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Factors affecting magnetic retention of particles in the upper airways: an in vitro and ex vivo study. 影响上呼吸道磁性颗粒滞留的因素:一项体外和离体研究。
J Ally, A Amirfazli, W Roa

This paper presents the results of experiments using an in vitro model and an ex vivo animal model (Rana catesbeiana) to study magnetic particle retention in the conducting airways, specifically the trachea and bronchi. The purpose of these experiments was to determine the significant factors for retention of magnetic particles deposited from an aerosol at the airway surface using a magnetic field. The results indicate that the apparent viscosity of the mucus layer at low shear rates is the most significant obstacle to particle retention. The results also show that particle size and aggregation play major roles in particle retention. The mucus transport rate, unlike the effect of fluid velocity in intravenous applications, did not appear to be a determining factor for particle retention. It was also found that a suitably designed magnetic system, aside from having a high intensity, needs to exert a strong radial field to promote particle aggregation. The findings suggest that one possible approach to magnetic particle retention could be delivery of a mucolytic agent along with the drug particles. This study provides the fundamentals needed for development of a targeted magnetic drug delivery system for inhaled therapeutic aerosol particles.

本文介绍了利用体外模型和离体动物模型(Rana catesbeiana)研究磁颗粒在导电气道(特别是气管和支气管)中的滞留的实验结果。这些实验的目的是利用磁场确定气溶胶沉积的磁性颗粒在气道表面保留的重要因素。结果表明,低剪切速率下黏液层的表观粘度是颗粒滞留的最大障碍。结果还表明,颗粒的大小和聚集对颗粒的保留起主要作用。黏液输送速率,不像静脉注射中液体流速的影响,似乎不是颗粒滞留的决定因素。还发现,设计合适的磁系统,除了具有高强度外,还需要施加强大的径向场来促进粒子聚集。研究结果表明,磁性颗粒保留的一种可能方法是随着药物颗粒一起递送黏液剂。这项研究为开发用于吸入治疗性气溶胶颗粒的靶向磁性药物输送系统提供了必要的基础。
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引用次数: 18
Advances in our understanding of aerosolized iloprost for pulmonary hypertension. 伊洛前列素雾化治疗肺动脉高压的研究进展。
P Diot, P Magro, L Vecellio, G C Smaldone
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引用次数: 5
Imaging the airways in 2006. 2006年的气道成像。
Dale L Bailey

Imaging has traditionally been separated into two distinct disciplines: functional imaging and structural imaging. Functional imaging encompasses applications such as nuclear medicine (single photon emission computed tomography [SPECT] and positron emission tomography [PET]), autoradiography, magnetic resonance spectroscopy (MRS) and magneto-encephalography (MEG), while structural, or anatomical, imaging includes planar radiography, x-ray computed tomography (CT), and magnetic resonance imaging (MRI). However, today, the distinctions between these are blurring due to advances in software fusion and the development of multi-modality (SPECT/CT, PET/CT) scanners. New techniques such as MRI using hyperpolarized gases (3H and 129Xe) and xenon K-edge synchrotron x-ray subtraction imaging are also being developed to provide the researcher with a variety of ways to probe the airways, and the distribution of pharmaceuticals and subsequent uptake and bio-distribution. This paper reviews advances in imaging to present a contemporary view of the tools available.

成像传统上分为两个不同的学科:功能成像和结构成像。功能成像包括核医学(单光子发射计算机断层扫描[SPECT]和正电子发射断层扫描[PET])、放射自显影、磁共振波谱(MRS)和脑磁成像(MEG)等应用,而结构或解剖成像包括平面放射成像、x射线计算机断层扫描(CT)和磁共振成像(MRI)。然而,今天,由于软件融合的进步和多模态(SPECT/CT, PET/CT)扫描仪的发展,这些之间的区别正在变得模糊。利用超极化气体(3H和129Xe)和氙k边同步加速器x射线减影成像等新技术也在开发中,为研究人员提供了多种方法来探测气道、药物分布以及随后的摄取和生物分布。本文回顾了成像方面的进展,以呈现可用工具的当代观点。
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引用次数: 17
Dry powder aerosol delivery systems: current and future research directions. 干粉气溶胶输送系统:当前和未来的研究方向。
Hak-Kim Chan

