several parameters upon which the dose calculation depends. To asses the dose due to inhalation of radon and its progeny, it is necessary to estimate the cumulative exposure. Historically, this has been done using WLM values estimated with measurements of radon concentration in air. The radon concentration in air varies significantly, however, in space with time, and the exposed individual is also constantly moving around. This makes it almost impossible to obtain a precise estimate of an individual's inhalation exposure. This work describes a pilot study to calculate lung dose from the deposition of radon progeny, via estimates of cumulative exposure derived from in vivo measurements of {sup 210} Pb, in subjects exposed to above-average radon and its progeny concentrations in their home environments. The measurements were performed in a whole body counter. With this technique, the exposed individuals become, in affect, their own samplers and dosimeters and the estimate of cumulative exposure is not affected by the variation of the atmospheric concentration of radon and its progeny in time and space. Forty individuals identified as living in homes with radon levels ranging from about 740 Bq/m{sup 3} to 150.000 Bq/m{sup 3} were measured. Also, additional 34 measurements were made on personnel from NYUMC/NIEM who live in a residential area surrounding the laboratory in which the levels of radon have been shown to be at below average values. To realize these measurements a methodology was developed to determine the subject's background, using a head phantom made with a cubic plastic container containing known amounts of potassium and calcium dissolved in four liters of water. The effective doses calculated from the in vivo measurements are compared to effective doses

  18. Neurotoxic, inflammatory, and mucosecretory responses in the nasal airways of mice repeatedly exposed to the macrocyclic trichothecene mycotoxin roridin A: dose-response and persistence of injury. (United States)

    Corps, Kara N; Islam, Zahidul; Pestka, James J; Harkema, Jack R


    Macrocyclic trichothecene mycotoxins encountered in water-damaged buildings have been suggested to contribute to illnesses of the upper respiratory tract. Here, the authors characterized the adverse effects of repeated exposures to roridin A (RA), a representative macrocyclic trichothecene, on the nasal airways of mice and assessed the persistence of these effects. Young, adult, female C57BL/6 mice were exposed to single daily, intranasal, instillations of RA (0.4, 2, 10, or 50 microg/kg body weight [bw]) in saline (50 microl) or saline alone (controls) over 3 weeks or 250 microg/kg RA over 2 weeks. Histopathologic, immunohistochemical, and morphometric analyses of nasal airways conducted 24 hr after the last instillation revealed that the lowest-effect level was 10 microg/kg bw. RA exposure induced a dose-dependent, neutrophilic rhinitis with mucus hypersecretion, atrophy and exfoliation of nasal transitional and respiratory epithelium, olfactory epithelial atrophy and loss of olfactory sensory neurons (OSNs). In a second study, the persistence of lesions in mice instilled with 250 microg/kg bw RA was assessed. Nasal inflammation and excess luminal mucus were resolved after 3 weeks, but OSN loss was still evident in olfactory epithelium (OE). These results suggest that nasal inflammation, mucus hypersecretion, and olfactory neurotoxicity could be important adverse health effects associated with short-term, repeated, airborne exposures to macrocyclic trichothecenes.

  19. Development of immunity against viral and bacterial antigens after repeated exposures to suberythemal doses of ultraviolet light

    Directory of Open Access Journals (Sweden)

    S. A. Snopov


    Full Text Available The effects of ultraviolet (UV radiation on human infectious immunity are not well studied. On the one hand, solar and artificial UU sources have been shown to change cytokine levels in human skin, lymphocyte subpopulation counts in parepheral blood, lymphocyte DNA synthesis and prolifarative response to mitogens. On the other hand, there are just only one or two observations suggesting an influence of UV radiation on human infection course. For instance, UV irradiations have been reported to induce a reccurence of orofacial vesicular lesions caused by herpes siplex virus. Moreover, there is a lack of data concerning immune effects of suberythtemal doses of UV in spite of a long history of using them by Russian prophylactic medicine. In this work we questioned whether such suberythemal UV exposures can affect the immune responses of children to infectious conjunctivitis, to simultaneous measles and polio vaccinations and to simultaneous polio and diphtheria-tetanus vaccinations. In peripheral blood of vaccinated children we examined leukocyte counts (monocytes, neutrophils, eosinophils, lymphocytes, percentages of lymphocyte subpopulations (CD3+, CD20+, CD4+, CD8+, CD25+, HLADR+, concentrations of cytokines (IL-1 beta, TNF-alpha, IFN- amma и IL-10, DNA-synthetic activity of lymphocytes and titres of antibodies against measles and diphtheria toxin. We observed no local or systemic reactions to the vaccines in the UV-group while a moderate rise in body temperature occured in several children from unexposed group. In the blood of childeren from UV-group we found increases in CD25+ и HLADR+ cell percentages, IL- 1 beta and IL-10 concentrations, PWMinduced DNA synthesis in mononuclears, and no decreases in formation of antibodies against measles and diphreria. We concluded that suberythemal UV exposures of children modulated their further responses to imminisations perhaps through the activation of a T helper 2-like

  20. Inalador dosimetrado com espaçador artesanal versus nebulizador no tratamento da crise de sibilância na criança Metered-dose inhaler with home-made spacer versus nebulizers to treat moderate wheezing attacks in children

    Directory of Open Access Journals (Sweden)

    Liana Consuelo Santana Vilarinho


    oximetria. A comparação dos parâmetros clínicos e de saturação de oxigênio, entre os grupos, não mostrou diferença significativa após as doses de salbutamol, havendo equivalência clínica entre doses diferentes (três vezes menor no grupo IDE, em relação ao grupo NEB; os tempos de preparo e administração da medicação e o custo do tratamento foram significativamente menores no grupo IDE. O grau de satisfação das famílias foi semelhante nos dois grupos. CONCLUSÃO: O inalador dosimetrado com espaçador artesanal pode ser utilizado na admini stração de salbutamol a crianças em crise de sibilância, com algumas vantagens em relação ao nebulizador.OBJECTIVE: To compare the effectiveness of salbutamol administration by metered-dose inhaler with a home-made spacer versus jet nebulizer in children with moderate wheezing attacks. MATERIAL AND METHODS: A randomized, single-blinded trial was performed with a convenience sample of children presenting wheezing. The children were enrolled in an emergency room and randomly assigned to one of two treatment groups: home-made spacer group or nebulizer group. Clinical scores and oxygen saturation were recorded at baseline and 15 minutes after salbutamol administration. Treatment with salbutamol (100 µg/3 kg in the spacer group, and 250 µg/3 kg in the nebulizer group was repeated at 20-minute intervals, until the child was considered to have improved significantly, with no need of any further dose, or until three doses were delivered. Treatment cost, time spent to prepare and deliver the drug, and level of parental satisfaction with the treatment were recorded. RESULTS: Fifty-four children with age between 22 days and 11.7 years were enrolled - 27 in each group. Baseline and demographic characteristics were similar for both groups. The spacer was as effective as the nebulizer in terms of clinical score and oxygen saturation. The different doses (100 µg/3 kg with the spacer, and 250 µg/3 kg with the nebulizer were

  1. Inhalational Monkeypox Virus Infection in Cynomolgus Macaques

    Directory of Open Access Journals (Sweden)

    Roy eBarnewall


    Full Text Available An inhalation exposure system was characterized to deliver aerosolized monkeypox virus (MPXV, and a nonhuman primate (NHP inhalation monkeypox model was developed in cynomologus macaques. A head-only aerosol exposure system was characterized, and two sampling methods were evaluated: liquid impingement via an impinger and impaction via a gelatin filter. The aerosol concentrations obtained with the gelatin filter and impinger were virtually identical, indicating that either method is acceptable for sampling aerosols containing MPXV. The mass median aerodynamic diameter (MMAD was for individual aerosol tests in the aerosol system characterization and the NHP study ranged from 1.08 to 1.15 µm, indicating that the aerosol particles were of a sufficient size to reach the alveoli. Six cynomolgus macaques (four male and two female were used on study. The animals were aerosol exposed with MPXV and received doses between 2.51 x 104 to 9.28 x 105 plaque forming units (pfu inhaled. Four of the six animals died or were euthanized due to their moribund conditions. Both animals that received the lowest exposure doses survived to the end of the observation period. The inhalation LD50 was determined to be approximately 7.8 x 104 pfu inhaled. These data demonstrate that an inhalation MPXV infection model has been developed in the cynomolgus macaque with disease course and lethal dose similar to previously published data.

  2. Evaluation of in vivo genotoxicity by thioacetamide in a 28-day repeated-dose liver micronucleus assay using male young adult rats. (United States)

    Sui, Hajime; Matsumoto, Hirotaka; Wako, Yumi; Kawasako, Kazufumi


    The repeated-dose liver micronucleus (RDLMN) assay has the potential to detect liver carcinogens and can be integrated into general toxicological studies. In this study, thioacetamide (TAA) was tested in 14- and 28-day RDLMN assays to assess the performance of the assay. The test substance, TAA, was administered orally to 6-week-old male Crl:CD (SD) rats once daily for 14 or 28 days at a dosage of 5, 10 or 20mg/kg/day. Hepatocytes were collected approximately 24h after the last TAA administration, and the incidence of micronuclei was assessed. In this study, bone marrow micronucleus assays were also conducted in the same animals. The 14- and 28-day RDLMN assays indicated that none of the TAA dosages significantly increased the proportion of micronucleated hepatocytes. Bone marrow micronucleus assays with TAA also provided negative results. It is known that TAA is a liver carcinogen in mice and rats. In the previous genotoxic studies, the Ames test and the chromosomal aberration test using CHL/IU cells have yielded negative results [1-4]. The liver micronucleus assay using young adult rats singly dosed with TAA (75 and 150mg/kg) also produced negative results [5]. TAA gave positive results only in the mouse bone marrow micronucleus assays [6,7].

  3. Profile of inhaled glycopyrronium bromide as monotherapy and in fixed-dose combination with indacaterol maleate for the treatment of COPD (United States)

    Prakash, Anoop; Babu, K Suresh; Morjaria, Jaymin B


    Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. The cornerstone of pharmacological treatment for COPD is bronchodilation. Inhaled glycopyrronium bromide is a long-acting muscarinic antagonist developed as a maintenance treatment for patients with COPD. Phase III trials have shown that glycopyrronium produces rapid and sustained bronchodilation with an efficacy similar to tiotropium and is well tolerated, with a low incidence of muscarinic side effects in patients with moderate to severe COPD. A combination of glycopyrronium bromide with indacaterol maleate (QVA149) has recently been approved as a once-daily maintenance therapy in adult patients with COPD. Phase III trials (the IGNITE program) with QVA149 have demonstrated significant improvements in lung function versus placebo, glycopyrronium, and tiotropium in patients with moderate to severe COPD, with no safety concerns of note. Hence QVA149 is a safe treatment option for moderate to severe COPD patients in whom long-acting muscarinic antagonist monotherapy is inadequate. PMID:25609944

  4. Profile of inhaled glycopyrronium bromide as monotherapy and in fixed-dose combination with indacaterol maleate for the treatment of COPD

    Directory of Open Access Journals (Sweden)

    Prakash A


    Full Text Available Anoop Prakash,1 K Suresh Babu,2 Jaymin B Morjaria1,31Department of Respiratory Medicine, Castle Hill Hospital, Cottingham, 2Department of Respiratory Medicine, Queen Alexandra Hospital, Cosham, Portsmouth, 3Department of Academic Respiratory Medicine, Hull York Medical School, University of Hull, Castle Hill Hospital, Cottingham, UKAbstract: Chronic obstructive pulmonary disease (COPD is a major cause of morbidity and mortality. The cornerstone of pharmacological treatment for COPD is bronchodilation. Inhaled glycopyrronium bromide is a long-acting muscarinic antagonist developed as a maintenance treatment for patients with COPD. Phase III trials have shown that glycopyrronium produces rapid and sustained bronchodilation with an efficacy similar to tiotropium and is well tolerated, with a low incidence of muscarinic side effects in patients with moderate to severe COPD. A combination of glycopyrronium bromide with indacaterol maleate (QVA149 has recently been approved as a once-daily maintenance therapy in adult patients with COPD. Phase III trials (the IGNITE program with QVA149 have demonstrated significant improvements in lung function versus placebo, glycopyrronium, and tiotropium in patients with moderate to severe COPD, with no safety concerns of note. Hence QVA149 is a safe treatment option for moderate to severe COPD patients in whom long-acting muscarinic antagonist monotherapy is inadequate.Keywords: chronic obstructive pulmonary disease, glycopyrronium bromide, indacaterol maleate, umeclidinium, QVA149, long-acting muscarinic antagonist

  5. Randomised, double-blind, placebo-controlled, cross-over single dose study of the bronchodilator duration of action of combination fluticasone furoate/vilanterol inhaler in adult asthma. (United States)

    Braithwaite, Irene; Williams, Mathew; Power, Sharon; Pilcher, Janine; Weatherall, Mark; Baines, Amanda; Moynihan, Jackie; Kempsford, Rodger; Beasley, Richard


    Fluticasone furoate (FF)/vilanterol (VI) is a once-daily maintenance treatment for asthma and chronic obstructive pulmonary disease. The duration of bronchodilation beyond 24 h has not been determined previously. Adults aged 18-65 (n = 32), with asthma and reversibility to salbutamol (≥15% and ≥200 mL increase in forced expiratory volume in 1 s [FEV1]) participated in a double-blind, placebo-controlled, crossover study. Patients were admitted to a clinical trials unit for 72 h, and inhaled, in random order, placebo or FF/VI 100/25 mcg via ELLIPTA dry powder inhaler on two occasions 7-14 days apart. FEV1 was measured at baseline, 15 and 30 min, 1, 2, 4, 12, 24, 36, 48, 60, and 72 h. The differences in change in FEV1 from baseline between treatments and corresponding two-sided 95% confidence intervals (CI) were calculated at each time point. FF/VI produced a rapid onset of bronchodilation (adjusted mean difference in change from baseline in FEV1 versus placebo at 15 min, 252 mL [95% CI 182-322]). Maximum bronchodilation was observed at 12 h (adjusted mean difference in the change from baseline in FEV1, 383 mL [95% CI 285-481]). Bronchodilation was maintained throughout the 72-h assessment period (adjusted mean difference in the change in FEV1 from baseline at 72 h, 108 mL (95% CI 15-200]). FF/VI was well tolerated and no serious side effects were reported. A single dose of FF/VI 100/25 mcg showed evidence of a 72-h bronchodilator duration of action in adults with asthma. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. A Review of Electronic Devices to Assess Inhaler Technique. (United States)

    Carpenter, Delesha M; Roberts, Courtney A; Sage, Adam J; George, Johnson; Horne, Robert


    Multiple electronic devices exist that provide feedback on the accuracy of patient inhaler technique. Our purpose is to describe the inhaler technique feedback provided by these devices, including specific technique steps measured, how feedback is displayed, target of feedback (patient, provider, researcher), and compatibility with inhaler type (metered-dose inhaler [MDI], diskus, etc.). We identified eight devices that provide feedback on inhaler technique. Only one device assessed all evidence-based MDI technique steps. Most devices provide limited real-time feedback to patients, if any feedback at all. Technologies to assess inhaler technique are advancing and hold great potential for improving patient inhaler technique. Many devices are limited in their ability to detect all evidence-based technique steps and provide real-time user-friendly feedback to patients and providers. Usability tests with patients and providers could identify ways to improve these devices to improve their utility in clinical settings.

  7. Genuair® in chronic obstructive pulmonary disease: a novel, user-friendly, multidose, dry-powder inhaler

    NARCIS (Netherlands)

    Palen, van der Job


    Inhaled corticosteroids and bronchodilators, which are pivotal to the management of respiratory diseases, are delivered by numerous devices, including pressurized metered-dose inhalers and dry-powder inhalers. However, patient adherence to these medications is suboptimal and incorrect inhaler techni

  8. Breath-synchronized plume-control inhaler for pulmonary delivery of fluticasone propionate. (United States)

    Shrewsbury, Stephen B; Armer, Thomas A; Newman, Stephen P; Pitcairn, Gary


    A novel breath-synchronized, plume-control inhaler (Tempo inhaler) was developed to overcome limitations of a pressurized metered-dose inhaler. This report compared the Tempo inhaler and a commercial inhaler for fine particle distribution and lung deposition of fluticasone propionate. In vitro fine particle distribution was determined using the Andersen Cascade Impactor at inspiration rates of 28.3 and 45L/min. In vivo lung deposition was assessed in a randomized, two-arm, crossover study of (99m)Tc-radiolabeled fluticasone propionate in 12 healthy adult subjects, analyzed by gamma scintigraphy. In vitro: fine particle fractions at 28.3 and 45L/min were 88.6+/-3.6% and 89.2+/-3.0% (Tempo inhaler) versus 40.4+/-4.7% and 43.1+/-4.4% (commercial inhaler). In vivo: lung deposition was 41.5+/-9.8% (Tempo inhaler) versus 13.8+/-7.4% (commercial inhaler) and oropharyngeal deposition was 18.3+/-7.7% (Tempo inhaler) versus 76.8+/-7.1% (commercial inhaler). Variability of lung deposition was reduced from 55% (commercial inhaler) to 24% (Tempo inhaler) of the delivered dose. The Tempo inhaler produced significantly higher fine particle fraction values, reduced oropharyngeal deposition by 75%, and increased whole, central, intermediate, and peripheral lung delivery by more than 200%. Thus, the Tempo inhaler enhances efficient drug delivery to the lungs.

  9. 1-Bromopropane, an alternative to ozone layer depleting solvents, is dose-dependently neurotoxic to rats in long-term inhalation exposure. (United States)

    Ichihara, G; Kitoh, J; Yu, X; Asaeda, N; Iwai, H; Kumazawa, T; Shibata, E; Yamada, T; Wang, H; Xie, Z; Takeuchi, Y


    1-Bromopropane has been newly introduced as an alternative to ozone layer-depleting solvents. We aimed to clarify the dose-dependent effects of 1-bromopropane on the nervous system. Forty-four Wistar male rats were randomly divided into 4 groups of 11 each. The groups were exposed to 200, 400, or 800 ppm of 1-bromopropane or only fresh air 8 h per day for 12 weeks. Grip strength of forelimbs and hind limbs, maximum motor nerve conduction velocity (MCV), and distal latency (DL) of the tail nerve were measured in 9 rats of each group every 4 weeks. The other 2 rats of each group were perfused at the end of the experiment for morphological examinations. The rats of the 800-ppm group showed poor kicking and were not able to stand still on the slope. After a 12-week exposure, forelimb grip strength decreased significantly at 800 ppm and hind limb grip strength decreased significantly at both 400 and 800 ppm or after a 12-week exposure. MCV and DL of the tail nerve deteriorated significantly at 800 ppm. Ovoid or bubble-like debris of myelin sheaths was prominent in the unraveled muscular branch of the posterior tibial nerve in the 800-ppm group. Swelling of preterminal axons in the gracile nucleus increased in a dose-dependent manner. Plasma creatine phosphokinase (CPK) decreased dose-dependently with significant changes at 400 and 800 ppm. 1-Bromopropane induced weakness in the muscle strength of rat limbs and deterioration of MCV and DL in a dose-dependent manner, with morphological changes in peripheral nerve and preterminal axon in the gracile nucleus. 1-Bromopropane may be seriously neurotoxic to humans and should thus be used carefully in the workplace.