Development of dry powder aerosol delivery system involves powder production, formulation, dispersion, delivery, and deposition of the powder aerosol in the airways. Insufficiency of conventional powder production by crystallization and milling has led to development of alternative techniques. Over the last decade, performance of powder formulations has been improved significantly through the use of engineered drug particles and excipient systems which are (i) of low aerodynamic diameters (being porous or of low particle density), and/or (ii) less cohesive and adhesive (via corrugated surfaces, low bulk density, reduced surface energy and particle interaction, hydrophobic additives, and fine carrier particles). Early insights into particle forces and surface energy that help explain the improvement have been provided by analytical techniques such as the atomic force microscopy (AFM) and inverse gas chromatography (IGC). Relative humidity is critical to the performance of dry powder inhaler (DPI) products via capillary force and electrostatic interaction. Electrostatic charge of different particle size fractions of an aerosol can now be measured using a modified electrical low-pressure impactor (ELPI). Compared with powders, much less work has been done on the inhaler devices at the fundamental level. Most recently, computational fluid dynamics has been applied to understand how the inhaler design (such as mouthpiece, grid structure, air inlet) affects powder dispersion. The USP throat is known to under-represent the oropharyngeal deposition of DPI aerosols. Studies using magnetic resonance imaging (MRI) model casts have been undertaken to explain the inter- and intra- subject variation in oropharyngeal deposition. Most of the lung deposition studies performed on commercial products did not allow a thorough understanding of the determinants affecting in vivo lung deposition. A more systematic approach would be necessary to build a useful database on the dependence of lung deposition on the breathing parameters, inhaler design, and powder formulation properties.

干粉气溶胶输送系统的开发涉及粉末生产、配方、分散、输送和粉末气溶胶在气道中的沉积。传统的结晶和磨粉生产方法的不足导致了替代技术的发展。在过去的十年中,通过使用工程药物颗粒和赋形剂系统,粉末配方的性能得到了显着改善,这些系统(i)具有低空气动力学直径(多孔或低颗粒密度),和/或(ii)凝聚力和粘合剂较差(通过波纹表面,低体积密度,降低表面能和颗粒相互作用,疏水添加剂和细载体颗粒)。原子力显微镜(AFM)和反相气相色谱(IGC)等分析技术提供了对粒子力和表面能的早期见解,有助于解释这种改进。相对湿度通过毛细管力和静电相互作用对干粉吸入器(DPI)产品的性能至关重要。现在可以使用改进的低压冲击器(ELPI)来测量气溶胶中不同粒径组分的静电荷。与粉末相比,在基本水平上对吸入器装置所做的工作要少得多。最近,计算流体动力学已被应用于了解吸入器的设计(如吹口、网格结构、进气口)如何影响粉末的分散。众所周知,USP咽喉不足以代表DPI气溶胶的口咽部沉积。使用磁共振成像(MRI)模型模型进行了研究,以解释口咽沉积的受试者之间和受试者内部的变化。大多数对商业产品进行的肺沉积研究都不能彻底了解影响体内肺沉积的决定因素。需要一个更系统的方法来建立一个有用的数据库,了解肺沉积对呼吸参数、吸入器设计和粉末配方特性的依赖。
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引用次数: 101
Advances in aerosols: adult respiratory disease. 气溶胶的进展:成人呼吸道疾病。
Gerald C Smaldone

Recognition of the importance of breathing pattern in aerosol delivery and deposition has led to the design of devices that allow targeting of deposition to airways and alveoli. Systems incorporating patient feedback provide control of factors affecting deposition, and the control of dose to the lung can now be expected. New devices combined with a medical realization of therapeutic need are beginning to affect the range of drugs now available to the caregiver or in development for the immediate future. The interface between the patient and the device represents a new area of practical research. Facemasks have been shown to be important in terms of drug delivery with different behavior in metered dose inhaler (MDI)/valved holding chambers compared to nebulizers. Recently completed clinical trials have demonstrated the usefulness of therapy targeted to the lungs in reducing systemic toxicity with enhanced efficacy. A prime example is aerosolized cyclosporine, used to prevent rejection in lung transplantation. This agent has recently been shown to reduce mortality in transplant recipients and will lead to a new drug application in the United States. For larger patient populations, the pursuit of therapies to reduce the incidence of ventilator-associated pneumonia (VAP) can affect the outcome of illness in the intubated patient in the Intensive Care Unit (ICU). Patients with idiopathic pulmonary fibrosis (IPF) may benefit from high doses of aerosolized interferon gamma. Patient and caregiver safety are additional factors that will affect future approaches to therapy.