  10. Patient preferences for inhaler devices in chronic obstructive pulmonary disease: experience with Respimat® Soft Mist™ Inhaler

    Directory of Open Access Journals (Sweden)

    Richard Hodder


    Full Text Available Richard Hodder,1 David Price21Divisions of Pulmonary and Critical Care, University of Ottawa, Ottawa, Ontario, Canada; 2Department of General Practice and Primary Care, University of Aberdeen, Aberdeen, ScotlandAbstract: Current guidelines for the management of chronic obstructive pulmonary disease (COPD recommend the regular use of inhaled bronchodilator therapy in order to relieve symptoms and prevent exacerbations. A variety of inhaler devices are currently available to COPD patients, and the choice of device is an important consideration because it can influence patients’ adherence to treatment, and thus potentially affect the long-term outcome. The Respimat® Soft Mist™ Inhaler (SMI generates a slow-moving aerosol with a high fine particle fraction, resulting in deposition of a higher proportion of the dose in the lungs than pressurized metered-dose inhalers (pMDIs or some dry powder inhalers (DPIs. We review clinical studies of inhaler satisfaction and preference comparing Respimat® SMI against other inhalers in COPD patients. Using objective and validated patient satisfaction instruments, Respimat® SMI was consistently shown to be well accepted by COPD patients, largely due to its inhalation and handling characteristics. In comparative studies with pMDIs, the patient total satisfaction score with Respimat® SMI was statistically and clinically significantly higher than with the pMDI. In comparative studies with DPIs, the total satisfaction score was statistically significantly higher than for the Turbuhaler® DPI, but only the performance domain of satisfaction was clinically significantly higher for Respimat® SMI. Whether the observed higher levels of patient satisfaction reported with Respimat® SMI might be expected to result in improved adherence to therapy and thus provide benefits consistent with those recently shown to be associated with sustained bronchodilator treatment in patients with COPD remains to be proven

  11. Biotransformation of 2,3,3,3-tetrafluoropropene (HFO-1234yf) in male, pregnant and non-pregnant female rabbits after single high dose inhalation exposure

    Energy Technology Data Exchange (ETDEWEB)

    Schmidt, Tobias [Institut für Toxikologie, Universität Würzburg, Versbacher Str. 9, 97078 Würzburg (Germany); Bertermann, Rüdiger [Institut für Anorganische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg (Germany); Rusch, George M. [Honeywell, P.O. Box 1057, Morristown, NJ 07962–1057 (United States); Hoffman, Gary M. [Huntingdon Life Sciences., East Millstone, NJ (United States); Dekant, Wolfgang, E-mail: [Institut für Toxikologie, Universität Würzburg, Versbacher Str. 9, 97078 Würzburg (Germany)


    2,3,3,3-Tetrafluoropropene (HFO-1234yf) is a novel refrigerant intended for use in mobile air conditioning. It showed a low potential for toxicity in rodents studies with most NOAELs well above 10,000 ppm in guideline compliant toxicity studies. However, a developmental toxicity study in rabbits showed mortality at exposure levels of 5,500 ppm and above. No lethality was observed at exposure levels of 2,500 and 4,000 ppm. Nevertheless, increased subacute inflammatory heart lesions were observed in rabbits at all exposure levels. Since the lethality in pregnant animals may be due to altered biotransformation of HFO-1234yf and to evaluate the potential risk to pregnant women facing a car crash, this study compared the acute toxicity and biotransformation of HFO-1234yf in male, female and pregnant female rabbits. Animals were exposed to 50,000 ppm and 100,000 ppm for 1 h. For metabolite identification by {sup 19}F NMR and LC/MS-MS, urine was collected for 48 h after inhalation exposure. In all samples, the predominant metabolites were S-(3,3,3-trifluoro-2-hydroxypropanyl)-mercaptolactic acid and N-acetyl-S-(3,3,3-trifluoro-2-hydroxypropanyl)-L-cysteine. Since no major differences in urinary metabolite pattern were observed between the groups, only N-acetyl-S-(3,3,3-trifluoro-2-hydroxypropanyl)-L-cysteine excretion was quantified. No significant differences in recovery between non-pregnant (43.10 ± 22.35 μmol) and pregnant female (50.47 ± 19.72 μmol) rabbits were observed, male rabbits exposed to 100,000 ppm for one hour excreted 86.40 ± 38.87 μmol. Lethality and clinical signs of toxicity were not observed in any group. The results suggest that the lethality of HFO-1234yf in pregnant rabbits unlikely is due to changes in biotransformation patterns or capacity in pregnant rabbits. -- Highlights: ► No lethality and clinical signs were observed. ► No differences in metabolic pattern between pregnant and non-pregnant rabbits. ► Rapid and similar metabolite

  12. Differential Effects of Inhaled Toluene on Locomotor Activity in Adolescent and Adult Rats (United States)

    Batis, Jeffery C.; Hannigan, John H.; Bowen, Scott E.


    Inhalant abuse is a world-wide public health concern among adolescents. Most preclinical studies have assessed inhalant effects in adult animals leaving unclear how behavioral effects differ in younger animals. We exposed adolescent (postnatal day [PN] 28) and adult (PN90) male rats to toluene using 1 of 3 exposure patterns. These patterns modeled those reported in toluene abuse in teens and varied concentration, number and length of exposures, as well as the inter-exposure interval. Animals were exposed repeatedly over 12 days to toluene concentrations of 0, 8,000 or 16,000 parts per million (ppm). Locomotor activity was quantified during toluene exposures and for 30 min following completion of the final daily toluene exposure. For each exposure pattern, there were significant toluene concentration-related increases and decreases in locomotor activity compared to the 0-ppm “air” controls at both ages. These changes depended upon when activity was measured – during or following exposure. Compared to adults, adolescents displayed greater locomotor activity on the first day and generally greater increases in activity over days than adults during toluene exposure. Adults displayed greater locomotor activity than adolescents in the “recovery” period following exposure on the first and subsequent days. Age group differences were clearest following the pattern of paced, brief (5-min) repeated binge exposures. The results suggest that locomotor behavior in rats during and following inhalation of high concentrations of toluene depends on age and the pattern of exposure. The results are consistent with dose-dependent shifts in sensitivity and sensitization or tolerance to repeated toluene in the adolescent animals compared to the adult animals. Alternate interpretations are possible and our interpretation is limited by the range of very high concentrations of toluene used. The results imply that both pharmacological and psychosocial factors contribute to the teen

  13. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study


    Collaku A; Yue Y.; Reed K


    Agron Collaku, Yong Yue, Kenneth Reed GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Background/objective: Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods: This multicenter, placebo-controlled, repeat-dose, parallel study randomly ass...

  14. Fine particle mass from the Diskus inhaler and Turbuhaler inhaler in children with asthma

    DEFF Research Database (Denmark)

    Bisgaard, H; Klug, B; Sumby, B S;


    The study aimed to investigate dose consistency and particle distribution from the dry powder inhalers Diskus and Turbuhaler. Full profiles of inhalation pressure versus time were recorded in 18 4 yr old and 18 8 yr old asthmatic children through Diskus and Turbuhaler inhalers. These data were used...... is a determinant of the quality of the aerosol. The mean (SD) amount of drug in large particles (>4.7 microm), fine particles (children and 71 (3), 18 (2) and 2...... (1) from the 8 yr old children, respectively. Similar particle fractions from the Budesonide Turbuhaler were 35 (9), 21 (10) and 7 (5) from 4 yr old children and 30 (7), 32 (9) and 12 (6) from 8 yr old children. In conclusion, the Diskus inhaler provides an improved dose consistency through...

  15. Effects of repeated high-dose methamphetamine and ceftriaxone post-treatments on tissue content of dopamine and serotonin as well as glutamate and glutamine. (United States)

    Althobaiti, Yusuf S; Almalki, Atiah H; Das, Sujan C; Alshehri, Fahad S; Sari, Youssef


    Repeated exposure to high doses of methamphetamine (METH) is known to alter several neurotransmitters in certain brain regions. Little is known about the effects of ceftriaxone (CEF), a β-lactam antibiotic, known to upregulate glutamate transporter subtype 1, post-treatment on METH-induced depletion of dopamine and serotonin (5-HT) tissue content in brain reward regions. Moreover, the effects of METH and CEF post-treatment on glutamate and glutamine tissue content are not well understood. In this study, Wistar rats were used to investigate the effects of METH and CEF post-treatment on tissue content of dopamine/5-HT and glutamate/glutamine in the nucleus accumbens (NAc) and prefrontal cortex (PFC). Rats received either saline or METH (10mg/kg, i.p. every 2h×4) followed by either saline or CEF (200mg/kg, i.p, every day×3) post-treatment. METH induced a significant depletion of dopamine and 5-HT in the NAc and PFC. Importantly, dopamine tissue content was completely restored in the NAc following CEF post-treatment. Additionally, METH caused a significant decrease in glutamate and glutamine tissue content in PFC, and this effect was attenuated by CEF post-treatment. These findings demonstrate for the first time the attenuating effects of CEF post-treatment on METH induced alterations in the tissue contents of dopamine, glutamate, and glutamine. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPARγ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Merilin Al Sharif


    Full Text Available Comprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPARγ ligand-dependent dysregulation as a key molecular initiating event (MIE for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPARγ. Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPARγ-dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPARγ-mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPARγ ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD concepts: (i PPARγ activation in hepatocytes and (ii PPARγ inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details.

  17. Estimation of acute oral toxicity using the No Observed Adverse Effect Level (NOAEL) from the 28 day repeated dose toxicity studies in rats. (United States)

    Bulgheroni, Anna; Kinsner-Ovaskainen, Agnieszka; Hoffmann, Sebastian; Hartung, Thomas; Prieto, Pilar


    Acute systemic toxicity is one of the areas of particular concern due to the 2009 deadline set by the 7th Amendment of the Cosmetics Directive (76/768/EEC), which introduces a testing and marketing ban of cosmetic products with ingredients tested on animals. The scientific community is putting considerable effort into developing and validating non-animal alternatives in this area. However, it is unlikely that validated and regulatory accepted alternative methods and/or strategies will be available in March 2009. Following the initiatives undertaken in the pharmaceutical industry to waive the acute oral toxicity testing before going to clinical studies by using information from other in vivo studies, we proposed an approach to identify non-toxic compounds (LD50>2000mg/kg) using information from 28 days repeated dose toxicity studies. Taking into account the high prevalence of non-toxic substances (87%) in the New Chemicals Database, it was possible to set a NOAEL threshold of 200mg/kg that allowed the correct identification of 63% of non-toxic compounds, while testing of cosmetic ingredients.

  18. Influence of coefficient of variation in determining significant difference of quantitative values obtained from 28-day repeated-dose toxicity studies in rats. (United States)

    Kobayashi, Katsumi; Sakuratani, Yuki; Abe, Takemaru; Yamazaki, Kazuko; Nishikawa, Satoshi; Yamada, Jun; Hirose, Akihiko; Kamata, Eiichi; Hayashi, Makoto


    In order to understand the influence of coefficient of variation (CV) in determining significant difference of quantitative values of 28-day repeated-dose toxicity studies, we examined 59 parameters of 153 studies conducted in accordance with Chemical Substance Control Law in 12 test facilities. Sex difference was observed in 12 parameters and 10 parameters showed large CV in females. The minimum CV was 0.74% for sodium. CV of electrolytes was comparatively small, whereas enzymes had large CV. Large differences in CV were observed for major parameters among 7-8 test facilities. The changes in CV were grossly classified into 11. Our study revealed that a statistical significant difference is usually detected if there is a difference of 7% in mean values between the groups and the groups have a CV of about 7%. A parameter with a CV as high as 30% may be significantly different, if the difference of the mean between the groups is 30%. It would be ideal to use median value to assess the treatment-related effect, rather than mean, when the CV is very high. We recommend using CV of the body weight as a standard to judge the adverse effect level.

  19. Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: A European consensus

    DEFF Research Database (Denmark)

    Heijerman, Harry; Westerman, Elsbeth; Conway, Steven;


    , mucolytics/mucous mobilizers, anti-inflammatory drugs, bronchodilators and combinations of solutions. Additionally, we review the current knowledge on devices for inhalation therapy with regard to optimal particle sizes and characteristics of wet nebulisers, dry powder and metered dose inhalers. Finally, we...... review the current status of inhaled medication in CF, including the mechanisms of action of the various drugs, their modes of administration and indications, their effects on lung function, exacerbation rates, survival and quality of life, as well as side effects. Specifically we address antibiotics...

  20. Inhalation therapy in mechanical ventilation (United States)

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


    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

  1. Unintended effects of inhaled corticosteroids : disease or drugs?

    NARCIS (Netherlands)

    Vries, F. de


    Patients with asthma or COPD are often treated with inhaled corticosteroids. These drugs reduce the inflammation in the lungs and patients suffer fewer exacerbations. In the late nineties, a tendency to treat patients in general with higher doses of inhaled corticosteroids was accompanied with an in

  2. Hidrofluoralcano como propelente dos aerossóis pressurizados de dose medida: histórico, deposição pulmonar, farmacocinética, eficácia e segurança Hydrofluoroalkane as a propellant for pressurized metered-dose inhalers: history, pulmonary deposition, pharmacokinetics, efficacy and safety

    Directory of Open Access Journals (Sweden)

    Cássio C. Ibiapina


    Full Text Available OBJETIVO: Rever a literatura sobre o hidrofluoralcano como propelente dos inaladores de dose medida contendo medicamentos empregados na asma. FONTES DOS DADOS: O levantamento bibliográfico foi realizado em bancos de dados eletrônicos - MEDLINE, MDConsult, HighWire, Medscape e LILACS - e por pesquisa direta - referentes aos últimos 15 anos -, utilizando-se as seguintes palavras-chaves: hidrofluoralcano, asma e infância. SÍNTESE DOS DADOS: Foram selecionados 43 artigos originais abordando a questão da substituição do clorofluorcarbono pelo hidrofluoralcano. Este gás mostrou-se como uma alternativa de propelente segura, com deposição pulmonar de 50 a 60% e eficácia significativa quando comparado com placebo (p OBJECTIVE: To review the literature about hydrofluoroalkane as a propellent of pressurized metered-dose inhalers containing anti-asthma drugs. SOURCES OF DATA: Bibliographic search in electronic databases (MEDLINE, MDConsult, HighWire, Medscape and LILACS and direct search referring to the past 15 years, using the key words hydrofluoroalkane, asthma and childhood were carried out. SUMMARY OF THE FINDINGS: 43 original articles on the replacement of clorofluorcarbon by hydrofluoralkane were selected. Hydrofluoralkane showed to be a safe propellent, with pulmonary deposition ranging from 50 to 60%, and to have significant efficacy, when compared with placebo (p < 0.003 in controlled clinical trials. Most works using hydrofluoralkane included beclomethasone diproprionate. Approximate annual cost of a treatment with beclomethasone diproprionate/hydrofluoralkane was lower than with beclomethasone diproprionate/clorofluorcarbon. Some studies assessed salbutamol, fluticasone, flunisolide and the association fluticasone-salmeterol, with hydrofluoralkane as propellent in pressurized metered-dose inhalers. CONCLUSIONS: Efficacy and safety of hydrofluoralkane as propellent of bronchodilators and inhaled corticosteroids in adults was evidenced

  3. Deposition and biokinetics of inhaled nanoparticles

    Directory of Open Access Journals (Sweden)

    Kreyling Wolfgang G


    Full Text Available Abstract Particle biokinetics is important in hazard identification and characterization of inhaled particles. Such studies intend to convert external to internal exposure or biologically effective dose, and may help to set limits in that way. Here we focus on the biokinetics of inhaled nanometer sized particles in comparison to micrometer sized ones. The presented approach ranges from inhaled particle deposition probability and retention in the respiratory tract to biokinetics and clearance of particles out of the respiratory tract. Particle transport into the blood circulation (translocation, towards secondary target organs and tissues (accumulation, and out of the body (clearance is considered. The macroscopically assessed amount of particles in the respiratory tract and secondary target organs provides dose estimates for toxicological studies on the level of the whole organism. Complementary, microscopic analyses at the individual particle level provide detailed information about which cells and subcellular components are the target of inhaled particles. These studies contribute to shed light on mechanisms and modes of action eventually leading to adverse health effects by inhaled nanoparticles. We review current methods for macroscopic and microscopic analyses of particle deposition, retention and clearance. Existing macroscopic knowledge on particle biokinetics and microscopic views on particle organ interactions are discussed comparing nanometer and micrometer sized particles. We emphasize the importance for quantitative analyses and the use of particle doses derived from real world exposures.

  4. Deposition and biokinetics of inhaled nanoparticles (United States)


    Particle biokinetics is important in hazard identification and characterization of inhaled particles. Such studies intend to convert external to internal exposure or biologically effective dose, and may help to set limits in that way. Here we focus on the biokinetics of inhaled nanometer sized particles in comparison to micrometer sized ones. The presented approach ranges from inhaled particle deposition probability and retention in the respiratory tract to biokinetics and clearance of particles out of the respiratory tract. Particle transport into the blood circulation (translocation), towards secondary target organs and tissues (accumulation), and out of the body (clearance) is considered. The macroscopically assessed amount of particles in the respiratory tract and secondary target organs provides dose estimates for toxicological studies on the level of the whole organism. Complementary, microscopic analyses at the individual particle level provide detailed information about which cells and subcellular components are the target of inhaled particles. These studies contribute to shed light on mechanisms and modes of action eventually leading to adverse health effects by inhaled nanoparticles. We review current methods for macroscopic and microscopic analyses of particle deposition, retention and clearance. Existing macroscopic knowledge on particle biokinetics and microscopic views on particle organ interactions are discussed comparing nanometer and micrometer sized particles. We emphasize the importance for quantitative analyses and the use of particle doses derived from real world exposures. PMID:20205860

  5. Application of electric-atomization inhalation of pulmicort respules in preventing repeated attack of asthmatic bronchitis%电动雾化吸入普米克令舒预防喘息样支气管炎反复发作的应用

    Institute of Scientific and Technical Information of China (English)

    金剑; 何梦藻; 滕懿群


    目的:探讨电动雾化吸入普米克令舒在预防喘息样支气管炎反复发作中的作用。方法:将68例反复发作≥2次的喘息样支气管炎患儿分成2组,对照组患儿出院后予常规口服止咳、抗过敏药物巩固治疗3~5天,观察组患儿出院后在常规巩固治疗基础上,加电驱动雾化吸入普米克令舒。对于IgE升高或有过敏史、遗传史者,2组均加孟鲁斯特口服(4mg qN )。随访1年,比较2组患儿喘息反复发作次数。结果:观察组复发率明显低于对照组,差异具有统计学意义( P<0.01)。结论:电动雾化吸入普米克令舒可有效预防喘息样支气管炎反复发作,值得临床推荐使用。%Objective ] To study the effects of electric-atomization inhalation of pulmicort respules in preventing repeated at-tacks of asthmatic bronchitis .[Method] A total of 62 chileren with asthmatic bronchitis who suffered from repeated attack ≥2 times were randomly divided into two groups .Control group was received conventional treatment of anti-cough and anti-al-lergy for 3-5days after discharge .On that basis ,electric-atomization inhalation of pulmicort respules were used in observa-tion group .Additional mantelukast (4mg ,po ,qn) were used in patients with elevated serum IgE ,allergy history or inherited his-tory in both groups .All patients were followed-up for one year and the recurrence rate of the wheezing were comparatively an-alyzed .[Result] The recurrence rate of the observation group was lower than that of the control group and the comparative dif-ference of the two groups was statically significant .[Conclusion] Electric-atomization inhalation of pulmicort respules could effectively prevent repeated attacks of asthmatic bronchitis .It holds promise for clinical application .

  6. Repeated treatment of recurrent uncomplicated Plasmodium falciparum malaria in Senegal with fixed-dose artesunate plus amodiaquine versus fixed-dose artemether plus lumefantrine: a randomized, open-label trial

    Directory of Open Access Journals (Sweden)

    Barry Aichatou


    Full Text Available Abstract Background The use of artemisinin-based combination therapy (ACT is currently recommended for treating uncomplicated malaria. The objective was to assess the efficacy and safety of repeated administrations of two fixed-dose presentations of ACT - artesunate plus amodiaquine (ASAQ and artemether-lumefantrine (AL - in subsequent episodes of Plasmodium falciparum malaria. Methods A randomized comparative study was conducted in a rural community of central Senegal from August 2007 to January 2009. Children and adults with uncomplicated P. falciparum malaria were randomized to receive open-label ASAQ once daily or AL twice daily for three days. Drug doses were given according to body weight. Treatments for first episodes were supervised. For subsequent episodes, only the first intake of study drug was supervised. ECGs and audiograms were performed in patients ≥12 years of age. Primary outcome was adequate clinical and parasitological response rate (ACPR after polymerase chain reaction (PCR correction on day 28 for the first episode. Results A total of 366 patients were enrolled in the two groups (ASAQ 184, AL 182 and followed up during two malaria transmission seasons. In the intent-to-treat population, PCR-corrected ACPRs at day 28 for the first episode were 98.4% and 96.2%, respectively, in the ASAQ and AL groups. For the per-protocol population (ASAQ 183, AL 182, PCR-corrected ACPRs at day 28 for the first episode were 98.9% and 96.7%, respectively. A 100% ACPR rate was obtained at day 28 in the 60 and four patients, respectively, who experienced second and third episodes. Treatment-related adverse events were reported in 11.7% of the patients, without significant differences between the two groups. A better improvement of haemoglobin at day 28 was noted in the ASAQ versus the AL group (12.2 versus 11.8 g/dL; p = 0.03. No sign of ototoxicity was demonstrated. A prolongation of the QTc interval was observed in both groups during

  7. Relative lung and systemic bioavailability of sodium cromoglycate inhaled products using urinary drug excretion post inhalation. (United States)

    Aswania, Osama; Chrystyn, Henry


    The relative lung and systemic bioavailability of sodium cromoglycate following inhalation by different methods have been determined using a urinary excretion pharmacokinetic method. On three separate randomised study days, 7 days apart, subjects inhaled (i) 4x5 mg from an Intal metered dose inhaler (MDI), (ii) 4x5 mg from an MDI attached to a large volume spacer (MDI+SP) and (iii) 20 mg from an Intal Spinhaler (DPI). Urine samples were provided at 0, 0.5, 1, 2, 5 and 24 h post dose. The mean (S.D.) amount of sodium cromoglycate excreted in the urine during the first 30 min post inhalation was 38.1 (27.5), 222.3 (120.3) and 133.1 (92.2) microg following MDI, MDI+SP and DPI, respectively. The mean ratio (90% confidence interval) of these amounts excreted in the urine over the first 30 min for MDI+SP vs. MDI, DPI vs. MDI and MDI+SP vs. DPI was 801.0 (358.0, 1244; psodium cromoglycate excreted over the 24 h post inhalation the ratios were 375.4 (232.9, 517.9; psodium cromoglycate from a metered dose inhaler attached to a large volume spacer.

  8. Real-life characteristics of asthma inhaler device use in South Korea

    NARCIS (Netherlands)

    Wan Yau Ming, S.; Rhee, C.K.; Park, H.Y.; Yoo, K.H.; Kim, D.K.; Van Boven, J.F.; Price, D.; Park, H.S.


    Background and Aims: Historically, dry powder inhalers (DPIs) were considered to provide better airway distribution, easier identification of empty devices, and easier handling when compared to pressurized metered dose inhalers (pMDIs). Prior research into the major handling errors with inhaler

  9. Inhalant Abuse and Dextromethorphan. (United States)

    Storck, Michael; Black, Laura; Liddell, Morgan


    Inhalant abuse is the intentional inhalation of a volatile substance for the purpose of achieving an altered mental state. As an important, yet underrecognized form of substance abuse, inhalant abuse crosses all demographic, ethnic, and socioeconomic boundaries, causing significant morbidity and mortality in school-aged and older children. This review presents current perspectives on epidemiology, detection, and clinical challenges of inhalant abuse and offers advice regarding the medical and mental health providers' roles in the prevention and management of this substance abuse problem. Also discussed is the misuse of a specific "over-the-counter" dissociative, dextromethorphan.

  10. Asthma Inhalers: Which One's Right for You? (United States)

    ... it seems like you're not getting enough medication. Replace your inhaler if it has passed its expiration date or it shows that all the doses have been used. References Scichilone N. Asthma control: The right ... asthma medications. American Academy of Allergy, Asthma and Immunology. http:// ...

  11. Reasons for Inhalant Use. (United States)

    Joe, George W.; Simpson, D. Dwayne


    Among 110 Mexican-American adolescents in a Texas drug abuse program, initial use of toxicant inhalants was related to availability and sensation-seeking, followed by psychological problems, parental and home problems, and peer influence. Quitting inhalant use was related to social pressures, attitude change, and perceived health risks. (Author/SV)

  12. Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: A European consensus. (United States)

    Heijerman, Harry; Westerman, Elsbeth; Conway, Steven; Touw, Daan; Döring, Gerd


    In cystic fibrosis inhalation of drugs for the treatment of CF related lung disease has been proven to be highly effective. Consequently, an increasing number of drugs and devices have been developed for CF lung disease or are currently under development. In this European consensus document we review the current status of inhaled medication in CF, including the mechanisms of action of the various drugs, their modes of administration and indications, their effects on lung function, exacerbation rates, survival and quality of life, as well as side effects. Specifically we address antibiotics, mucolytics/mucous mobilizers, anti-inflammatory drugs, bronchodilators and combinations of solutions. Additionally, we review the current knowledge on devices for inhalation therapy with regard to optimal particle sizes and characteristics of wet nebulisers, dry powder and metered dose inhalers. Finally, we address the subject of testing new devices before market introduction.

  13. Inhalants in Peru. (United States)

    Lerner, R; Ferrando, D


    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

  14. Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33. (United States)

    Ritter, G; Cohen, L S; Williams, C; Richards, E C; Old, L J; Welt, S


    Mouse monoclonal antibody A33 (mAb A33) recognizes a M(r) 43,000 cell surface glycoprotein (designated A33) expressed in human colonic epithelium and colon cancer but absent from most other normal tissues. In patients, mAb A33 localizes with high specificity to colon cancer and is retained for up to 6 weeks in the cancer but cleared rapidly from normal colon (5-6 days). As a carrier of (125)I or (131)I, mAb A33 has shown antitumor activity. Induction of strong human anti-mouse antibody (immunoglobulin; HAMA) responses in patients, however, limits the use of the murine mAb A33 to very few injections. A humanized version of this antibody (huAb A33) has been prepared for Phase I and II clinical studies in patients with colon cancer. In those studies, immunogenicity of huAb A33 has been monitored using a novel, highly sensitive BIACORE method, which allows measurement of human anti-human antibodies (HAHAs) without the use of secondary reagents. We found that 63% (26 of 41) of the patients treated with repeated doses of huAb A33 developed HAHAs against a conformational antigenic determinant located in the V(L) and V(H) regions of huAb A33. Detailed serological analysis showed two distinct types of HAHAs. HAHA of type I (49% of patients) was characterized by an early onset with peak HAHA levels after 2 weeks of treatment, which declined with ongoing huAb A33 treatment. HAHA of type II (17% of patients) was characterized by a typically later onset of HAHA than in type I and by progressively increasing HAHA levels with each subsequent huAb A33 administration. Colon cancer patients with type I HAHAs did not develop infusion-related adverse events. In contrast, HAHA of type II was indicative of infusion-related adverse events. By using this new method, we were able to distinguish these two types of HAHAs in patients while on antibody treatment, allowing patients to be removed from study prior to the onset of severe infusion-related adverse events.

  15. Urine and serum concentrations of inhaled and oral terbutaline

    DEFF Research Database (Denmark)

    Elers, Jimmi; Hostrup, Morten; Pedersen, Lars


    We examined urine and serum concentrations after therapeutic use of single and repetitive doses of inhaled and supratherapeutic oral use of terbutaline. We compared the concentrations in 10 asthmatics and 10 healthy subjects in an open-label, cross-over study with 2 mg inhaled and 10 mg oral....... Median (IQR) urine concentrations peaked in the period 0-4 h after inhalation with Cmax 472 (324) ng/mL in asthmatics and 661 (517) ng/mL in healthy subjects, and 4-8 h after oral use with Cmax 666 (877) ng/mL in asthmatic and 402 (663) ng/mL in healthy subjects. In conclusion we found no significant...... differences in urine and serum concentrations between asthmatic and healthy subjects. We compared urine and serum concentrations after therapeutic inhaled doses and supratherapeutic oral doses and observed significant statistical differences in both groups but found it impossible to distinguish between...

  16. Inhalation exposure to chloramine T induces DNA damage and inflammation in lung of Sprague-Dawley rats. (United States)

    Shim, Ilseob; Seo, Gyun-Baek; Oh, Eunha; Lee, Mimi; Kwon, Jung-Taek; Sul, Donggeun; Lee, Byung-Woo; Yoon, Byung-Il; Kim, Pilje; Choi, Kyunghee; Kim, Hyun-Mi


    Chloramine T has been widely used as a disinfectant in many areas such as kitchens, laboratories and hospitals. It has been also used as a biocide in air fresheners and deodorants which are consumer products; however, little is known about its toxic effects by inhalation route. This study was performed to identify the subacute inhalation toxicity of chloramine T under whole-body inhalation exposure conditions. Male and female groups of rats were exposed to chloramine T at concentrations of 0.2, 0.9 and 4.0 mg/m³ for 6 hr/day, 5 days/week during 4 weeks. After 28-day repeated inhalation of chloramine T, there were dose-dependently significant DNA damage in the rat tissues evaluated and inflammation was histopathologically noted around the terminal airways of the lung in both genders. As a result of the expression of three types of antioxidant enzymes (SOD-2, GPx-1, PRX-1) in rat's lung after exposure, there was no significant change of all antioxidant enzymes in the male and female rats. The results showed that no observed adverse effect level (NOAEL) was 0.2 mg/m³ in male rats and 0.9 mg/m³ in female rats under the present experimental condition.

  17. Interspecies extrapolation based on the RepDose database--a probabilistic approach. (United States)

    Escher, Sylvia E; Batke, Monika; Hoffmann-Doerr, Simone; Messinger, Horst; Mangelsdorf, Inge


    Repeated dose toxicity studies from the RepDose database (DB) were used to determine interspecies differences for rats and mice. NOEL (no observed effect level) ratios based on systemic effects were investigated for three different types of exposure: inhalation, oral food/drinking water and oral gavage. Furthermore, NOEL ratios for local effects in inhalation studies were evaluated. On the basis of the NOEL ratio distributions, interspecies assessment factors (AF) are evaluated. All data sets were best described by a lognormal distribution. No difference was seen between inhalation and oral exposure for systemic effects. Rats and mice were on average equally sensitive at equipotent doses with geometric mean (GM) values of 1 and geometric standard deviation (GSD) values ranging from 2.30 to 3.08. The local AF based on inhalation exposure resulted in a similar distribution with GM values of 1 and GSD values between 2.53 and 2.70. Our analysis confirms former analyses on interspecies differences, including also dog and human data. Furthermore it supports the principle of allometric scaling according to caloric demand in the case that body doses are applied. In conclusion, an interspecies distribution animal/human with a GM equal to allometric scaling and a GSD of 2.5 was derived.

  18. Inhaled nitric oxide plus iloprost in the setting of post-left assist device right heart dysfunction. (United States)

    Antoniou, Theofani; Prokakis, Christos; Athanasopoulos, Georgios; Thanopoulos, Apostolos; Rellia, Panagiota; Zarkalis, Dimitrios; Kogerakis, Nektarios; Koletsis, Efstratios N; Bairaktaris, Andreas


    Pulmonary hypertension and right ventricular (RV) dysfunction may complicate the implantation of a left ventricular assist device (LVAD). We examined whether inhaled vasodilators can sufficiently reduce RV afterload, avoiding the need for temporary RV mechanical support. The study includes 7 patients with RV dysfunction after LVAD insertion. Treatment consisted of inotropes, inhaled nitric oxide (10 ppm), and iloprost (10 μg) in repeated doses. Full hemodynamic profile was obtained before inhalation, during administration of inhaled NO alone (before and after iloprost), as well as after the first two doses of inhaled iloprost. Tricuspid annular velocity was estimated at baseline and before and after adding iloprost. There was a statistically significant reduction in pulmonary vascular resistance (PVR), mean pulmonary artery pressure (MPAP), RV systolic pressure, and pulmonary capillary wedge pressure, and a considerable increase in LVAD flow, LV flow rate index, and tricuspid annular velocity at all points of evaluation versus baseline. By the end of the protocol, MPAP/mean systemic arterial pressure, and PVR/systemic vascular resistance ratios were reduced by 0.17±0.03 (95% confidence interval, 0.10 to 0.25, p=0.001) and 0.12±0.025 (95% confidence interval, 0.06 to 0.18; p=0.003), respectively. The tricuspid annular velocity increased by 2.3±0.18 cm/s (95% confidence interval, 1.83 to 2.73 cm/s; piloprost showed an important decrease in PVR (p=0.022), MPAP (p=0.001), pulmonary capillary wedge pressure (p=0.002), and RV systolic pressure (piloprost sufficiently decreased PVR and MPAP on the basis of an additive effect, improved RV function, and avoided the need for RV assist device. Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  19. A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354 in subjects with asthma

    Directory of Open Access Journals (Sweden)

    Roskos Lorin


    Full Text Available Abstract Background IL-13 has been implicated in the development of airway inflammation and hyperresponsiveness. This study investigated the multiple-dose pharmacokinetics and safety profile of human anti-IL-13 antibody (CAT-354 in adults with asthma. Methods This was a multiple-dose, randomised, double-blind, placebo-controlled phase 1 study in asthmatics (forced expiratory volume in 1 second [FEV1] ≥ 80% predicted. Subjects were randomised to receive three intravenous infusions of CAT-354 (1 mg/kg, 5 mg/kg or 10 mg/kg or placebo at 28-day intervals. Blood samples were taken for pharmacokinetic measurements. Safety was assessed by adverse events, vital signs, ECGs, laboratory and pulmonary function parameters. Results Twenty-three subjects (aged 21-60 years, FEV1 88-95% predicted received ≥ 1 dose of study medication. The half-life of CAT-354 was 12-17 days and was dose-independent. The maximum serum concentration and area under the curve were dose-dependent. Clearance (2.2-2.6 mL/day/kg and volume of distribution (44-57 mL/kg were both low and dose-independent. The observed maximum serum concentration after each dose increased slightly from dose 1 through dose 3 at all dose levels, consistent with an accumulation ratio of 1.4 to 1.7 for area under the curve. Most adverse events were deemed mild to moderate and unrelated to study medication. One SAE was reported and deemed unrelated to study drug. There were no effects of clinical concern for vital signs, ECG, laboratory or pulmonary parameters. Conclusions CAT-354 exhibited linear pharmacokinetics and an acceptable safety profile. These findings suggest that at the doses tested, CAT-354 can be safely administered in multiple doses to patients with asthma. Trial registration NCT00974675.

  20. Rapid transition from inhaled iloprost to inhaled treprostinil in patients with pulmonary arterial hypertension. (United States)

    Bourge, Robert C; Tapson, Victor F; Safdar, Zeenat; Benza, Raymond L; Channick, Richard N; Rosenzweig, Erika B; Shapiro, Shelley; White, R James; McSwain, Christopher Shane; Gotzkowsky, Stephen Karl; Nelsen, Andrew C; Rubin, Lewis J


    Inhaled treprostinil is a prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) that may provide a more convenient treatment option for patients receiving inhaled iloprost while maintaining the clinical benefit of inhaled prostacyclin therapy. In this open-label safety study, 73 PAH patients were enrolled with primarily World Health Organization Class II (56%) or III (42%) symptoms. At baseline, most patients (93%) were receiving 5 μg of iloprost per dose but 38% of patients reported a dosing frequency below the labeled rate of 6-9 times daily. Patients initiated inhaled treprostinil at 3 breaths four times daily (qid) at the immediate next scheduled iloprost dose. The primary objective was to assess the safety of rapid transition from iloprost to inhaled treprostinil; clinical status and quality of life were also assessed. Most patients (84%) achieved the target treprostinil dose of 9 breaths qid and remained on study until transition to commercial therapy (89%). The most frequent adverse events (AEs) were cough (74%), headache (44%), and nausea (30%), and five patients prematurely discontinued study drug due to AE (n = 3), disease progression (n = 1), or death (n = 1). At week 12, the time spent on daily treatment activities was reduced compared to baseline, with a mean total savings of 1.4 h per day. Improvements were also observed at week 12 for 6-min walk distance (+16.0; P iloprost to inhaled treprostinil while maintaining clinical status. © 2012 Blackwell Publishing Ltd.

  1. Formoterol Oral Inhalation (United States)

    ... of lung diseases that includes chronic bronchitis and emphysema) in adults. Formoterol inhalation powder is also used with another medication to treat asthma and to prevent breathing difficulties during exercise in ...

  2. Indacaterol Oral Inhalation (United States)

    Indacaterol inhalation is used to control wheezing, shortness of breath, coughing, and chest tightness caused by chronic obstructive pulmonary disease (COPD). Indacaterol is in a class of medications called long- ...

  3. Pentamidine Oral Inhalation (United States)

    Pentamidine is an anti-infective agent that helps to treat or prevent pneumonia caused by the organism ... Pentamidine comes as a solution to be inhaled using a nebulizer. It usually is used once every ...

  4. Insulin Human Inhalation (United States)

    Insulin inhalation is used in combination with a long-acting insulin to treat type 1 diabetes (condition in which the body does not produce insulin and therefore cannot control the amount of sugar ...

  5. Design and evaluation of a new dry powder inhaler

    Directory of Open Access Journals (Sweden)

    "Rouholamini Najafabadi AH


    Full Text Available Three versions of a new dry powder inhaler (DPI, RG-haler, were designed using two kinds of grid inserts. Salbutamol sulfate/lactose blend (Ventolin Rotacaps® was selected as a model formulation to analyze the performance of all inhalers and compare their efficiency with three marketed devices (Rotahaler®, Spinhaler® and ISF inhalator® using the twin impinger (TI. Deposition of the drug in device was significantly (P<0.05 lower for ISF inhalator® and all kinds of RG-halers in comparison with those of Rotahaler® and Spinhaler®. The amount of drug deposited in the stage 2 and the respirable dose for RG-halers were similar to those of ISF inhalator® and significantly (P<0.05 higher than those of Rotahaler® and Spinhaler®. The results suggest efficient aerosol generating capability of the RG-haler.

  6. Syringe, pen, inhaler - the evolution of insulin therapy. (United States)

    Harsch, I A; Hahn, E G; Konturek, P C


    The therapy with inhalable insulin can be expected to change the present concepts and the market of subcutaneous insulin dramatically within the next years. Several companies are currently developing formulations of inhalable insulin. In the most advanced concept, insulin is delivered as a dry-powder insulin formulation via a special aerosol device system. The phase III studies evaluating the efficiency of the inhaled insulin are already on their way. The recent phase II studies have shown, that the lung is capable of absorbing new insulin formulation in a dose-dependent and reproducible manner. However, a relatively small number of diabetic patients have been included in these studies, yet. The therapeutic efficacy and safety of the inhaled insulin is comparable to that of the usual subcutaneous insulin treatment regimens. The most important advantage of the new therapy is the enhanced therapeutic comfort of the patient who does not need to inject insulin for meal time glucose control. Generally, in terms of glycemic control, inhalable insulin offers no advantages in type 1 diabetics in comparison to an intensified conventional insulin therapy. However, before a large-scale marketing, several open questions have to be carefully investigated, the most important being the possible long-term effects of insulin inhalation for the lung, since insulin is known to have growth-promoting properties. There is still no available clinical data concerning the efficiency of the inhaled insulin in patients with pulmonary diseases which may cause problems in absorption of inhaled insulin due to the smaller cumulative alveolar surface. In smokers without pulmonary disease seems the inhaled insulin to act stronger and faster. Since therapy with inhalable insulin requires larger doses of insulin in comparison to subcutaneous insulin to achieve the same systemic effect, the costs of this therapy need to be clarified, too.

  7. How to match the optimal currently available inhaler device to an individual child with asthma or recurrent wheeze

    DEFF Research Database (Denmark)

    van Aalderen, W. M.; Garcia-Marcos, L.; Gappa, M.;


    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...

  8. A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster

    DEFF Research Database (Denmark)

    Langkilde, Søren; Mandimika, T.; Schrøder, Malene


    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanum tuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine...... to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity...... of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios...

  9. Randomized, controlled, assessor-blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides, trichuris trichiura, and hookworm infection. (United States)

    Adegnika, Ayola A; Zinsou, Jeannot F; Issifou, Saadou; Ateba-Ngoa, Ulysse; Kassa, Roland F; Feugap, Eliane N; Honkpehedji, Yabo J; Dejon Agobe, Jean-Claude; Kenguele, Hilaire M; Massinga-Loembe, Marguerite; Agnandji, Selidji T; Mordmüller, Benjamin; Ramharter, Michael; Yazdanbakhsh, Maria; Kremsner, Peter G; Lell, Bertrand


    In many regions where soil-transmitted helminth infections are endemic, single-dose albendazole is used in mass drug administration programs to control infections. There are little data on the efficacy of the standard single-dose administration compared to that of alternative regimens. We conducted a randomized, controlled, assessor-blinded clinical trial to determine the efficacies of standard and extended albendazole treatment against soil-transmitted helminth infection in Gabon. A total of 175 children were included. Adequate cure rates and egg reduction rates above 85% were found with a single dose of albendazole for Ascaris infection, 85% (95% confidence interval [CI], 73, 96) and 93.8% (CI, 87.6, 100), respectively, while two doses were necessary for hookworm infestation (92% [CI, 78, 100] and 92% [CI, 78, 100], respectively). However, while a 3-day regimen was not sufficient to cure Trichuris (cure rate, 83% [CI, 73, 93]), this regimen reduced the number of eggs up to 90.6% (CI, 83.1, 100). The rate ratios of two- and three-dose regimens compared to a single-dose treatment were 1.7 (CI, 1.1, 2.5) and 2.1 (CI, 1.5, 2.9) for Trichuris and 1.7 (CI, 1.0, 2.9) and 1.7 (CI, 1.0, 2.9) for hookworm. Albendazole was safe and well tolerated in all regimens. A single-dose albendazole treatment considerably reduces Ascaris infection but has only a moderate effect on hookworm and Trichuris infections. The single-dose option may still be the preferred regimen because it balances efficacy, safety, and compliance during mass drug administration, keeping in mind that asymptomatic low-level helminth carriage may also have beneficial effects. (This study has been registered at under registration number NCT01192802.).