认识到呼吸模式在气溶胶输送和沉积中的重要性,导致设计了能够靶向沉积到气道和肺泡的设备。纳入患者反馈的系统可以控制影响沉积的因素,并且现在可以预期对肺剂量的控制。与医疗治疗需求相结合的新设备开始影响护理人员现有药物的范围,或在不久的将来开发药物。病人和设备之间的接口代表了一个新的实用研究领域。与雾化器相比,口罩在计量吸入器(MDI)/阀式保持室中具有不同的行为,在药物输送方面具有重要作用。最近完成的临床试验已经证明了针对肺部的治疗在减少全身毒性和增强疗效方面的有效性。一个典型的例子是用于防止肺移植排斥反应的雾化环孢素。这种药物最近被证明可以降低移植受者的死亡率,并将导致一种新药在美国的应用。对于更大的患者群体,寻求降低呼吸机相关性肺炎(VAP)发生率的治疗方法可能会影响重症监护病房(ICU)插管患者的疾病结局。特发性肺纤维化(IPF)患者可能受益于高剂量雾化干扰素γ。患者和护理人员的安全是影响未来治疗方法的其他因素。
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引用次数: 44
Aerosol deposition in the upper airways of a child. 儿童上呼吸道的气溶胶沉积。
F H C de Jongh, M J G Rinkel, H W M Hoeijmakers

In a small child, normally only a small amount of inhaled aerosol particles reaches the lungs because the majority deposits in the upper airways. In this study, the upper airways of a 9- month-old child, based on computed tomography (CT) data, are modeled to serve as input for a computational fluid dynamics package (CFX). Verification of the validity of aerosol deposition calculations by this package is accomplished by evaluating two test cases, which also can be solved analytically. The numerically found sedimentation fraction in a horizontally placed straight pipe shows deviations from the exact solution for small particle sizes (less than 3 micron) due to small velocities generated by the use of an unstructured mesh. Although these velocities are small compared to the mainstream velocity, they are comparable with the terminal settling velocity of such a particle. Also the test case for inertial impaction in a bend pipe demonstrated the same problem. With this in mind, the aerosol deposition of 3.7-micron particles in the upper airway model of the child (SAINT-model) was calculated. Results were compared with experimentally found results in the literature. For small tidal volumes and flow rates, the computational results matched the experimentally measured results. However, large deviations were found for higher flow rates and small particle sizes. Most probably the incompletely modeled entrance at the nose and inertial effects due to turbulence might be responsible.

对于小孩子来说,通常只有少量吸入的气溶胶颗粒到达肺部,因为大部分都沉积在上呼吸道。在这项研究中,基于计算机断层扫描(CT)数据,对一个9个月大的婴儿的上呼吸道进行建模,作为计算流体动力学包(CFX)的输入。通过对两个测试用例的评估,验证了该软件包对气溶胶沉降计算的有效性,这两个测试用例也可以解析解决。在水平放置的直管中,由于使用非结构化网格产生的小速度,数值发现的沉降分数与小颗粒尺寸(小于3微米)的精确解存在偏差。虽然这些速度与主流速度相比很小,但它们与这种颗粒的最终沉降速度相当。弯曲管惯性冲击的试验也证明了同样的问题。考虑到这一点,我们计算了3.7微米颗粒在儿童上呼吸道模型(SAINT-model)中的气溶胶沉积。结果与文献中的实验结果进行了比较。对于小潮量和小流量,计算结果与实验测量结果吻合。然而,在高流速和小颗粒尺寸下,发现了较大的偏差。最可能的原因是机头入口的不完全建模和湍流引起的惯性效应。
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引用次数: 0
Two-dimensional and three-dimensional imaging show ciclesonide has high lung deposition and peripheral distribution: a nonrandomized study in healthy volunteers. 二维和三维成像显示环来奈德具有高肺沉积和周围分布:一项健康志愿者的非随机研究。
Chet L Leach, Thomas D Bethke, Robert J Boudreau, Bruce E Hasselquist, Anton Drollmann, Patricia Davidson, Wilhelm Wurst