  10. 雾化吸入小剂量氨溴索对开胸食道手术患者单肺通气时炎性反应的影响%Effects of inhaled aerosolized low dose ambroxol on inflammatory response to one-lung ventilation in patients undergoing open-chest esophagus surgery

    Institute of Scientific and Technical Information of China (English)

    李明川; 李毅海; 丁素春


    Objective To investigate the effects of inhaled aerosolized low dose ambroxol on the inflammatory response to one-lung ventilation (OLV) in patients undergoing open-chest esophagus surgery.Methods Sixty patients (aged 39-64 years,weighing 50-85 kg and with height of 153-181 cm) with normal heart and lung function undergoing open-chest esophagus surgery were randomly divided into three groups:20 patients receiving intravenous infusion of normal saline (control group,group C),20 receiving intravenous infusion of ambroxol 10 mg/kg after induction of anesthesia (group IA) and 20 inhaling aerosolized ambroxol 30 mg after induction of anesthesia (group AIA).Arterial blood samples were taken after induction of anesthesia before ambroxol administration (T0,baseline),after 90 minutes of OLV (T1) and at 30 minutes after OLV (T2) for determination of plasma concentrations of tumor necrosis factor-alpha (TNF-α),interleukin-1 beta (IL-1β),IL-8 and IL-10 by enzyme linked immunosorbent assay (ELISA).Results The levels of TNF-α,IL-1β,and IL-8 in plasma significantly increased while the level of IL-10 in plasma significantly decreased at T1 and T2 as compared with the baseline at T0 in all the three groups.The levels of TNF-α,IL-1β,and IL-8 in plasma were significantly lower and the level of IL-10 in plasma was significantly higher at T1 and T2 in groups IA and AIA than in group C.Conclusion Both intravenous injection of large dose ambroxol and inhaled aerosolized low dose ambroxol can inhibit the inflammatory response to OLV in patients undergoing open-chest esophagus surgery.

  11. Effects of repeated inhalation of sevoflurane under sub-anesthetic concen-tration in neonatal period of rats on capability of learning and memory in adult period%新生大鼠重复吸入亚麻醉浓度七氟醚对成年期学习记忆能力的影响

    Institute of Scientific and Technical Information of China (English)

    郑淑文; 朱昭琼; 张超; 朱宇航


    目的:探讨新生期重复吸入亚麻醉浓度七氟醚对大鼠成年期学习记忆能力的影响。方法:24只7日龄SD大鼠随机分为2组,每组12只。实验组分别于出生7、14、21 d吸入体积分数1.5%七氟醚1 h,对照组吸入运载气体,于第91~95天行定位航行和空间探索实验,记录逃避潜伏期、原平台象限滞留时间百分比、原平台象限运动距离百分比及原平台象限进入次数百分比;于第96~104天行不固定平台实验,记录成功到达平台的次数和达到标准所用总时间。结果:与对照组相比,实验组逃避潜伏期延长,原平台象限滞留时间百分比及运动距离百分比减小(F组间=41.297,t=3.421和3.122,P均<0.05);2组大鼠成功到达平台的次数及达到标准所用总时间比较,差异无统计学意义(F组间=2.184和1.143,P均>0.05)。结论:新生期重复吸入亚麻醉浓度七氟醚会损害大鼠成年期学习记忆能力,而对工作记忆能力无影响。%Aim:To investigate the effects of repeated inhalation of sevoflurane under sub -anesthetic concentration in the neonatal period of rats on capability of learning and memory in the adult period .Methods:Seven-day old SD rats were randomly allocated into 2 groups,experimental group(n=12,group S) and control group(n=12,group C).The rats in group S were anesthetized with 1.5%( V/V) sevoflurane for 1 h on the 7th,14th and 21st d after birth respectively ,while group C inhaled carrier gas instead .Place trial and probe trial were carried out on the 91st-95th d after birth,and the es-cape latency ,the residence time ,movement distance and the number of entering into the platform area were recorded .Learn-ing to reach criterion test was carried out on the 96th-104th d after birth,and the number of entering into the platform and the time used to reach the criteria were recorded .Results:Compared with group C ,the escape

  12. Repeat-dose toxicology evaluation in cynomolgus monkeys of AVI-4658, a phosphorodiamidate morpholino oligomer (PMO) drug for the treatment of duchenne muscular dystrophy. (United States)

    Sazani, Peter; Ness, Kirk P Van; Weller, Doreen L; Poage, Duane W; Palyada, Kiran; Shrewsbury, Stephen B


    AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) drug designed to restore dystrophin expression in a subset of patients with Duchenne muscular dystrophy (DMD). Previous reports demonstrated this clinical proof-of-principle in patients with DMD following intramuscular injection of AVI-4658. This preclinical study evaluated the toxicity and toxicokinetic profile of AVI-4658 when administered either intravenously (IV) or subcutaneously (SC) to cynomolgus monkeys once weekly over 12 weeks, at doses up to the maximum feasible dose of 320 mg/kg per injection. No drug-related effects were noted on survival, clinical observations, body weight, food consumption, opthalmoscopic or electrocardiographic evaluations, hematology, clinical chemistry, urinalysis, organ weights, and macroscopic evaluations. Drug-related microscopic renal effects were dose-dependent, apparently reversible, and included basophilic granules (minimal), basophilic tubules (minimal to moderate), and tubular vacuolation (minimal to mild). These data establish the tolerability of AVI-4658 at doses up to and including the maximum feasible dose of 320 mg/kg by IV bolus or SC injection.

  13. Inflammatory Mediators in Smoke Inhalation Injury (United States)


    of arte- rial oxygen to the fraction of inspired oxygen ( PFR ) until a certain “threshold” smoke dose has been delivered; thereaf- ter, decreases in... PFR are steep [11, 16]. Pathologically, these models demonstrate evidence of tracheal and lobar bronchial mucosal sloughing with pseudomembrane...during an inhalation injury [31]. Initial animal research on six sheep given intravenous heparin improved PFR , improved peak airway pressures and

  14. Effectiveness and success factors of educational inhaler technique interventions in asthma & COPD patients: a systematic review. (United States)

    Klijn, Sven L; Hiligsmann, Mickaël; Evers, Silvia M A A; Román-Rodríguez, Miguel; van der Molen, Thys; van Boven, Job F M


    With the current wealth of new inhalers available and insurance policy driven inhaler switching, the need for insights in optimal education on inhaler use is more evident than ever. We aimed to systematically review educational inhalation technique interventions, to assess their overall effectiveness, and identify main drivers of success. Medline, Embase and CINAHL databases were searched for randomised controlled trials on educational inhalation technique interventions. Inclusion eligibility, quality appraisal (Cochrane's risk of bias tool) and data extraction were performed by two independent reviewers. Regression analyses were performed to identify characteristics contributing to inhaler technique improvement. Thirty-seven of the 39 interventions included (95%) indicated statistically significant improvement of inhaler technique. However, average follow-up time was relatively short (5 months), 28% lacked clinical relevant endpoints and all lacked cost-effectiveness estimates. Poor initial technique, number of inhalation procedure steps, setting (outpatient clinics performing best), and time elapsed since intervention (all, p education group size (individual vs. group training) and inhaler type (dry powder inhalers vs. pressurised metered dose inhalers) did not play a significant role. Notably, there was a trend (p = 0.06) towards interventions in adults being more effective than those in children and the intervention effect seemed to wane over time. In conclusion, educational interventions to improve inhaler technique are effective on the short-term. Periodical intervention reinforcement and longer follow-up studies, including clinical relevant endpoints and cost-effectiveness, are recommended.

  15. A 13-week repeated dose study of three 3-monochloropropane-1,2-diol fatty acid esters in F344 rats. (United States)

    Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Mizuta, Yasuko; Yoshida, Midori; Nishikawa, Akiyoshi; Ogawa, Kumiko


    3-monochloropropane-1,2-diol (3-MCPD), a rat renal and testicular carcinogen, has been reported to occur in various foods and food ingredients as free or esterified forms. Since reports about toxicity of 3-MCPD esters are limited, we conducted a 13-week rat subchronic toxicity study of 3-MCPD esters (palmitate diester: CDP, palmitate monoester: CMP, oleate diester: CDO). We administered a carcinogenic dose (3.6 × 10(-4) mol/kg B.W./day) of 3-MCPD or these esters at equimolar concentrations and two 1/4 lower doses by gavage with olive oil as a vehicle five times a week for 13 weeks to F344 male and female rats. As a result, five out of ten 3-MCPD-treated females died from acute renal tubular necrosis, but none of the ester-treated rats. Decreased HGB was observed in all high-dose 3-MCPD fatty acid ester-treated rats, except CDO-treated males. The absolute and relative kidney weights were significantly increased in the ester-treated rats at medium and high doses. Relative liver weights were significantly increased in the esters-treated rat at high dose, except for CMP females. Significant increase in apoptotic epithelial cells in the initial segment of the epididymis of high-dose ester-treated males was also observed. The results suggested that although acute renal toxicity was lower than 3-MCPD, these three 3-MCPD fatty acid esters have the potential to exert subchronic toxicity to the rat kidneys and epididymis, to a similar degree as 3-MCPD under the present conditions. NOAELs (no-observed-adverse-effect levels) of CDP, CMP and CDO were suggested to be 14, 8 and 15 mg/kg B.W./day, respectively.

  16. Emerging inhaled bronchodilators: an update. (United States)

    Cazzola, M; Matera, M G


    Bronchodilators remain central to the symptomatic management of chronic obstructive pulmonary disease and asthma, and, for this reason and also because the patent protection of many bronchodilators has expired, several companies have reinitiated research into the field. The only limits set for the development of a long-lasting bronchodilator with a new product profile are medical needs and marketing opportunities. The incorporation of once-daily dose administration is an important strategy for improving adherence and is a regimen preferred by most patients. A variety of beta(2)-agonists and antimuscarinic agents with longer half-lives and inhalers containing a combination of several classes of long-acting bronchodilator are currently under development. The present article reviews all of the most important compounds under development, describing what has been done and discussing their genuine advantage.

  17. A 28-day repeat dose toxicity study of steroidal glycoalkaloids a-solanine and a-chaconine in the Syrian Golden Hamster

    NARCIS (Netherlands)

    Langkilde, S.; Mandimika, T.; Schroder, M.; Meyer, O.; Slob, W.; Peijnenburg, A.A.C.M.; Poulsen, M.


    Glycoalkaloids ¿-solanine and ¿-chaconine are naturally present toxicants in the potato plant (Solanum tuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of ¿-solanine to ¿-chaconine m

  18. A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster. (United States)

    Langkilde, Søren; Mandimika, Tafadzwa; Schrøder, Malene; Meyer, Otto; Slob, Wout; Peijnenburg, Ad; Poulsen, Morten


    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanumtuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios resulted in distended and fluid filled small intestines and stomach. Animals receiving the ratio with the reduced content of alpha-solanine were less affected compared to those receiving the other ratio. Gene expression profiling experiments were conducted using RNA from epithelial scrapings from the small intestines of the hamsters administered the highest doses of the glycoalkaloid treatments. In general, more differential gene expression was observed in the epithelial scrapings of the hamsters fed the ratio of 1:3.7. Mostly, pathways involved in lipid and energy metabolism were affected by the ratio of 1:3.7.

  19. Inhaled dust and disease

    Energy Technology Data Exchange (ETDEWEB)

    Holt, P.F.


    This book discusses the following: the respiratory system; respirable dust; the fate of inhaled dust; translocation and some general effects of inhaled dust; silicosis; experimental research on silica-related disease; natural fibrous silicates; asbestos dust levels and dust sources; asbestos-related diseases - asbestosis, lung cancer, mesothelioma and other diseases, cancers at sites other than lung and pleura; experimental research relating to asbestos-related diseases; asbestos hazard - mineral types and hazardous occupations, neighbourhood and domestic hazard; silicates other than asbestos-man-made mineral fibres, mineral silicates and cement; metals; coal mine dust, industrial carbon and arsenic; natural and synthetic organic substances; dusts that provoke allergic alveolitis; tobacco smoke.

  20. [Evoked potentials and inhalation anesthetics]. (United States)

    Thiel, A; Russ, W; Hempelmann, G


    Intraoperative monitoring of evoked potentials can be affected by various factors including volatile anaesthetics. These effects have to be considered in order to give correct interpretations of the obtained data. Visual evoked potentials (VEP) and auditory evoked potentials (AEP) will show strong alterations under general anaesthesia whereas brainstem auditory evoked potentials (BAEP) are slightly affected. The effects of nitrous oxide, halothane, enflurane, and isoflurane on somatosensory evoked potentials (SEP) after median nerve stimulation were studied in 35 healthy adult patients. pCO2 and tympanic membrane temperature were held constant. Simultaneous cervical and cortical SEP recording was performed using surface electrodes. After induction of anaesthesia SEP were recorded during normoventilation with 100% oxygen and after inhalation of 66.6% nitrous oxide. 10 patients received halothane at inspired concentrations of 0.5, 1.0, 1.5, and 2.0%. After nitrous oxide had been replaced by oxygen, halothane was reduced in steps of 0.5%. SEP were recorded at the end of each period (15 min). Equipotent doses of enflurane or isoflurane were administered to 15 and 10 patients, respectively. Nitrous oxide depressed early cortical SEP amplitude. Halothane, enflurane, and isoflurane caused dose dependent increases of latencies. Reduction of amplitude was most pronounced with isoflurane. Using high doses of enflurane in oxygen cortical SEP showed unusual high amplitudes associated with marked increases of latencies. Even under high concentrations of volatile anaesthetics cervical SEP were minimally affected. The effects of anaesthetic gases have to be considered when SEP are recorded intraoperatively.

  1. Inhalation drug delivery devices: technology update

    Directory of Open Access Journals (Sweden)

    Ibrahim M


    Full Text Available Mariam Ibrahim, Rahul Verma, Lucila Garcia-ContrerasDepartment of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USAAbstract: The pulmonary route of administration has proven to be effective in local and systemic delivery of miscellaneous drugs and biopharmaceuticals to treat pulmonary and non-pulmonary diseases. A successful pulmonary administration requires a harmonic interaction between the drug formulation, the inhaler device, and the patient. However, the biggest single problem that accounts for the lack of desired effect or adverse outcomes is the incorrect use of the device due to lack of training in how to use the device or how to coordinate actuation and aerosol inhalation. This review summarizes the structural and mechanical features of aerosol delivery devices with respect to mechanisms of aerosol generation, their use with different formulations, and their advantages and limitations. A technological update of the current state-of-the-art designs proposed to overcome current challenges of existing devices is also provided.Keywords: pulmonary delivery, asthma, nebulizers, metered dose inhaler, dry powder inhaler

  2. [Inhaled corticosteroids for COPD

    NARCIS (Netherlands)

    Dekhuijzen, P.N.R.


    Over 60% of patients with COPD are treated with inhaled corticosteroids (ICS), even though their use is still subject to debate. The inflammatory process in the lungs of patients with COPD is dominated by macrophages, CD8+ T-lymphocytes, neutrophilic granulocytes and mast cells, as well as an increa

  3. Inhalants. Specialized Information Service. (United States)

    Do It Now Foundation, Phoenix, AZ.

    The document presents a collection of articles about inhalant abuse. Article 1 presents findings on the psychophysiological effects related to the use of amyl or butyl nitrate as a "recreational drug." Article 2 suggests a strong association between chronic sniffing of the solvent toulene and irreversible brain damage. Article 3 warns…

  4. Inhalational Lung Disease

    Directory of Open Access Journals (Sweden)

    S Kowsarian


    Full Text Available Inhalational lung diseases are among the most important occupational diseases. Pneumoconiosis refers to a group of lung diseases result from inhalation of usually inorganic dusts such as silicon dioxide, asbestos, coal, etc., and their deposition in the lungs. The resultant pulmonary disorders depend on the susceptibility of lungs; size, concentration, solubility and fibrogenic properties of the inhaled particles; and duration of exposure. Radiographic manifestations of pneumoconiosis become apparent several years after exposure to the particles. However, for certain types of dusts, e.g., silicone dioxide crystal and beryllium, heavy exposure within a short period can cause an acute disease. Pulmonary involvement in asbestosis is usually in the lower lobes. On the contrary, in silicosis and coal worker pneumoconiosis, the upper lobes are involved predominantly. For imaging evaluation of pneumoconiosis, high-resolution computed tomography (CT is superior to conventional chest x-ray. Magnetic resonance imaging (MRI and positron emission tomography (PET scan are helpful in those with suspected tumoral lesions. In this essay, we reviewed the imaging aspects of inhalational lung disease.

  5. Self-reported osteoporosis prevention in inhaled corticosteroid users in community pharmacy setting

    Directory of Open Access Journals (Sweden)

    Valerie Chan


    Full Text Available Objectives: The use of inhaled corticosteroids is the standard maintenance therapy in asthma therapy and as adjunct therapy in moderate to severe chronic obstructive pulmonary disease. A dose-related increase in fracture risk is associated with inhaled corticosteroid use; there is an inverse relationship between bone mineral density and duration and cumulative dose of inhaled corticosteroid. Adequate intake of calcium and vitamin D are cornerstones of osteoporosis prevention. The objectives are to assess whether the proportion of patients receiving inhaled corticosteroids are taking calcium and vitamin D; the association between long-term inhaled corticosteroid use and abnormal bone mineral density or fractures; and how many qualified patients received bone mineral density scans. Methods: Patients who filled a prescription for inhaled corticosteroids at selected community pharmacies across Alberta were recruited for a survey of their osteoporosis prevention activities. Results: A total of 256 patients from 12 community pharmacies were included. The average age was 60 ± 17.4 years with 65% female. There were 21%, 51%, and 28% of patients on high, medium, and low dose inhaled corticosteroids, respectively. Only 17% of patients >50 years old received recommended calcium and vitamin D supplementation and 87 (73% of the qualified patients received bone mineral density scan. Conclusion: Osteoporosis prevention in inhaled corticosteroid users is currently poorly addressed. More promotion is needed to raise pharmacist awareness of the risks of inhaled corticosteroids.

  6. Triple inhaled therapy for chronic obstructive pulmonary disease. (United States)

    Montuschi, Paolo; Malerba, Mario; Macis, Giuseppe; Mores, Nadia; Santini, Giuseppe


    Combining individual drugs in a single inhaler is the most convenient way to deliver triple therapy. A long-acting muscarinic receptor antagonist (LAMA) added to an inhaled corticosteroid (ICS)/long-acting β2-adrenoceptor agonist (LABA) fixed-dose combination (FDC) can improve efficacy of pharmacological treatment of patients with chronic obstructive pulmonary disease (COPD). New inhaled ICS/LABA/LAMA FDCs, including fluticasone furoate/vilanterol/umeclidinium, budesonide/formoterol/glycopyrronium and beclometasone/formoterol/glycopyrronium, are in Phase III of clinical development for COPD. Triple inhaled therapy might be particularly useful in patients with severe to very severe COPD, above all in those with peripheral blood or sputum eosinophilia, asthma-COPD overlap syndrome (ACOS) or frequent exacerbators. Future prospective studies should assess efficacy and safety of triple ICS/LABA/LAMA therapy in selected COPD phenotypes.

  7. Interactions between diltiazem and inhalation anaesthetics in the isolated heart. (United States)

    Carceles, M D; Miralles, F S; Laorden, M L; Hernandez, J


    It has been postulated that inhalation anaesthetics may interfere with calcium movement across cell membranes. We have evaluated the interaction between diltiazem and the inhalation anaesthetics halothane and isoflurane on sinus automaticity in the isolated right atrium (SAIRA). Isoflurane significantly reduced atrial rate at all concentrations tested. However, halothane produced only a small but significant decrease at the higher concentrations used (1-2 v/v%). Diltiazem modified the maximal negative chronotropic response to inhalation anaesthetics. Maximum depression of SAIRA was significantly greater in the presence of two different doses of diltiazem compared with exposure to halothane and isoflurane alone. These results suggest that inhalation anaesthetics may block the influx of extracellular calcium through voltage-dependent calcium channels inhibited by diltiazem.

  8. Single- and repeated-dose oral toxicity studies of citicoline free-base (choline cytidine 5'-pyrophosphate) in Sprague-Dawley rats. (United States)

    Schauss, A G; Somfai-Relle, S; Financsek, I; Glavits, R; Parent, S C; Endres, J R; Varga, T; Szücs, Z; Clewell, A


    The dietary supplement Citicoline free-base (choline cytidine 5'-pyrophosphate) was toxicologically evaluated in Sprague-Dawley rats using oral gavage. In an acute 14-day study, 2000 mg/kg was well tolerated. In a 90-day study, 100, 350, and 1000 mg/kg/day doses resulted in no mortality. In males, slight significant increases in serum creatinine (350 and 1000 mg/kg/day), and decreases in urine volume (all treated groups) were observed. In females, slight significant increases in total white blood cell and absolute lymphocyte counts (1000 mg/kg/day), and blood urea nitrogen (BUN) (100 and 350, but not 1000 mg/kg/day) were noted. A dose-related increase in renal tubular mineralization, without degenerative or inflammatory reaction, was found in females (all treated groups) and two males (1000 mg/kg/day). Renal mineralization in rats (especially females) is influenced by calcium:phosphorus ratios in the diet. A high level of citicoline consumption resulted in increased phosphorus intake in the rats, and likely explains this result.

  9. Quantitative biokinetic analysis of radioactively labelled, inhaled Titanium dioxide Nanoparticles in a rat model

    Energy Technology Data Exchange (ETDEWEB)

    Kreyling, Wolfgang G.; Wenk, Alexander; Semmler-Behnke, Manuela [Helmholtz Zentrum Muenchen, Deutsches Forschungszentrum fuer Gesundheit und Umwelt GmbH (Germany). Inst. fuer Lungenbiologie und Erkrankungen, Netzwerk Nanopartikel und Gesundheit


    The aim of this project was the determination of the biokinetics of TiO{sub 2} nanoparticles (NP) in the whole body of healthy adult rats after NP administration to the respiratory tract - either via inhalation or instillation. We developed an own methodology to freshly synthesize and aerosolize TiO{sub 2}-NP in our lab for the use of inhalation studies. These NP underwent a detailed physical and chemical characterization providing pure polycrystalline anatase TiO{sub 2}-NP of about 20 nm (geometric standard deviation 1.6) and a specific surface area of 270 m{sup 2}/g. In addition, we developed techniques for sufficiently stable radioactive {sup 48}V labelling of the TiO{sub 2} NP. The kinetics of solubility of {sup 48}V was thoroughly determined. The methodology of quantitative biokinetics allows for a quantitative balance of the retained and excreted NP in control of the administered NP dose and provides a much more precise determination of NP fractions and concentrations of NP in organs and tissues of interest as compared to spotting biokinetics studies. Small fractions of TiO{sub 2}-NP translocate across the air-blood-barrier and accumulate in secondary target organs, soft tissue and skeleton. The amount of translocated TiO{sub 2}-NP is approximately 2% of TiO{sub 2}-NP deposited in the lungs. A prominent fraction of these translocated TiO{sub 2}-NP was found in the remainder. Smaller amounts of TiO{sub 2}-NP accumulate in secondary organs following particular kinetics. TiO{sub 2}-NP translocation was grossly accomplished within the first 2-4 hours after inhalation followed by retention in all organs and tissues studied without any detectable clearance of these biopersistent TiO{sub 2}-NP within 28 days. Therefore, our data suggest crossing of the air-blood-barrier of the lungs and subsequent accumulation in secondary organs and tissues depends on the NP material and its physico-chemical properties. Furthermore, we extrapolate that during repeated or chronic

  10. Repeated long-term potentiation induces mossy fibre sprouting and changes the sensibility of hippocampal granule cells to subconvulsive doses of pentylenetetrazol. (United States)

    Hassan, H; Pohle, W; Rüthrich, H; Brödemann, R; Krug, M


    Electrical and chemical kindling induces sprouting of the mossy fibre system and potentiation of evoked field potentials in the dentate gyrus. It has been postulated that such changes may also be induced by repeated induction of long-term potentiation (LTP) with tetanic stimulation of the perforant pathway. LTP was induced in rats chronically implanted with stimulation electrodes in the ipsilateral and contralateral angular bundles and with a recording electrode in the ipsilateral dorsal dentate gyrus. The animals were stimulated 10 times on 10 consecutive days but with different tetanization strengths. Sprouting of the mossy fibres terminating in the CA3 region was significantly induced only in the group of 'strongly' tetanized animals, but not in that of 'weakly' tetanized animals, or in low-frequency stimulated animals. Additionally, a novel form of potentiation which was previously found in pentylenetetrazol (PTZ)-kindled animals was also observed in the group of 'strongly' and 'weakly' tetanized rats. Differences in duration of this potentiation were found between the two groups of animals tetanized with different strengths. The results further demonstrate that morphological and functional changes in the hippocampus, similar to those seen after kindling, can also occur in an activation paradigm leading to long-lasting synaptic plasticity but not accompanied by seizure activity.

  11. Comparative in vitro performance of the new drug aclidinium in a novel multidose dry powder inhaler

    NARCIS (Netherlands)

    Gjaltema, Doetie; Hagedoorn, Paul; Grasmeijer, Floris; Huijbers, Bernardus G.; Frijlink, Henderik W.; De Boer, Anne H.


    Background: With new inhalation products, lack of knowledge of how much drug is deposited at the site of action in the lungs plus variation in performance of inhalation devices can lead to inaccurate conclusions about drug efficacy. Aim: To compare the consistency of delivered dose (DD) and fine

  12. Comparative in vitro performance of the new drug aclidinium in a novel multidose dry powder inhaler

    NARCIS (Netherlands)

    Gjaltema, Doetie; Hagedoorn, Paul; Grasmeijer, Floris; Huijbers, Bernardus G.; Frijlink, Henderik W.; De Boer, Anne H.


    Background: With new inhalation products, lack of knowledge of how much drug is deposited at the site of action in the lungs plus variation in performance of inhalation devices can lead to inaccurate conclusions about drug efficacy. Aim: To compare the consistency of delivered dose (DD) and fine par

  13. An investigation into the predictive value of cascade impactor results for side effects of inhaled salbutamol

    NARCIS (Netherlands)

    Weda, M; Zanen, P; de Boer, A H; Barends, D M; Frijlink, H W


    The aim of this study was to compare the Multistage Liquid Impinger (MSLI) and the Andersen Cascade Impactor (ACI) with respect to their power to predict differences in side effects of salbutamol delivered by a dry powder inhaler. Three preparations with the same nominal dose and the same inhaler de

  14. Retail sales of inhalation devices in European countries: so much for a global policy.

    NARCIS (Netherlands)

    Lavorini, F.; Corrigan, C.J.; Barnes, P.J.; Dekhuijzen, P.N.R.; Levy, M.L.; Pedersen, S.; Roche, N.; Vincken, W.; Crompton, G.K.


    OBJECTIVE: To evaluate the retail sales of pressurised metered-dose inhalers (pMDIs), dry-powder inhalers (DPIs) and liquids for nebulisation in 16 European countries. METHODS: Retail sales data relating to pMDIs, DPIs and liquids for nebulisation delivering short- and long-acting bronchodilators, c

  15. Evaluation of sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride. Results of a prospective, randomized, double-blind, placebo-controlled trial. (United States)

    Dulin, J; Kovács, L; Ramm, S; Horvath, F; Ebeling, L; Kohnen, R


    Sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride (Mydocalm), a centrally active muscle-relaxing agent, were evaluated in a placebo-controlled double-blind clinical trial. A total of 72 healthy young adults balanced by sex were randomized to receive 50 mg or 150 mg tolperisone hydrochloride or placebo t.i.d. for a period of 8 days. Control examinations were performed in the mornings of days 1 and 8 before intake of the morning dose and at 1.5, 4 and 6 hours postdose. The psychomotoric test battery used in this trial revealed no sedative effects of tolperisone hydrochloride in the given doses at any control examination. Subjective mood ratings quantified by the Welzel Colored Scales were not impaired either. The lack of differences in sedative potentials of tolperisone hydrochloride and placebo was confirmed by tests on differences and by tests on equivalence using 95% CI. The present study substantiates clinical experience and previous clinical trials demonstrating that tolperisone hydrochloride, though being a centrally active muscle relaxant, does not cause any sedation and does not impair reaction times.

  16. Neonatal Repeated Exposure to Isoflurane not Sevoflurane in Mice Reversibly Impaired Spatial Cognition at Juvenile-Age. (United States)

    Liu, Jianhui; Zhao, Yanhong; Yang, Junjun; Zhang, Xiaoqing; Zhang, Wei; Wang, Peijun


    Inhalation anesthetics facilitate surgical procedures in millions of children each year. However, animal studies demonstrate that exposure to the inhalation anesthetic isoflurane may cause neuronal cell death in developing brains. The long-term cytotoxic effects of sevoflurane, the most popular pediatric anesthetic, have not been compared with isoflurane. Thus, this study was designed to compare the effects of equipotent doses of these two anesthetics on neonatal long-term neurotoxicity. Postnatal 7-day-old (P7) C57/BL male mice were exposed to 1.5% isoflurane or 2.2% sevoflurane 2 h a day for 3 days. Non-anesthetized mice served as controls. The effects of anesthesia on learning and memory were assessed using the Morris Water Maze (MWM) at Postnatal days 30 (P30) and P60 respectively. The hippocampal content of N-methyl-D-aspartate receptor subunits (NMDA), brain-derived neurotrophic factor (BDNF), and synaptophysin (Syn) were determined by Western Blot. Neuron structure and apoptosis were assessed via Nissl and TUNEL staining, respectively. The isoflurane group exhibited cognitive impairment at P30. Repeated inhalation of isoflurane or sevoflurane caused different degrees of apoptosis and damaged hippocampal neurons in neonatal mice, particularly isoflurane. In neonatal mice, repeated exposure to isoflurane, but not sevoflurane, caused spatial cognitive impairments in juvenile mice. Our findings suggest that isoflurane induces significantly greater neurodegeneration than an equipotent minimum alveolar concentration of sevoflurane.

  17. Dry powder inhalable formulations for anti-tubercular therapy. (United States)

    Parumasivam, Thaigarajan; Chang, Rachel Yoon Kyung; Abdelghany, Sharif; Ye, Tian Tian; Britton, Warwick John; Chan, Hak-Kim


    Tuberculosis (TB) is an intracellular infectious disease caused by the airborne bacterium, Mycobacterium tuberculosis. Despite considerable research efforts, the treatment of TB continues to be a great challenge in part due to the requirement of prolonged therapy with multiple high-dose drugs and associated side effects. The delivery of pharmacological agents directly to the respiratory system, following the natural route of infection, represents a logical therapeutic approach for treatment or vaccination against TB. Pulmonary delivery is non-invasive, avoids first-pass metabolism in the liver and enables targeting of therapeutic agents to the infection site. Inhaled delivery also potentially reduces the dose requirement and the accompanying side effects. Dry powder is a stable formulation of drug that can be stored without refrigeration compared to liquids and suspensions. The dry powder inhalers are easy to use and suitable for high-dose formulations. This review focuses on the current innovations of inhalable dry powder formulations of drug and vaccine delivery for TB, including the powder production method, preclinical and clinical evaluations of inhaled dry powder over the last decade. Finally, the risks associated with pulmonary therapy are addressed. A novel dry powder formulation with high percentages of respirable particles coupled with a cost effective inhaler device is an appealing platform for TB drug delivery.

  18. A Preference Study of Two Placebo Dry Powder Inhalers in Adults with COPD: ELLIPTA® Dry Powder Inhaler (DPI) versus DISKUS® DPI. (United States)

    Yun Kirby, Suyong; Zhu, Chang-Qing; Kerwin, Edward M; Stanford, Richard H; Georges, George


    Patients' preference is an important factor in selecting an inhaler treatment for COPD. The DISKUS® dry powder inhaler (DPI), which has been available to deliver several COPD medications for a decade, and the ELLIPTA® DPI, developed for the delivery of newer once-daily medications for patients with COPD, were studied in terms of patient preference and inhaler-specific attributes. We conducted a randomized, open-label, crossover study in patients with COPD. Patients used placebo ELLIPTA DPI once daily and placebo DISKUS DPI twice daily, for ∼1 week each, while continuing their COPD medications. Endpoints were: inhaler preference based on size of the numbers on the dose-counter (primary); the number of steps needed and inhaler size (secondary); and based on comfort of the mouthpiece, ease of opening, overall preference, and dosing regimen preference ('other'). Safety assessments included adverse events (AEs). A total of 287 patients were randomized. A significantly (p ELLIPTA DPI over DISKUS DPI for each of the tested attributes and overall, and preferred once-daily over twice-daily dosing. AEs were reported for 36 patients (13%); one (dry mouth) was considered to be related to the placebo-containing DISKUS DPI. Three patients had five non-fatal serious AEs, none were deemed inhaler-related. This study demonstrated that more patients with COPD preferred five specific inhaler attributes of the ELLIPTA DPI over DISKUS DPI and overall, and preferred once-daily versus twice-daily dosing. Safety profiles were consistent with those expected for COPD.

  19. Relative bioavailability of sodium cromoglycate to the lung following inhalation, using urinary excretion (United States)

    Aswania, O A; Corlett, S A; Chrystyn, H


    Aims To determine if a urinary excretion method, previously described for salbutamol, could also indicate the relative bioavailability of sodium cromoglycate to the lung following inhalation from a metered dose inhaler. Method Inhaled (INH), inhaled+oral charcoal (INHC), oral (ORAL) and oral+oral charcoal (ORALC) 20 mg doses of sodium cromoglycate were given via a randomised cross-over design to 11 healthy volunteers trained on how to use a metered dose inhaler. Urine samples were collected at 0.0, 0.5, 1.0 and up to 24 h post dosing and the sodium cromoglycate urinary concentration was measured using a high performance liquid chromatographic method. Results No sodium cromoglycate was detected in the urine up to 24 h following ORALC dosing. A mean (s.d.) of 3.6 (4.3) μg, 10.4 (10.9) μg and 83.7 (71.1) μg of the ORAL dose was excreted, in the urine, during the 0.5, 1.0 and 24 h post dose collection periods, respectively. Following INH dosing, the renal excretion was significantly higher (P < 0.01) with 32.9 (14.5) μg, 61.2 (28.3) μg and 305.6 (82.3) μg excreted, respectively. The SCG excreted at 0.5, 1.0 and 24 h collection periods following INHC dosing were 26.3 (8.4) μg, 49.3 (18.1) μg and 184.9 (98.4) μg, respectively. There was no significant difference between the excretion rate of sodium cromoglycate following INHC when compared with INH dosing in the first 0.5 and 1.0 h. Conclusions The urinary excretion of sodium cromoglycate in the first 0.5 h post inhalation can be used to compare the relative lung deposition of two inhaled products or of the same product using different inhalation techniques. This represents the relative bioavailability of sodium cromoglycate to the lung following inhalation. Similar 24 h urinary excretion of sodium cromoglycate can be use to compare the total dose delivered to the body from two different inhalation products/inhalation methods. This represents the relative bioavailability of sodium cromoglycate to the body

  20. Lung deposition of inhaled drugs increases with age

    DEFF Research Database (Denmark)

    Onhøj, J; Thorsson, L; Bisgaard, H


    versus time (AUC). Terminal half-life (T(1/2)) was evaluated. Dose to patient, AUC, and T(1/2) were similar in the three age groups (p > 0.35). Nebuchamber delivers the same dose of budesonide to young children and adults. Yet the plasma concentration of budesonide was similar in young children...... and adults. Therefore, lung dose is increased with age. This suggests that from a safety perspective, the prescribed dose of budesonide inhaled from a pMDI with Nebuchamber spacer need not be adjusted for age or use of facemask. Children and adults can use the same nominal dose of budesonide via Nebuchamber...

  1. Inhaled insulin--does it become reality? (United States)

    Siekmeier, R; Scheuch, G


    , shortness of breath, sore throat and dry mouth. Physical exercise increases the transport of inhaled insulin into the circulation and in consequence the likelihood of hypoglycemia. Other problems were the inability to deliver precise insulin doses, because the smallest blister pack available contained the equivalent of 3 U of regular insulin and this dose would make it difficult for many people using insulin to achieve accurate control, which is the real goal of any insulin therapy. For example, someone on 60 U of insulin per day would lower the blood glucose about 90 mg/dl (5 mmol) per 3 U pack, while someone on 30 U a day would drop 180 mg/dl (10 mmol) per pack. Precise control was not possible, especially compared with an insulin pump that can deliver one twentieth of a unit with precision. Another disadvantage was the size of the device. The Exubera inhaler, when closed, was about the size of a 200 ml water glass. It opened to about twice the size for delivery. To our information also other companies (Eli Lilly in cooperation with ALKERMES, Novo Nordisk (AERx, Liquid), Andaris (Powder)) stopped further development and it is unclear whether an inhaled form of insulin will ever be marketed, because of the problems that have occurred. Only Mannkind (Technosphere, Powder) is still working on a Phase III trial. However, our review will briefly summarize the experience regarding inhalant administration of insulin and will describe potential future developments for this type of therapy focussing on the lung.

  2. Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study (United States)

    Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu


    The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3+, CD4+, CD8+, and CD19+) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs. PMID:28280324

  3. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study. (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth


    Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed.

  4. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth


    Background/objective Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed. PMID:28356767

  5. Inhaled formulations and pulmonary drug delivery systems for respiratory infections. (United States)

    Zhou, Qi Tony; Leung, Sharon Shui Yee; Tang, Patricia; Parumasivam, Thaigarajan; Loh, Zhi Hui; Chan, Hak-Kim


    Respiratory infections represent a major global health problem. They are often treated by parenteral administrations of antimicrobials. Unfortunately, systemic therapies of high-dose antimicrobials can lead to severe adverse effects and this calls for a need to develop inhaled formulations that enable targeted drug delivery to the airways with minimal systemic drug exposure. Recent technological advances facilitate the development of inhaled anti-microbial therapies. The newer mesh nebulisers have achieved minimal drug residue, higher aerosolisation efficiencies and rapid administration compared to traditional jet nebulisers. Novel particle engineering and intelligent device design also make dry powder inhalers appealing for the delivery of high-dose antibiotics. In view of the fact that no new antibiotic entities against multi-drug resistant bacteria have come close to commercialisation, advanced formulation strategies are in high demand for combating respiratory 'super bugs'.

  6. Antidepressant-like effect of tetrahydroisoquinoline amines in the animal model of depressive disorder induced by repeated administration of a low dose of reserpine: behavioral and neurochemical studies in the rat. (United States)

    Antkiewicz-Michaluk, Lucyna; Wąsik, Agnieszka; Możdżeń, Edyta; Romańska, Irena; Michaluk, Jerzy


    Animal models are widely used to study antidepressant-like effect in rodents. However, it should be mentioned that pharmacological models do not always take into account the complexity of the disease process. In the present paper, we demonstrated that repeated but not acute treatment with a low dose of reserpine (0.2 mg/kg i.p.) led to a pharmacological model of depression which was based on its inhibitory effect on the vesicular monoamine transporter 2, and monoamines depleting action in the brain. In fact, we observed that chronic treatment with a low dose of reserpine induced a distinct depressive-like behavior in the forced swim test (FST), and additionally, it produced a significant decrease in the level of dopamine, noradrenaline, and serotonin in the brain structures. 1,2,3,4-Tetrahydroisoquinoline (TIQ) and its close methyl derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) are exo/endogenous amines present naturally in the mammalian brain which demonstrated a significant antidepressant-like effect in the FST and the reserpine model of depression in the rat. Both compounds, TIQ and 1MeTIQ, administered chronically in a dose of 25 mg/kg (i.p.) together with reserpine completely antagonized reserpine-produced depression as assessed by the immobility time and swimming time. Biochemical data were in agreement with behavioral experiments and demonstrated that chronic treatment with a low dose of reserpine in contrast to acute administration produced a significant depression of monoamines in the brain structures and impaired their metabolism. These neurochemical effects obtained after repeated reserpine (0.2 mg/kg i.p.) in the brain structures were completely antagonized by joint TIQ or 1MeTIQ (25 mg/kg i.p.) administration with chronic reserpine. A possible molecular mechanism of action of TIQ and 1MeTIQ responsible for their antidepressant action is discussed. On the basis of the presented behavioral and biochemical studies, we suggest that both

  7. Repeated low-dose 17β-estradiol treatment prevents activation of apoptotic signaling both in the synaptosomal and cellular fraction in rat prefrontal cortex following cerebral ischemia. (United States)

    Stanojlović, Miloš; Zlatković, Jelena; Guševac, Ivana; Grković, Ivana; Mitrović, Nataša; Zarić, Marina; Horvat, Anica; Drakulić, Dunja


    Disturbance in blood circulation is associated with numerous pathological conditions characterized by cognitive decline and neurodegeneration. Activation of pro-apoptotic signaling previously detected in the synaptosomal fraction may underlie neurodegeneration in the prefrontal cortex of rats submitted to permanent bilateral common carotid arteries occlusion (two-vessel occlusion, 2VO). 17β-Estradiol (E) exerts potent neuroprotective effects in the brain affecting, among other, ischemia-induced pathological changes. As most significant changes in rats submitted to 2VO were observed on 7th day following the insult, of interest was to examine whether 7 day treatment with low dose of E (33.3 µg/kg/day) prevents formerly reported neurodegeneration and may represent additional therapy during the early post-ischemic period. Role of E treatment on apoptotic pathway was monitored on Bcl-2 family members, cytochrome c, caspase 3 and PARP protein level in the synaptosomal (P2) fraction of the prefrontal cortex. Furthermore, changes of these proteins were examined in the cytosolic, mitochondrial and nuclear fraction, with the emphasis on potential involvement of extracellular signal-regulated kinases (ERK) and protein kinase B (Akt) activation and their role in nuclear translocation of transcriptional nuclear factor kappa B (NF-kB) associated with alteration of Bax and Bcl-2 gene expression. The extent of cellular damage was determined using DNA fragmentation and Fluoro-Jade B staining. The absence of activation of apoptotic cascade both in the P2 and cell accompanied with decreased DNA fragmentation and number of degenerating neurons clearly indicates that E treatment ensures the efficient protection against ischemic insult. Moreover, E-mediated modulation of pro-apoptotic signaling in the cortical cellular fractions involves cooperative activation of ERK and Akt, which may be implicated in the observed prevention of neurodegenerative changes.