Drug deposition is an important factor that contributes to safety and efficacy outcomes of inhaled steroid therapy. Ciclesonide is a nonhalogenated, inhaled corticosteroid under investigation for the treatment of asthma. Therefore, this study was performed to assess lung deposition of ciclesonide. Technetium-99m (99mTc)-labeled ciclesonide (where the 99mTc-label is physically dissolved in the ciclesonide-hydrofluoroalkane [HFA] solution aerosol) inhaled by healthy volunteers was analyzed by two-dimensional (2-D) and three-dimensional (3-D) imaging to determine lung deposition. Six healthy volunteers inhaled one puff of 40 microg (exactuator, equivalent to 50 microg ex-valve) ciclesonide for 2-D imaging, and two healthy volunteers inhaled 10 puffs of 40 microg ciclesonide for 2-D and 3-D imaging. The ciclesonide aerosol was administered via metered-dose inhaler (MDI) containing HFA-134a as propellant. The ex-actuator mean (+/- standard deviation) deposition of ciclesonide in the lungs was higher (52% +/- 11%) than in the mouth/pharynx (38% +/- 14%). Two-dimensional and 3-D imaging showed that ciclesonide reached all regions of the lung. Mean percent deposition in peripheral regions (47% and 34%) was higher than in lower central regions (17% and 30%), as revealed by 3-D and 2-D imaging, respectively. Inhalation of up to 400 microg of ciclesonide produced no drug-related side effects. In conclusion, ciclesonide administered via metered-dose inhaler using HFA-134a as a propellant provided high lung deposition (>50%), greater distribution throughout peripheral regions of the lungs, and relatively low oropharyngeal deposition.

药物沉积是影响吸入类固醇治疗安全性和有效性的重要因素。环来奈德是一种非卤化的吸入性皮质类固醇,目前正在研究用于治疗哮喘。因此,本研究旨在评估环来奈德的肺沉积。通过二维(2-D)和三维(3-D)成像分析健康志愿者吸入的锝-99m (99mTc)标记的环来奈德(99mTc标签物理溶解在环来奈德-氢氟烷烃[HFA]溶液气溶胶中),以确定肺部沉积。六名健康志愿者吸入一口40微克(呼气,相当于50微克呼气)的环赛奈德进行二维成像,两名健康志愿者吸入10口40微克的环赛奈德进行二维和三维成像。环奈德气溶胶通过含有HFA-134a作为推进剂的计量吸入器(MDI)给药。环来奈德在肺中的平均(+/-标准差)沉积(52% +/- 11%)高于在口腔/咽部(38% +/- 14%)。二维和三维成像显示环索内德到达肺的所有区域。3-D和2-D成像分别显示,外周区域的平均沉积百分比(47%和34%)高于中下区域(17%和30%)。吸入高达400微克的环奈德不会产生与药物相关的副作用。总之,使用HFA-134a作为推进剂通过计量吸入器给药的环来奈德提供了高肺沉积(>50%),更大的分布在肺周围区域,相对较低的口咽沉积。
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引用次数: 81
Factors influencing the in vitro deposition of tobramycin aerosol: a comparison of an ultrasonic nebulizer and a high-frequency vibrating mesh nebulizer. 影响妥布霉素气雾剂体外沉积的因素:超声雾化器与高频振动网状雾化器的比较。
Kenneth Manby Pedersen, Vagn Neerup Handlos, Lars Heslet, Henning Gjelstrup Kristensen

The aim of the study was to elaborate recommendations for inhalation during mechanical ventilation that could optimize delivery. Delivery of aerosols in vitro from nebulizers during mechanical ventilation is dependent on the dimensions of the ventilator circuit, the nebulizer type, and the ventilator settings. A review of the literature shows that some ventilator settings have a larger influence on the amount of aerosol delivered than others. It has been shown in an in vitro model that the factors influencing delivered aerosol are the ventilator flow rate, the diameter of the endotracheal tube, and the time spent in inspiration (all p < 0.05). Two different nebulizer types were used in the study: an ultrasonic nebulizer (SUN 345) and a high-frequency vibrating mesh nebulizer (Aeroneb Pro). No difference in the amount delivered was seen with different nebulizer types (p = 0.215). For optimizing the amount delivered, the largest possible flow, endotracheal tube, and time spent in inspiration should be used.

该研究的目的是详细介绍机械通气期间的吸入建议,以优化分娩。在机械通气过程中,体外气溶胶从雾化器输送取决于呼吸机回路的尺寸、雾化器类型和呼吸机设置。对文献的回顾表明,一些呼吸机的设置对气溶胶释放量的影响比其他设置更大。体外模型显示,影响输送气溶胶的因素为呼吸机流量、气管插管直径和吸气时间(均p < 0.05)。研究中使用了两种不同类型的雾化器:超声波雾化器(SUN 345)和高频振动网状雾化器(Aeroneb Pro)。不同雾化器类型的给药量没有差异(p = 0.215)。为了优化产出量,应该使用最大可能的流量、气管插管和吸气时间。
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引用次数: 29
Steroid effects on mucociliary clearance in outpatient asthma. 类固醇对门诊哮喘纤毛粘膜清除的影响。
Rasik V Shah, Mohammad Amin, Sanjay Sangwan, Gerald C Smaldone