  8. Inhalational and dermal exposures during spray application of biocides. (United States)

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


    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

  9. Factors related to the incorrect use of inhalers by asthma patients

    Directory of Open Access Journals (Sweden)

    Paulo de Tarso Roth Dalcin


    Full Text Available OBJECTIVE: To evaluate inhaler technique in outpatients with asthma and to determine associations between the correctness of that technique and the level of asthma control. METHODS: This was a cross-sectional study involving patients > 14 years of age with physician-diagnosed asthma. The patients were recruited from the Asthma Outpatient Clinic of the Hospital de Clínicas de Porto Alegre, in the city of Porto Alegre, Brazil. The patients completed two questionnaires (a general questionnaire and an asthma control questionnaire based on the 2011 Global Initiative for Asthma guidelines, demonstrated their inhaler technique, and performed pulmonary function tests. Incorrect inhaler technique was defined as the incorrect execution of at least two of the predefined steps. RESULTS: We included 268 patients. Of those, 81 (30.2% showed incorrect inhaler technique, which was associated with poor asthma control (p = 0.002. Logistic regression analysis identified the following factors associated with incorrect inhaler technique: being widowed (OR = 5.01; 95% CI, 1.74-14.41; p = 0.003; using metered dose inhalers (OR = 1.58; 95% CI, 1.35-1.85; p 2 comorbidities (OR = 3.80; 95% CI, 1.03-14.02; p = 0.045. CONCLUSIONS: In the sample studied, incorrect inhaler technique was associated with poor asthma control. Widowhood, use of metered dose inhalers, low socioeconomic level, and the presence of > 2 comorbidities were associated with incorrect inhaler technique.

  10. Spray Inhalation of Different Doses of Budesonide Suspensions in Adjunctive Treatment of Bronchiolitis%不同剂量布地奈德混悬液雾化吸入辅助治疗毛细支气管炎临床研究∗

    Institute of Scientific and Technical Information of China (English)

    何亚薇; 冯斌; 吴玫; 李玉


    Objective:To compare the safety and clinical efficacy of spray inhalations of different doses of budesonide suspensions in adjunctive treatment of bronchiolitis. Method:90 eligible patients were select-ed and randomly divided into group A, B, and C, with 30 patients in each group. The group A received spray inhalation of budesonide suspension, 1. 0mg 3 times daily; the group B received spray inhalation of budesonide suspension, 0.5mg 3 times daily; and the group C received spray inhalation of budesonide sus-pension, 1.0mg 3 times daily initially, and after symptomatic relief, 0.5mg twice daily;each course of treat-ment was 7 days. And the changes in the clinical symptoms and physical signs in the patients of the three groups were observed and recorded. Result:The differences in times for disappearances of fever, dyspnea, short breath, cough, wheezing sound, and moist rales in the patients between the group A and the group C were all statistically insignificant ( P>0.05) , but the times for disappearances of the symptoms and physical signs in the patients of the group A and the group C were both less than those in the patients of the group B, and the differences were statistically significant ( P0.05) , but the patients of both groups had higher clinical total response rates than the patients of the group B, and the differences were statistically significant (P0.05),但是A组及C组患儿症状及体征消失时间均快于B组,差异有统计学意义( P0.05),但是均高于B组,差异有统计学意义(P<0.05)。 A组患儿1例出现嗜睡、1例出现声音嘶哑,B组和C组患儿均未发生不良反应。结论:毛细支气管炎急性期采用大剂量布地奈德混悬液雾化吸入能快速缓解患者的临床症状及体征,病情缓解后减少剂量,不影响临床治疗效果,可降低不良反应,提高用药安全性。

  11. Evaluation of the repeated-dose liver micronucleus assay using N-nitrosomorpholine in young adult rats: report on collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study (MMS) Group. (United States)

    Hayashi, Aya; Kosaka, Mizuki; Kimura, Aoi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi


    The present study was conducted to evaluate the suitability of a repeated-dose liver micronucleus (LMN) assay in young adult rats as a collaborative study by the Mammalian mutagenicity study (MMS) group. All procedures were performed in accordance with the standard protocols of the MMS Group. Six-week-old male Crl:CD(SD) rats (5 animals/group) received oral doses of the hepatocarcinogen N-nitrosomorpholine (NMOR) at 0 (control), 5, 10, and 30mg/kg/day (10mL/kg) for 14 days. Control animals received vehicle (water). Hepatocytes were collected from the liver 24h after the last dose, and the number of micronucleated hepatocytes (MNHEPs) was determined by microscopy. The number of micronucleated immature erythrocytes (MNIMEs) in the femoral bone marrow was also determined. The liver was examined using histopathologic methods after formalin fixation. The results showed statistically significant and dose-dependent increases in the number of MNHEPs in the liver at doses of 10mg/kg and greater when compared with the vehicle control. However, no significant increase was noted in the number of MNIMEs in the bone marrow at doses of up to 30mg/kg. Histopathology of the liver revealed hypertrophy and single cell necrosis of hepatocytes at doses of 5mg/kg and above. These results showed that the induction of micronuclei by NMOR was detected by the repeated-dose LMN assay, but not by the repeated-dose bone marrow micronucleus assay.

  12. Statistical tools for analysing the data obtained from repeated dose toxicity studies with rodents: a comparison of the statistical tools used in Japan with that of used in other countries. (United States)

    Kobayashi, Katsumi; Pillai, K Sadasivan; Guhatakurta, Soma; Cherian, K M; Ohnishi, Mariko


    In the present study, an attempt was made to compare the statistical tools used for analysing the data of repeated dose toxicity studies with rodents conducted in 45 countries, with that of Japan. The study revealed that there was no congruence among the countries in the use of statistical tools for analysing the data obtained from the above studies. For example, to analyse the data obtained from repeated dose toxicity studies with rodents, Scheffé's multiple range and Dunnett type (joint type Dunnett) tests are commonly used in Japan, but in other countries use of these statistical tools is not so common. However, statistical techniques used for testing the above data for homogeneity of variance and inter-group comparisons do not differ much between Japan and other countries. In Japan, the data are generally not tested for normality and the same is true with the most of the countries investigated. In the present investigation, out of 127 studies examined, data of only 6 studies were analysed for both homogeneity of variance and normal distribution. For examining homogeneity of variance, we propose Levene's test, since the commonly used Bartlett's test may show heterogeneity in variance in all the groups, if a slight heterogeneity in variance is seen any one of the groups. We suggest the data may be examined for both homogeneity of variance and normal distribution. For the data of the groups that do not show heterogeneity of variance, to find the significant difference among the groups, we recommend Dunnett's test, and for those show heterogeneity of variance, we recommend Steel's test.

  13. Are children with asthma overconfident that they are using their inhalers correctly? (United States)

    Alexander, Dayna S; Geryk, Lorie; Arrindell, Courtney; DeWalt, Darren A; Weaver, Mark A; Sleath, Betsy; Carpenter, Delesha M


    The objectives of this study were to quantify the extent to which children with asthma are overconfident that they are using their inhalers correctly and determine whether demographic and clinical characteristics are associated with children being overconfident. Children (n = 91) ages 7-17 with persistent asthma were recruited at two pediatric practices in North Carolina and demonstrated their inhaler technique for metered dose inhalers during an office visit. Children were dichotomized into two groups based on how confident they were that they were using their inhalers correctly: "completely confident" or "not completely confident". The mean number of inhaler steps (out of 8) children performed incorrectly was examined. We applied linear regression models for children in the "completely confident" group to determine whether demographic and clinical factors predicted their overconfidence, defined as the number of inhaler steps performed incorrectly. Children were primarily male (56%) and non-Hispanic White (60%). Sixty-eight (75%) children were "completely confident" that they were using their inhalers correctly. The "completely confident" group missed an average of 1.5 steps. In the "completely confident" group, males (p children in our sample missed an average of 1-2 steps on an inhaler technique assessment. Findings from this study provide new evidence that it is insufficient to ask children if they are using their inhalers correctly. Therefore, it is vital that providers ask children to demonstrate their inhaler technique during health encounters.

  14. Deployment Repeatability (United States)


    controlled to great precision, but in a Cubesat , there may be no attitude determination at all. Such a Cubesat might treat sun angle and tumbling rates as...could be sensitive to small differences in motor controller timing. In these cases, the analyst might choose to model the entire deployment path, with...knowledge of the material damage model or motor controller timing precision. On the other hand, if many repeated and environmentally representative

  15. Inhalers and nebulizers: which to choose and why. (United States)

    Pedersen, S


    It is obvious that many factors should be considered when an inhaler is prescribed. Based upon the information discussed above, a rational inhaler strategy could be as follows: (1) Children valve system (and a face mask for the children) for the delivery of all drugs. When they are severely obstructed, some may need a nebulizer. If the patient cannot be taught the correct use of a spacer, a nebulizer should be prescribed. (2) Children > or = 5 years and adults are prescribed a spacer or a Turbuhaler for the administration of inhaled corticosteroids and a dry powder inhaler (preferably multiple dose) or a breath-actuated MDI for other drugs. If these alternatives are not available or the patient prefers, a conventional MDI can be used (preferably not for other corticosteroids than fluticasone propionate) provided that careful tuition is given. Fluticasone dipropionate may be given by DPI, Spacer or MDI. (3) Nebulizers are mainly reserved for severe acute attacks of bronchoconstriction. With this approach, most patients can be taught effective inhaler use with a minimum of instructional time. Finally, it must always be remembered to consider the patient's wish, since prescription of an inhaler which the physician likes but the patient does not is likely to reduce compliance.

  16. 氟利昂替代后吸入气雾剂(MDIs)的研究要求和进展Ⅱ抛射剂替代的MDIs的技术挑战和工业化生产%Transition of Propellants in Metered Dose Inhalers (MDIs) Ⅱ.Technical Challenge and Industrial Manufacture of Alternative Propellant MDIs

    Institute of Scientific and Technical Information of China (English)

    侯曙光; 魏农农; 金方


    吸入气雾剂(MDIs)中抛射剂氟利昂(CFC)的替代并非制剂中简单的辅料替换.综述了氢氟烷烃(HFA)替代CFC过程中所涉及的处方组成改变、工艺参数优化、给药装置的选择、制药设备的更新以及产业化过程中的特殊要求.%The propellant transition in metered dose inhalers (MDIs) is not a simple replacement of CFC by HFA in the formulations. This paper reviews the technical challenges for the development of alternative propellant MDIsincluding changes of formulation composition, optimization of product process, selection of container closure system,improvement of manufacture equipment, and requirements for industrial manufacture.

  17. Terbutaline accumulates in blood and urine following daily therapeutic inhalation

    DEFF Research Database (Denmark)

    Krogh, Nanna; Rzeppa, Sebastian; Dyreborg, Anders


    PURPOSE: This study investigated pharmacokinetics of terbutaline after single and seven consecutive days of inhalation in exercising trained men. METHODS: Twelve healthy young trained men underwent two pharmacokinetic trials comparing single dose (2 mg) and seven consecutive days (2 mg×d) of inha...

  18. Integrating murine gene expression studies to understand obstructive lung disease due to chronic inhaled endotoxin.

    Directory of Open Access Journals (Sweden)

    Peggy S Lai

    Full Text Available RATIONALE: Endotoxin is a near ubiquitous environmental exposure that that has been associated with both asthma and chronic obstructive pulmonary disease (COPD. These obstructive lung diseases have a complex pathophysiology, making them difficult to study comprehensively in the context of endotoxin. Genome-wide gene expression studies have been used to identify a molecular snapshot of the response to environmental exposures. Identification of differentially expressed genes shared across all published murine models of chronic inhaled endotoxin will provide insight into the biology underlying endotoxin-associated lung disease. METHODS: We identified three published murine models with gene expression profiling after repeated low-dose inhaled endotoxin. All array data from these experiments were re-analyzed, annotated consistently, and tested for shared genes found to be differentially expressed. Additional functional comparison was conducted by testing for significant enrichment of differentially expressed genes in known pathways. The importance of this gene signature in smoking-related lung disease was assessed using hierarchical clustering in an independent experiment where mice were exposed to endotoxin, smoke, and endotoxin plus smoke. RESULTS: A 101-gene signature was detected in three murine models, more than expected by chance. The three model systems exhibit additional similarity beyond shared genes when compared at the pathway level, with increasing enrichment of inflammatory pathways associated with longer duration of endotoxin exposure. Genes and pathways important in both asthma and COPD were shared across all endotoxin models. Mice exposed to endotoxin, smoke, and smoke plus endotoxin were accurately classified with the endotoxin gene signature. CONCLUSIONS: Despite the differences in laboratory, duration of exposure, and strain of mouse used in three experimental models of chronic inhaled endotoxin, surprising similarities in gene

  19. Opportunities for inhaler device selection in elderly patients with asthma or COPD

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    Barrons R


    Full Text Available Robert Barrons,1 James Wheeler,2 J Andrew Woods1 1Wingate University School of Pharmacy, Wingate, NC, USA; 2University of Tennessee Health Science Center, Nashville, TN, USA Abstract: An anticipated surge in the elderly population will be accompanied by a rise in aging patients with asthma or COPD. Clinician selection of inhalers needs to address the unique challenges to elderly patients. These challenges to the use of inhalers include diminished physical and cognitive abilities, as well as cost reimbursement issues associated with polypharmacy and the Medicare gap. Clinicians should consider patient preferences for an inhaler device that provides ease of administration, and addresses conveniences such as portability, visual, and auditory indicators of dosing completion. The addition of spacer devices resolves hand-breath coordination difficulty with pressurized metered dose inhalers, but reduces overall inhaler convenience. Soft mist inhalers (Respimat® improve ease of administration, but use may be limited by cost and formulary availability. Multiple dose dry powder inhalers provide convenience and simplified use by requiring only one to two steps prior to administration, but concerns of peak inspiratory flow requirements remain among patients with advanced age and severity of COPD. If unaddressed, these challenges to inhaler selection contribute to inappropriate use of inhalers in 41% to 69% of patients, accompanied by at least 51% non-adherence to treatment. Clinicians must first avail themselves of reputable educational resources regarding new inhaler developments and administration, for competent patient instruction. Patient education should include a checklist of inhaler technique, with physical demonstration of each device by the patient and provider. Device demonstration significantly improves inhaler technique and identifies the need for nebulization therapy. Clinician and patient knowledge of available inhalers and their

  20. Local and systemic tolerability of a 2'O-methoxyethyl antisense oligonucleotide targeting interleukin-4 receptor-α delivery by inhalation in mouse and monkey. (United States)

    Fey, Robert A; Templin, Michael V; McDonald, Jacob D; Yu, Rosie Z; Hutt, Julie A; Gigliotti, Andrew P; Henry, Scott P; Reed, Matthew D


    Antisense oligonucleotides (ASOs) bind and facilitate degradation of RNA and inhibit protein expression in pathways not easily targeted with small molecules or antibodies. Interleukin (IL)-4 and IL-13 potentiate signaling through the shared IL-4 receptor-α (IL-4Rα) subunit of their receptors. ASO targeting of IL-4Rα mRNA in a mouse model of asthma led to attenuation of airway hyperactivity, demonstrating potential benefit in asthma patients. This study focused on tolerability of inhaled IL-4Rα-targeting ASOs. Toxicity studies were performed with mouse- (ISIS 23189) and human-specific (ISIS 369645) sequences administered by inhalation. Four week (monkey) or 13 week (mouse) repeat doses at levels of up to 15 mg/kg/exposure (exp) and 50 mg/kg/exp, respectively, demonstrated dose-dependent effects limited to increases in macrophage size and number in lung and tracheobronchial lymph nodes. The changes were largely non-specific, reflecting adaptive responses that occur during active exposure and deposition of ASO and other material in the lung. Reversibility was observed at a rate consistent with the kinetics of tissue clearance of ASO. Systemic bioavailability was minimal, and no systemic toxicity was observed at exposure levels appreciably above pharmacological doses and doses proposed for clinical trials.

  1. Novolizer: how does it fit into inhalation therapy? (United States)

    Magnussen, Helgo


    Inhalation therapy is the preferred route of administration of anti-asthmatic drugs to the lungs. However, the vast majority of patients cannot use their inhalers correctly, particularly pressurised metered dose inhalers (pMDIs). The actual proportion of patients who do not use their inhalers correctly may even be under-estimated as GPs tend to over-estimate correct inhalation technique. Dry powder inhalers (DPIs) have many advantages over pMDIs. Unlike pMDIs, they are environmentally-friendly, contain no propellant gases and, more importantly, they are breath-activated, so that the patient does not need to coordinate actuation of the inhaler with inspiration. Three key parameters for correct inhaler use should be considered when evaluating existing or future DPI devices and especially when choosing the appropriate device for the patient: (1) usability, (2) particle size distribution of the emitted drug and (3) intrinsic airflow resistance of the device. The Novolizer is a breath-activated, multidose, refillable DPI. It is easy to use correctly, has multiple feedback and control mechanisms which guide the patient through the correct inhalation manoeuvre. In addition, the Novolizer has an intelligent dose counter, which resets only after a correct inhalation and may help to monitor patient compliance. The Novolizer has a comparable or better lung deposition than the Turbuhaler at similar or higher peak inspiratory flow (PIF) rates. A flow trigger valve system ensures a clinically effective fine particle fraction (FPF) and sufficient drug delivery, which is important for a good lung deposition. The FPF produced through the Novolizer is also relatively independent of flow rate and the device shows better reproducibility of metering and delivery performance compared to the Turbuhaler. The low-to-medium airflow resistance means that the Novolizer is easy for patients to use correctly. Even children, patients with severe asthma and patients with moderate

  2. Avaliação do conhecimento sobre o uso de inaladores dosimetrados entre profissionais de saúde de um hospital pediátrico Evaluation of the knowledge of health professionals at a pediatric hospital regarding the use of metered-dose inhalers

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    Fábio Pereira Muchão


    Full Text Available OBJETIVO: Avaliar os conhecimentos sobre o uso e manejo de inaladores pressurizados dosimetrados entre profissionais de um hospital pediátrico terciário. MÉTODOS: Foram realizadas avaliações sobre o conhecimento do uso de inaladores pressurizados dosimetrados através de questionários teóricos e práticos, com médicos, fisioterapeutas, enfermeiras e auxiliares de enfermagem, atribuindo-se uma nota de 0 a 10 para cada avaliação. Calcularam-se as medianas das notas obtidas pelos profissionais de cada categoria, as questões com maiores e menores índices de erros, e foi feita a comparação descritiva do desempenho das diversas categorias profissionais. A análise estatística foi feita através do método de Kruskal-Wallis de comparação de medianas. Também foi realizada a análise através de regressão logística múltipla seqüencial. RESULTADOS: Foram avaliados 30 médicos residentes ou estagiários de pediatria, 23 médicos assistentes, 29 fisioterapeutas, 33 enfermeiras e 31 auxiliares de enfermagem. Os médicos residentes, fisioterapeutas e médicos assistentes obtiveram desempenho significativamente superior aos dos enfermeiros e auxiliares de enfermagem. Apenas os médicos residentes obtiveram mediana superior a 6. CONCLUSÕES: O conhecimento a respeito do uso de inaladores dosimetrados entre os profissionais de saúde da instituição é insatisfatório, principalmente entre enfermeiros e auxiliares de enfermagem, diretamente envolvidos na aplicação prática dos inaladores dosimetrados.OBJECTIVE: To evaluate health professionals working at a tertiary pediatric hospital in terms of their knowledge regarding the practical use of metered-dose inhalers. METHODS: Practical and written tests on the use of metered-dose inhalers were applied to physicians, physical therapists, nurses and nursing assistants. A score from 0 to 10 was assigned to each evaluation, and median scores were calculated for each professional category

  3. Formulation and evaluation of CFC free inhalers for beclomethasone dipropionate

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    Gopala Krishna Murthy Talasila


    Full Text Available Beclomethasone dipropionate CFC free inhalation formulations were developed with a view to treat asthma prophylactically. Dry powder inhalers (DPI for beclomethasone dipropionate were prepared with different grades of lactose monohydrate. The influence of carrier and overages on performance of DPI was studied. Metered dose inhalers (MDI with HFA based propellants were formulated with various doses, overages and different concentrations of alcohol. Formulated DPI and MDI were evaluated for various official and unofficial quality control tests. The influence of over doses on valve delivery, effect of overages on emitted dose and influence of alcohol on spray pattern from MDI were studied. The better fine particle fraction and emitted dose were obtained from the DPI formulated with 10:90 ratio of fine lactose: coarse lactose and with 20% w/w overages. The studies on MDI revealed that the 15% of overdoses are required for effective valve delivery and 20% overages are required for 100% drug delivery. 5-10%v/v alcohol was found to be preferable to get optimum emitted dose and fine particle fraction.

  4. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

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    Collaku A


    Full Text Available Agron Collaku, Yong Yue, Kenneth Reed GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Background/objective: Guaifenesin, an over-the-counter (OTC expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods: This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0= not present to 10= unbearable recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results: A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion: Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of

  5. 沙丁胺醇气雾剂在健康受试者体内的药物动力学和相对生物利用度%Pharmacokinetics and relative bioavailability of salbutamol metered-dose inhaler in healthy volunteers

    Institute of Scientific and Technical Information of China (English)

    杜小莉; 朱珠; 傅强; 李大魁; 许文兵


    目的:研究沙丁胺醇气雾剂在健康受试者的药物动力学和生物利用度.方法:十名健康男性志愿者单剂量吸入1.2 mg沙丁胺醇气雾剂或口服沙丁胺醇水溶液.用HPLC法测定人血浆中沙丁胺醇浓度.以非房室模型计算药物动力学参数,计算气雾剂相对水溶液的生物利用度.结果:气雾剂和口服溶液的药物动力学参数如下:Tmax(0.22±0.07)和(1.8±0.6)h,Cmax(3.4±1.1)和(3.9±1.4)μg@L-1,T1/2(4.5±1.5)和(4.6±1.1)h,AUC0-20min(0.9±0.3)和(0.16±0.10)μg@h@L-1.两种给药途径的Tmax和AUC0-20min之间差异显著(P<0.01).AUC0-20min(inhal)为AUC0-20min(po)的8倍.沙丁胺醇气雾剂相对口服溶液的生物利用度为57%±24%.结论:沙丁胺醇气雾剂在人体的吸收过程与口服溶液差异有显著性.%AIM: To study the pharmacokinetics and relative bioavailability of salbutamol metered-dose inhaler (MDI)in healthy volunteers. METHODS: An HPLC method for the determination of salbutamol in human plasma was improved. Ten healthy male Chinese volunteers were enrolled in a randomized crossover study. After the subjects inhaled or orally administered 1.2 mg salbutamol, fourteen blood samples were collected at predetermined time points. The concentrations of salbutamol in plasma were assessed with non-compartment model to obtain the pharmacokinetic parameters. The relative bioavailability of MDI versus water solution was calculated. RESULTS: The HPLC assay was sensitive, specific, accurate, and precise. The pharmacokinetics of salbutamol MDI was described well with twocompartment model. The parameters for salbutamol inhaled and orally administered were as following: Tmax (0.22±0.07) and (1.8±0.6) h, Cmax(3.4± 1.1) and (3.9±1.4) μg@L-1, T1/2(4.5±1.5) and (4.6±1.1)h, AUC0-20min(0.9±0.3) and (0.16±0.10) μg@h@L-1, respectively. There were significant differences in Tmax and AUC0-20 min between the two dosage forms.The AUC0-20min ( inhal ) was 8 times as high as the AUC0

  6. Risk from inhaled mycotoxins in indoor office and residential environments. (United States)

    Kelman, Bruce J; Robbins, Coreen A; Swenson, Lonie J; Hardin, Bryan D


    Mycotoxins are known to produce veterinary and human diseases when consumed with contaminated foods. Mycotoxins have also been proposed to cause adverse human health effects after inhalation exposure to mold in indoor residential, school, and office environments. Epidemiologic evidence has been inadequate to establish a causal relationship between indoor mold and nonallergic, toxigenic health effects. In this article, the authors model a maximum possible dose of mycotoxins that could be inhaled in 24 h of continuous exposure to a high concentration of mold spores containing the maximum reported concentration of aflatoxins B1 and B2, satratoxins G and H, fumitremorgens B and C, verruculogen, and trichoverrols A and B. These calculated doses are compared to effects data for the same mycotoxins. None of the maximum doses modeled were sufficiently high to cause any adverse effect. The model illustrates the inefficiency of delivery of mycotoxins via inhalation of mold spores, and suggests that the lack of association between mold exposure and mycotoxicoses in indoor environments is due to a requirement for extremely high airborne spore levels and extended periods of exposure to elicit a response. This model is further evidence that human mycotoxicoses are implausible following inhalation exposure to mycotoxins in mold-contaminated home, school, or office environments.

  7. Efficacy and Cost Benefit of Inhaled Corticosteroids in Patients Considered to Have Mild Asthma in Primary Care Practice

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    Paul O'Byrne


    Full Text Available OBJECTIVE: Inhaled corticosteroids are infrequently used as asthma therapy in patients considered to have mild asthma in primary care practice. The purpose of this study was to determine whether the use of low doses of inhaled corticosteroids (budesonide, supplemented with bronchodilators as needed, provides clinical benefit and is cost beneficial compared with therapy with bronchodilators alone, in patients considered by their physicians in a primary care setting to have mild asthma, not requiring inhaled corticosteroids.

  8. Exubera. Inhale therapeutic systems. (United States)

    Bindra, Sanjit; Cefalu, William T


    Inhale, in colaboration with Pfizer and Aventis Pharma (formerly Hoechst Marion Roussel; HMR), is developing an insulin formulation utilizing its pulmonary delivery technology for macromolecules for the potential treatment of type I and II diabetes. By July 2001, the phase III program had been completed and the companies had begun to assemble data for MAA and NDA filings; however, it was already clear at this time that additional data might be required for filing. By December 2001, it had been decided that the NDA should include an increased level of controlled, long-term pulmonary safety data in diabetic patients and a major study was planned to be completed in 2002, with the NDA filed thereafter (during 2002). US-05997848 was issued to Inhale Therapeutic Systems in December 1999, and corresponds to WO-09524183, filed in February 1995. Equivalent applications have appeared to date in Australia, Brazil, Canada, China, Czech Republic, Europe, Finland, Hungary, Japan, Norway, New Zealand, Poland and South Africa. This family of applications is specific to pulmonary delivery of insulin. In February 1999, Lehman Brothers gave this inhaled insulin a 60% probability of reaching market, with a possible launch date of 2001. The analysts estimated peak sales at $3 billion in 2011. In May 2000, Aventis predicted that estimated peak sales would be in excess of $1 billion. In February 2000, Merrill Lynch expected product launch in 2002 and predicted that it would be a multibillion-dollar product. Analysts Merril Lynch predicted, in September and November 2000, that the product would be launched by 2002, with sales in that year of e75 million, rising to euro 500 million in 2004. In April 2001, Merrill Lynch predicted that filing for this drug would occur in 2001. Following the report of the potential delay in regulatory filing, issued in July 2001, Deutsche Banc Alex Brown predicted a filing would take place in the fourth quarter of 2002 and launch would take place in the first

  9. Evaluating inhaler use technique in COPD patients

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    Pothirat C


    Full Text Available Chaicharn Pothirat, Warawut Chaiwong, Nittaya Phetsuk, Sangnual Pisalthanapuna, Nonglak Chetsadaphan, Woranoot Choomuang Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand Background: Poor inhalation techniques are associated with decreased medication delivery and poor disease control in chronic obstructive pulmonary disease (COPD. The purpose of this study was to evaluate techniques for using inhaler devices in COPD patients.Methods: A prospective cross-sectional study was conducted to assess patient compliance with correct techniques for using inhaler devices across four regimens, ie, the pressurized metered-dose inhaler (pMDI, the pMDI with a spacer, the Accuhaler®, and the Handihaler®. The percentage of compliance with essential steps of correct device usage for each regimen was recorded without prior notification when COPD patients presented for a routine visit, and 1 month after receiving face-to-face training. We compared the percentage of compliance between the devices and risk factors related to incorrect techniques using logistic regression analysis. Percentage of patient compliance with correct techniques was compared between the two visits using the chi-square test. Statistical significance was set at P<0.05.Results: A total of 103 COPD patients (mean age 71.2±9.2 years, males 64.1%, low education level 82.5%, and percent predicted forced expiratory volume in 1 second 51.9±22.5 were evaluated. Seventy-seven patients (74.8% performed at least one step incorrectly. Patients using the Handihaler had the lowest compliance failure (42.5%, and the odds ratio for failure with the other devices compared with the Handihaler were 4.6 (95% confidence interval [CI] 1.8–11.8 for the pMDI, 3.1 (95% CI 1.2–8.2 for the pMDI with a spacer, and 2.4 (95% CI 1.1–5.2 for the Accuhaler. Low education level was the single most important factor related

  10. Florida Red Tide: Inhalation Toxicity of Karenia brevis Extract in Rats


    Benson, J M; Hahn, F F; Tibbetts, B.M.; Bowen, L.E.; March, T.F.; Langley, R. J.; Murray, T.F.; Bourdelais, A.J.; Naar, J.; Zaias, J.; Baden, D. G.


    Brevetoxins are neurotoxins produced by the marine dinoflagellate Karenia brevis. Histopathologic examination of marine mammals dying following repeated exposure of brevetoxins during red tide events suggests that the respiratory tract, nervous, hematopoietic, and immune systems are potential targets for toxicity in repeatedly exposed individuals. The purpose of this experiment was to evaluate the effects of repeated inhalation of K. brevis extract on these potential target systems in rats. M...

  11. Relative lung bioavailability of generic sodium cromoglycate inhalers used with and without a spacer device. (United States)

    Aswania, O; Chrystyn, H


    The relative lung bioavailability of sodium cromoglycate following inhalation has been evaluated using urinary drug excretion in nine healthly volunteers. Each inhaled four 5 mg sodium cromoglycate doses from a generic metered dose inhaler (MDI) and when it was attached to large volume spacer (MDI + VOL). A breath-actuated MDI was also evaluated either used on its own (EB) or attached to a small volume spacer tube (EBO). The mean (SD) urinary excretion of sodium cromoglycate in the first 30 min post-inhalation was 34.1 (20.2), 211.7 (123.5), 29.3 (19.5) and 52.8 (36.0) microg following MDI, MDI+VOL, EB and EBO, respectively. The cumulative mean (SD) urinary excretion of sodium cromoglycate over the 24 h post-inhalation was 364.7 (266.2), 1227.1 (459.0), 280.2 (155.4) and 429.5 (176.7) microg. A metered dose inhaler attached to a large volume spacer delivers more sodium cromoglycate to the lungs than any other inhalation method.

  12. Preclinical safety evaluation of inhaled cyclosporine in propylene glycol. (United States)

    Wang, Tao; Noonberg, Sarah; Steigerwalt, Ronald; Lynch, Maryellen; Kovelesky, Rosemary A; Rodríguez, Carlos A; Sprugel, Katherine; Turner, Nancy


    Cyclosporine inhalation solution has the potential to improve outcomes following lung transplantation by delivering high concentrations of an immunosuppressant directly to the allograft while minimizing systemic drug exposure and associated toxicity. The objective of these studies was to evaluate the potential toxicity of aerosolized cyclosporine formulated in propylene glycol when given by inhalation route to rats and dogs for 28 days. Sprague-Dawley rats received total inhaled doses of 0 (air), 0 (vehicle, propylene glycol), 7.4, 24.3, and 53.9 mg cyclosporine/kg/day. In a separate study, beagle dogs were exposed to 0, 4.4, 7.7, and 9.7 mg cyclosporine/kg/day. Endpoints used to evaluate potential toxicity of inhaled cyclosporine were clinical observations, body weight, food consumption, respiratory functions, toxicokinetics, and clinical/anatomic pathology. Daily administration of aerosolized cyclosporine did not result in observable accumulation of cyclosporine in blood or lung tissue. Toxicokinetic analysis from the rat study showed that the exposure of cyclosporine was approximately 18 times higher in the lung tissue compared to the blood. Systemic effects were consistent with those known for cyclosporine. There was no unexpected systemic toxicity or clinically limiting local respiratory toxicity associated with inhalation exposure to cyclosporine inhalation solution at exposures up to 2.7 times the maximum human exposure in either rats or dogs. There were no respiratory or systemic effects of high doses of propylene glycol relative to air controls. These preclinical studies demonstrate the safety of aerosolized cyclosporine in propylene glycol and support its continued clinical investigation in patients undergoing allogeneic lung transplantation.

  13. Subchronic inhalation toxicity of gold nanoparticles

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    Chung Yong


    Full Text Available Abstract 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

  14. Subchronic inhalation toxicity of gold nanoparticles. (United States)

    Sung, Jae Hyuck; Ji, Jun Ho; Park, Jung Duck; Song, Moon Yong; Song, Kyung Seuk; Ryu, Hyeon Ryol; Yoon, Jin Uk; Jeon, Ki Soo; Jeong, Jayoung; Han, Beom Seok; Chung, Yong Hyun; Chang, Hee Kyung; Lee, Ji Hyun; Kim, Dong Won; Kelman, Bruce J; Yu, Il Je


    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. 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 nanoparticles showed a dose

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

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


    Inhaler technique can be corrected with training, but skills drop off quickly without repeated training. The aim of our study was to explore the effect of novel inhaler technique labels on the retention of correct inhaler technique. In this single-blind randomized parallel-group active-controlled study, clinical pharmacists enrolled asthma patients using controller medication by Accuhaler [Diskus] or Turbuhaler. Inhaler technique was assessed using published checklists (score 0-9). Symptom control was assessed by asthma control test. Patients were randomized into active (ACCa; THa) and control (ACCc; THc) groups. All patients received a "Show-and-Tell" inhaler technique counseling service. Active patients also received inhaler labels highlighting their initial errors. Baseline data were available for 95 patients, 68% females, mean age 44.9 (SD 15.2) years. Mean inhaler scores were ACCa:5.3 ± 1.0; THa:4.7 ± 0.9, ACCc:5.5 ± 1.1; THc:4.2 ± 1.0. Asthma was poorly controlled (mean ACT scores ACCa:13.9 ± 4.3; THa:12.1 ± 3.9; ACCc:12.7 ± 3.3; THc:14.3 ± 3.7). After training, all patients had correct technique (score 9/9). After 3 months, there was significantly less decline in inhaler technique scores for active than control groups (mean difference: Accuhaler -1.04 (95% confidence interval -1.92, -0.16, P = 0.022); Turbuhaler -1.61 (-2.63, -0.59, P = 0.003). Symptom control improved significantly, with no significant difference between active and control patients, but active patients used less reliever medication (active 2.19 (SD 1.78) vs. control 3.42 (1.83) puffs/day, P = 0.002). After inhaler training, novel inhaler technique labels improve retention of correct inhaler technique skills with dry powder inhalers. Inhaler technique labels represent a simple, scalable intervention that has the potential to extend the benefit of inhaler training on asthma outcomes. REMINDER LABELS IMPROVE INHALER TECHNIQUE: Personalized

  16. Withdrawal of inhaled glucocorticoids and exacerbations of COPD

    DEFF Research Database (Denmark)

    Magnussen, Helgo; Disse, Bernd; Rodriguez-Roisin, Roberto


    BACKGROUND: Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long-acting bronchod......BACKGROUND: Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long......-acting bronchodilators has not been fully explored. METHODS: In this 12-month, double-blind, parallel-group study, 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid...... fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary end point was the time to the first moderate or severe COPD exacerbation. Spirometric...

  17. Randomised placebo-controlled trial of inhaled sodium cromoglycate in 1-4-year-old children with moderate asthma

    NARCIS (Netherlands)

    M.J.A. Tasche (Marjolein); J.C. van der Wouden (Hans); J.H.J.M. Uijen (Hans); B.P. Ponsioen (Ben); R.M.D. Bernsen (Roos); L.W.A. van Suijlekom-Smit (Lisette); J.C. de Jongste (Johan)


    textabstractAbstract BACKGROUND: Inhalation therapy with sodium cromoglycate is recommended as the first-line prophylactic treatment for moderate asthma in children. The availability of spacer devices with face-masks has extended the applicability of metered-dose inhalers to younger children. We st

  18. Enhancement of systemic and sputum granulocyte response to inhaled endotoxin in people with the GSTM1 null genotype (United States)

    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...

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

    Directory of Open Access Journals (Sweden)

    Darbà J


    Full Text Available Josep Darbà,1 Gabriela Ramírez,2 Antoni Sicras,3 Pablo Francoli,4 Saku Torvinen,5 Rainel Sánchez-de la Rosa4 1Department of Economics, Universitat de Barcelona, 2BCN Health Economics and Outcomes Research SL, 3Dirección de Planificación, Badalona Serveis Assistencials, SA, Barcelona, 4Medical Department, TEVA Pharmaceutical, Madrid, Spain; 5Market Access Department, TEVA Pharmaceutical Europe BV, Amsterdam, the Netherlands Objective: 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.Methods: 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.Results: 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

  20. Potent Inhalational Anesthetics for Dentistry. (United States)

    Satuito, Mary; Tom, James


    Nitrous oxide and the volatile inhalational anesthetics have defined anxiety and pain control in both dentistry and medicine for over a century. From curious experimentation to spectacular public demonstrations, the initial work of 2 dentists, Horace Wells and William T. G. Morton, persists to this day in modern surgery and anesthesia. This article reviews the history, similarities, differences, and clinical applications of the most popular inhalational agents used in contemporary dental surgical settings.

  1. Combination formoterol and budesonide as maintenance and reliever therapy versus inhaled steroid maintenance for chronic asthma in adults and children. (United States)

    Cates, Christopher J; Lasserson, Toby J


    Traditionally inhaled treatment for asthma has been considered as preventer and reliever therapy. The combination of formoterol and budesonide in a single inhaler introduces the possibility of using a single inhaler for both prevention and relief of symptoms (single inhaler therapy). The aim of this review is to compare formoterol and corticosteroid in single inhaler for maintenance and relief of symptoms with inhaled corticosteroids for maintenance and a separate reliever inhaler. We last searched the Cochrane Airways Group trials register in September 2008. Randomised controlled trials in adults and children with chronic asthma. Two review authors independently assessed studies for inclusion and extracted the characteristics and results of each study. Authors or manufacturers were asked to supply unpublished data in relation to primary outcomes. Five studies on 5,378 adults compared single inhaler therapy with current best practice, and did not show a significant reduction in participants with exacerbations causing hospitalisation (Peto OR 0.59; 95% CI 0.24 to 1.45) or treated with oral steroids (OR 0.83; 95% CI 0.66 to 1.03). Three of these studies on 4281 adults did not show a significant reduction in time to first severe exacerbation needing medical intervention (HR 0.96; 95% CI 0.85 to 1.07). These trials demonstrated a reduction in the mean total daily dose of inhaled corticosteroids with single inhaler therapy (mean reduction ranged from 107 to 267 micrograms/day, but the trial results were not combined due to heterogeneity). The full results from four further studies on 4,600 adults comparing single inhaler therapy with current best practice are awaited.Three studies including 4,209 adults compared single inhaler therapy with higher dose budesonide maintenance and terbutaline for symptom relief. No significant reduction was found with single inhaler therapy in the risk of patients suffering an asthma exacerbation leading to hospitalisation (Peto OR 0

  2. Efficacy of Clarithromycin and Inhalation with Salmeterol/Middle-dose Fluticasone for the Treatment of Patients with Severe COPD in Stable Phase%克拉霉素联合吸入沙美特罗+中剂量替卡松治疗稳定期重度COPD的疗效

    Institute of Scientific and Technical Information of China (English)

    双庆翠; 周治平; 银春阳; 邓玎玎; 曾少章; 朱丹


    [目的]评价长期口服低剂量克拉霉素联合吸入沙美特罗+中剂量替卡松粉吸入剂治疗稳定期重度慢性阻塞性肺疾病(COPD)患者的疗效和安全性.[方法]51例稳定期重度COPD患者随机分为两组,治疗组予口服克拉霉素联合吸入沙美特罗+中剂量替卡松粉吸入剂(50/250 μg,2吸/日)、对照组吸入沙美特罗+高剂量替卡松粉吸入剂(50/500 μg,2吸/日)治疗1年,评估COPD急性加重(AECOPD)次数、圣乔治呼吸问卷(SGRQ)总分、肺功能和不良反应.[结果]42例COPD患者完成治疗,治疗组22例,对照组20例,治疗组年平均急性加重次数为(0.91±0.52)次,对照组为(0.95±0.36)次,两组相比较差异无显著性(P<0.05).治疗组和对照组用药1年后与用药前SGRQ总分分别减少(6.73士4.62)次、(5.47±4.25)次,均达到临床改善,两组变化值相比较差异无显著性(P<0.05).肺功能FEV1%预计值无改善.两组患者未见不良反应.[结论]长期低剂量克拉霉素联合吸入沙美特罗+中剂量替卡松粉吸入剂治疗稳定期重度COPD患者有效,可以减少丙酸氟替卡松用量.%[Objective]To evaluate the efficacy and safety of low dose clarithromycin and inhalation with salmeterol/middle-dose fluticasone for the treatment of patients with severe chronic obstructive pulmonary disease(COPD) in stable phase.[Methods] A total of 51 severe COPD patients in stable phase were divided into treatment two groups.The treatment group was given oral clarithromycin and inhalation with salmeterol/middle-dose fluticasone(50/250μg,twice a day).The control group was given the inhalation with salmeterol/highdose fluticasone(50/500μg,twice a day).The treatment course was one year.The frequency of acute exacerbation of COPD(AECOPD),total scores of St.George's respiratory questionnaire(SGRQ),pulmonary function and side effects were evaluated.[Results] Of 51 patients,42 COPD patients(22 patients in treatment group and 20 patients in control

  3. AB034. Comparative effectiveness of prescribing similarversusdissimilar inhalers for COPD therapy (United States)

    Bosnic-Anticevich, Sinthia; Chrystyn, Henry; Costello, Richard; Dolovich, Myrna; Fletcher, Monica; Lavorini, Federico; Rodríguez-Roisin, Roberto; Ryan, Dermot; Ming, Simon Wan Yau; Skinner, Derek; Price, David


    Background Prescription of different inhaler types for patients with chronic obstructive pulmonary disease (COPD) may lead to poorer outcomes through increased demands on patients to master dissimilar inhalation and dose preparation manoeuvres. To describe the demographic, co-morbidity, and clinical characteristics of patients with COPD prescribed ‘dissimilar’versus‘similar’ inhalers. Methods The study was a historical cohort observational design assessing a 1-year baseline period for patient characterization and categorisation of inhalers, and an index date to signal the last date of data extraction from the UK Optimum Patient Care Research Database (OPCRD). Patients had 1-year of continuous data between February 2008 and February 2015, a Quality and Outcomes Framework (QOF) coded diagnosis for COPD, were aged 40 and over, and had evidence of two or more inhaled respiratory treatments. Descriptive statistics included demographic, co-morbidity and clinical characteristics of patients, and comparison of patients prescribed similarversusdissimilar inhalers by GOLD group, FEV1, and number of exacerbations. Based on inhalation technique and dose preparation data in the OPCRD, two different categorisations were used to describe prescribed inhaler type: ‘similar inhalers’ included those patients prescribed either aerosols or similar dry-powder inhalers (DPIs), while ‘dissimilar inhalers’ included those prescribed both aerosols and DPIs. Results A total of 53,817 patients were selected [mean age of 71 years (SD 10.6); males: 51% in total population]. 13% were non-smokers, 30% current smokers, 52% ex-smokers and 5% with missing smoking status. In the baseline year, 39% received a QOF coded diagnosis for asthma, 36% for diabetes, 26% for ischaemic heart disease, 6% for actively treated rhinitis, and 1.3% for diagnosis for pneumonia. Patients prescribed dissimilar inhalers were of similar age to those prescribed similar inhalers (mean age of 71 in each cohort

  4. Evaluation of factors that allow the clinician to taper inhaled corticosteroids in childhood asthma

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    Kentaro Matsuda


    Full Text Available Inhaled corticosteroids are potent and effective treatment agents for controlling symptoms of childhood asthma. However, there are no predictive factors that help to determine which patients with asthma are likely to be tapered off inhaled corticosteroids successfully. We examined whether any factor or combination of factors could help the clinician safely discontinue inhaled steroid therapy. Thirty-six asthmatic children whose symptoms were stable on low-dose beclomethasone dipropionate (BDP were divided by parental choice into two groups: maintenance BDP (n = 11 and no BDP (n = 25. Methacholine inhalation tests were performed at the beginning of the study and after 1 month. Twelve children (48% who had BDP discontinued developed exacerbations after 2–3 months, whereas there were no problems in the maintenance group. The no BDP group was retrospectively divided into two subgroups: exacerbation (+ and (−. The threshold to methacholine in the exacerbation (+ subgroup decreased significantly in advance of clinical symptoms. The two subgroups were analyzed statistically by two-group discriminant function analysis. The change in threshold to methacholine, the dose and potency of drugs, duration of asthma and gender (female correlated with exacerbation. These results suggest that discontinuation of inhaled steroids should be done carefully, even in stable asthmatic children. The methacholine inhalation test, gender, drugs and history may be used as references for discontinuing inhaled steroids.

  5. Therapeutic application of inhaled nitric oxide in adult cardiac surgical patients. (United States)

    Makker, Robina; Mehta, Yatin; Trehan, Naresh; Bapna, Rk


    Increased pulmonary vascular resistance can be detrimental to the cardiac output in post-operative cardiac surgical patients. Pulmonary vasodilator therapy by systemic pharmacologic agents is non-selective. Inhaled nitric oxide is a selective pulmonary vasodilator and does not cause systemic hypotension. In this prospective study, 14 adult post-operative cardiac surgical patients with pulmonary hypertension underwent inhaled nitric oxide therapy and their hemodynamic changes were evaluated. Inhaled nitric oxide was administered in doses of 5 ppm-25 ppm. The result was a decrease in pulmonary vascular resistance from 456.57 +/- 137.13 to 357.64 +/- 119.80 dynes-sec- Continued. - See Free Full Text.

  6. Behavioral effects of subchronic inhalation of toluene in adult rats. (United States)

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


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

  7. Montelukast as Add-On Therapy to Inhaled Corticosteroids in the Management of Asthma (The SAS Trial

    Directory of Open Access Journals (Sweden)

    J Mark FitzGerald


    Full Text Available AIM: To evaluate the effectiveness of montelukast as add-on therapy for asthmatic patients who remain uncontrolled with low, moderate or high doses of inhaled corticosteroid monotherapy.


    NARCIS (Netherlands)



    Background - Propranolol inhalation provocation tests are used to measure indirect airways responsiveness in the investigation of asthma. In this study the effects of repeated propranolol inhalation provocation tests within the same day on normal diurnal variation in the forced expiratory volume in

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

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


    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

  10. The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holding chamber is independent of age and body size

    DEFF Research Database (Denmark)

    Govoni, Mirco; Piccinno, Annalisa; Lucci, Germano


    BACKGROUND: Asthma guidelines recommend prescription of inhaled corticosteroids at a reduced dosage in children compared to older patients in order to minimize the systemic exposure and risk of unwanted side effects. In children, pressurized metered dose inhalers (pMDI) are recommended in combina......BACKGROUND: Asthma guidelines recommend prescription of inhaled corticosteroids at a reduced dosage in children compared to older patients in order to minimize the systemic exposure and risk of unwanted side effects. In children, pressurized metered dose inhalers (pMDI) are recommended...

  11. From inhaler to lung: clinical implications of the formulations of ciclesonide and other inhaled corticosteroids

    Directory of Open Access Journals (Sweden)

    Nave R


    Full Text Available Ruediger Nave, Helgert Mueller Nycomed: a Takeda Company, Nycomed GmbH, Konstanz, Germany Abstract: Asthma continues to be a global health problem and currently available treatments such as corticosteroids can cause unwanted side effects. Inhaled corticosteroids (ICS are recommended as first-line therapy for reducing airway inflammation and have a distinct advantage over oral preparations as they provide a direct route of delivery to the lungs. However, local deposition of ICS in the oropharynx can lead to oral candidiasis, dysphonia, and pharyngitis. The pharmaceutical quality is a primary concern of any ICS asthma treatment, with a higher quality product resulting in improved efficacy and safety profiles. The particle size distribution and the spray force velocity of an ICS may directly influence lung deposition, and the spray duration of a device is another important factor when coordinating inhalation. Recent advances in ICS device and formulation technology have resulted in significant improvements in the efficacy of available asthma treatments. In particular, hydrofluoroalkane (HFA solution technology and the development of smaller particle sizes have resulted in the production of new ICS formulations that have the ability to directly target drug delivery to the site of airway inflammation. Both the ICS formulation and the pressurized metered-dose inhaler device used to administer ciclesonide (CIC HFA have been developed to treat the underlying chronic inflammation associated with asthma. CIC is administered as a prodrug which is activated in the lungs, leading to minimal oropharyngeal deposition. The small particle size of CIC results in the delivery of a high fraction of respirable particles to the small airways of the lungs, resulting in high lung deposition and continual dose consistency. This review summarizes how CIC administered as an HFA formulation is an effective treatment for asthma. Keywords: ciclesonide, asthma, small airways

  12. Medical Modeling of Particle Size Effects for CB Inhalation Hazards (United States)


    of body orientation ( posture ) on deposition, and availability of 30 stochastic lung geometry for more realistic assessment of variation of dose in... hygiene community, with their role of monitoring and protecting workers in the workplace, has had a key role in developing standard models of...M.G., Miller, F.J. and Raabe, O.G. (1995). Particle Inhalability Curves for Humans and Small Laboratory Animals. Annals of Occupational Hygiene 39

  13. Inhaled corticosteroids stabilize constrictive bronchiolitis after hematopoietic stem cell transplantation. (United States)

    Bashoura, L; Gupta, S; Jain, A; Couriel, D R; Komanduri, K V; Eapen, G A; Safdar, A; Broglio, K R; Adachi, R; Dickey, B F


    Post transplantation constrictive bronchiolitis (PTCB) is the most common pulmonary complication among long-term survivors of allogeneic hematopoietic stem cell transplantation (HSCT). It is a late manifestation of GVHD. Its treatment with high-dose systemic corticosteroids and other immunosuppressive regimens is associated with multiple side effects. Topical corticosteroids are used for the treatment of other manifestations of GVHD to minimize these side effects. We conducted a retrospective analysis of a series of adult patients to evaluate the efficacy of high-dose inhaled corticosteroids in the treatment of PTCB. Seventeen patients with new-onset airflow obstruction were diagnosed with PTCB. Their forced expiratory volume in 1 s (FEV1) declined from a median of 84% (range, 56-119) before HSCT to 53% (26-82) after HSCT. All patients received inhaled fluticasone propionate 500-940 microg two times daily. Symptoms of airway obstruction improved and FEV1 stabilized 3-6 months after treatment. We conclude that high-dose inhaled corticosteroids may be effective in the treatment of PTCB and propose a plausible mechanism of its action. A prospective evaluation of its efficacy is warranted.

  14. Self-administered, inhaled methoxyflurane improves patient comfort during nasoduodenal intubation for computed tomography enteroclysis for suspected small bowel disease: a randomized, double-blind, placebo-controlled trial

    Energy Technology Data Exchange (ETDEWEB)

    Moss, A., E-mail: [Department of Gastroenterology and Hepatology, Box Hill Hospital, Melbourne (Australia); Department of Medicine, Monash University, Box Hill Campus, Melbourne (Australia); Parrish, F.J.; Naidoo, P.; Upton, A. [Department of Radiology, Box Hill Hospital, Melbourne (Australia); Prime, H.; Leaney, B. [Department of Radiology, Epworth Eastern Hospital, Melbourne, Victoria (Australia); Gibson, P.R. [Department of Gastroenterology and Hepatology, Box Hill Hospital, Melbourne (Australia); Department of Medicine, Monash University, Box Hill Campus, Melbourne (Australia)


    Aim: To determine the efficacy and safety of self-administered, inhaled analgesic, methoxyflurane, used to improve patient comfort during computed tomography enteroclysis (CTE). Materials and methods: A randomized, double-blind, placebo-controlled trial was performed at two Australian hospitals (one tertiary referral public hospital and one private hospital). Patients were randomized to 3 ml methoxyflurane or saline (scented to maintain blindness) via hand-held inhaler. The main outcome measures were patient comfort during each stage of CTE and an overall rating as recorded by patients 1 h post-procedure on a 10 cm visual analogue scale. Patient willingness to undergo repeat CTE, radiologist-rated ease of nasoduodenal intubation, and patient-rated ease of use of the inhaler were also assessed. Results: Sixty patients (mean age 45 years; 41 women) were enrolled; 30 received methoxyflurane and were well matched to 30 receiving placebo. Procedural success was 98%. The mean dose of methoxyflurane consumed was 0.9 ml (SD 0.5). Patient comfort during nasoduodenal intubation was better with methoxyflurane {l_brace}5.0 [95% confidence intervals (CI) 4.0-6.0]{r_brace} than with placebo [2.7 (95% CI 1.8-3.7); p = 0.002, t-test), but there were no significant differences for comfort levels at other times or overall. The inhaler was easy to use, was well tolerated, and there were no episodes of oxygen desaturation, aspiration, or anaphylaxis. Conclusions: Inhalational methoxyflurane safely improves patient comfort during nasoduodenal intubation, but does not improve overall procedure comfort.

  15. Zinc toxicology following particulate inhalation

    Directory of Open Access Journals (Sweden)

    Cooper Ross


    Full Text Available The current mini-review describes the toxic effects of zinc inhalation principally in the workplace and associated complications with breathing and respiration. The International Classification of Functioning, Disability and Health Criteria were used to specifically select articles. Most of the commercial production of zinc involves the galvanizing of iron and the manufacture of brass. The recommended daily allowance for adults is 15 mg zinc/day. Metal fume fever associated with inhalation of fumes of ZnO is characterized by fatigue, chills, fever, myalgias, cough, dyspnea, leukocytosis, thirst, metallic taste and salivation. ZnCl 2 inhalation results in edema in the alveolar surface and the protein therein the lavage fluid is elevated. Particular pathological changes associated with zinc intoxication include: pale mucous membranes; jaundice; numerous Heinz bodies; and marked anemia. Adequate ambient air monitors for permissible exposure limits, excellent ventilation and extraction systems, and approved respirators are all important in providing adequate protection.

  16. Uranium in vitro bioassay action level used to screen workers for chronic inhalation intakes of uranium mill tailings. (United States)

    Reif, R H; Turner, J B; Carlson, D S


    A uranium in vitro bioassay (urinalysis) action level was derived for use at the Department of Energy's Uranium Mill Tailings Remedial Action Project sites to identify chronic inhalation intakes of uranium mill tailings causing 0.5 mSv (50 mrem) annual effective dose equivalent. All radionuclides in the 238U decay chain that contribute 1% or more to the annual effective dose equivalent from an inhalation intake of uranium mill tailings were included in the derivation of the urinalysis action level. Using a chronic inhalation intake model, the uranium urinalysis action level for a 24-h urine sample, collected on a quarterly schedule, was calculated to be 1.5 micrograms.

  17. Compared biokinetic and biological studies of chronic and acute inhalations of uranium compounds in the rat; Etudes biocinetique et biologique comparees d'inhalations chroniques et aigues de composes uraniferes chez le rat

    Energy Technology Data Exchange (ETDEWEB)

    Monleau, M


    Uranium is a natural, radioactive heavy metal, widely used in the nuclear industry in various chemical and isotopic forms. Its use in the fuel cycle involves the risk of radiological exposure for the workers, mainly via the inhalation of uranium particles. According to the workplace configuration, uranium contaminations can be acute or repeated, involve various chemical forms and different levels of enrichment, as well as involving one or several components. The dosimetric concepts and models available for workers' radiological protection, as well as most of the studies of the biological effects, correspond to acute exposure situations. Moreover the processes leading to pathological effects are little known in vivo. In this context, the main question is to know whether exposures due to repeated inhalation by rats induce the element kinetics and toxicity, which may be different from those observed after an acute exposure. In this study, comparison of the experimental and theoretical biokinetics of an insoluble uranium repeatedly inhaled over three weeks shows that a chronic contamination is correctly modelled, except for bone retention, by the sum of acute, successive and independent incorporations. Moreover, the kinetics of a soluble uranium inhaled irregularly can be modified by previous repeated exposure to an insoluble uranium. In certain cases therefore, exposure to uranium could modify its biokinetics during later exposures. At a toxicological level, the study demonstrates that the uranium particles inhaled repeatedly induce behavioural disruptions and genotoxic effects resulting in various sorts of DNA damage, in several cell types and certainly depending on the quantity inhaled. Exposures involving several uraniferous components produce a synergy effect. Moreover, repeated inhalations worsen the genotoxic effects in comparison to an acute exposure. This work demonstrates the importance of not ignoring the effects of the repetition of uranium exposure

  18. The Evaluation of Family Physicians’ Knowledge on the Use of Inhalation Devices

    Directory of Open Access Journals (Sweden)

    Elif Tanrıverdi


    Full Text Available Objective: Nowadays, inhalation techniques have an important role in treatment of asthma and chronic obstructive pulmonary disease (COPD. Correct application of inhalation devices is important for optimal therapeutic efficacy. Showing inhalation techniques to patients receiving inhaler therapy in more than one visit reduce the device usage errors. It is important to observe the deficiencies and errors of the patients in the primary health care where the patients frequently admitted. In our study we aimed to evaluate the knowledge of family physians on inhaler device usage in their clinical practice. Methods: Family physicians who work in primary health care services were visited face to face. Fifty family physicians who were in the institution at visit day and agreed to participate in the study were included in the study. The questionnaire consisting of 15 questions were asked each family physician. Then, seven different inhalation devices were evaluated with 10 step scoring system of inhaler device usage. Results: Twenty eight (56% physicians were female and 22 (44% were male. The mean age was 36.3±6.7 years and mean working time as a family physician was 5.12±2.8 years. Nineteen physicians participated to a meeting about usage of inhaler devices in the past. Average scores for inhaler devices were found 7.96±2.91 for metered-dose inhaler, 7.54±3.93 for discus, 7.28±4.04 for handihaler, 6.38±4.4 for aerolizer, 6.12±4.22 for turbuhaler, 5.98±4 for easyhaler and 5.72±4.59 for sanohaler, respectively. There was no relation between the inhaler devices usage scores and sex, age, duration of being family physician (p>0.05. The average scores of physicians who participated to a training were better than the physicians who didn’t participate for metered-dose inhalers, turbuhaler, aerolizer and handihaler (p=0.049, p=0.05, p=0.013 and p=0.021, respectively. Conclusion: We thought that training of family physicians for inhaler devices is

  19. Inhalant Abuse: Is Your Child at Risk? (United States)

    ... can be valuable as well. With help, your child can end inhalant abuse and learn how to make healthy choices for a lifetime. References Baydala L. Inhalant abuse. Paediatrics and Child Health. 2010;15:443. Results from the 2013 ...

  20. AB036. Real-life experience of COPD patients on ease and accuracy of inhaler use: the REAL survey (United States)

    Keininger, Dorothy L.; Price, David; Viswanad, Boomi; Gasser, Matthias; Walda, Susann


    Background Many patients with chronic obstructive pulmonary disease (COPD) achieve incomplete benefit from their treatment, due to reasons including inadequate device training or incorrect inhaler technique. Dosing frequency has also been shown to impact COPD treatment compliance with inhaler overuse and underuse being the most common form of noncompliance. Between 28–68% of patients do not use their inhalers correctly, and 39–67% of health care professionals (HCPs) do not effectively train patients to correctly