Asthma, a chronic inflammatory condition of airways, responds to therapy with anti-inflammatory medications, for example, inhaled (ICS) and/or systemic (SS) corticosteroids. It is associated with impaired clearance of airway secretions. We studied effects of ICS and SS on mucociliary clearance (MC) in outpatient asthma through an in vivo, randomized, placebo-controlled single blind study with patients acting as their own control. Using a gamma camera and radiolabeled aerosol, we measured MC at baseline, after 4 days of nebulized treatment and after 5 days of oral prednisone. MC was expressed as percent of retained activity over time. Spirometry was performed before each MC study. Treatment with nebulized budesonide did not affect MC or forced expiratory volume at 1 sec (FEV1). Treatment with SS was associated with a significant improvement in MC at 24 h (baseline, 41 +/- 6; post-SS, 36 +/- 5; p = 0.04). Post hoc analysis revealed that MC changed only in those patients with significant changes in deposition (specific Central-to-Peripheral ratio C/P--baseline, 1.57 +/- 0.16; post-SS, 1.73 +/- 0.21; n = 6; p = 0.05), suggesting that the changes in MC were not directly related to therapy. In outpatient asthma, MC is unaffected by 4-5 days of anti-inflammatory therapy in spite of significant changes in FEV1.

哮喘是呼吸道的一种慢性炎症,对抗炎药物治疗有反应,例如吸入(ICS)和/或全身(SS)皮质类固醇。它与气道分泌物的清除受损有关。我们通过一项体内、随机、安慰剂对照的单盲研究,研究了ICS和SS对门诊哮喘患者粘液纤毛清除(MC)的影响,患者作为自己的对照。在雾化治疗4天和口服强的松治疗5天后,我们使用伽马照相机和放射性标记气溶胶测量了基线时的MC。MC表示为随着时间的推移保留活动的百分比。在每次MC研究前进行肺活量测定。布地奈德雾化治疗不影响MC或1秒用力呼气量(FEV1)。SS治疗与24小时MC显著改善相关(基线41 +/- 6;后ss, 36 +/- 5;P = 0.04)。事后分析显示,MC仅在沉积显著变化的患者中发生变化(特异性中央与外周比值C/P—基线,1.57 +/- 0.16;后ss, 1.73 +/- 0.21;N = 6;p = 0.05),表明MC的改变与治疗无直接关系。在门诊哮喘患者中,尽管FEV1发生了显著变化,但4-5天的抗炎治疗对MC没有影响。
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引用次数: 9
Rationale for the selection of an aerosol delivery system for gene delivery. 选择气溶胶传递系统进行基因传递的基本原理。
Yvonne K Lentz, Thomas J Anchordoquy, Corinne S Lengsfeld

Genetic therapeutics show great promise toward the treatment of illnesses associated with the lungs; however, current methods of delivery such as jet and ultrasonic nebulization decrease the activity and effectiveness of these treatments. Extremely low transfection rates exhibited by non-complexed plasmid DNA in these nebulizers have been primarily attributed to poor translocation and loss of molecular integrity as a consequence of shear-induced degradation. Current research focusing on methods to increase transfection rates via the pulmonary delivery route has largely concentrated on the incorporation of carbon dioxide in the air stream to increase breath depth as well as the addition of cationic agents that condense DNA into compact, ordered complexes. The purpose of this study was to examine the impact of several classic as well as the latest atomization devices on the structure of non-complexed DNA. Various sizes of plasmid and cosmid DNA were processed through an electrostatic spray, ultrasonic nebulizer, vibrating mesh nebulizer, and jet nebulizer. Results varied dramatically based upon atomization device as well as DNA size. This may explain the inefficiency experienced by genetic therapeutics during pulmonary delivery. More importantly, this suggests that the selection of an atomization device should consider DNA size in order to achieve optimal gene delivery to the lungs.

基因疗法在治疗与肺部有关的疾病方面显示出巨大的希望;然而,目前的输送方法,如喷射和超声雾化降低了这些治疗的活性和有效性。在这些喷雾器中,非复杂质粒DNA表现出极低的转染率,主要归因于剪切诱导降解导致的易位不良和分子完整性丧失。目前研究的重点是通过肺输送途径提高转染率的方法,主要集中在空气流中加入二氧化碳以增加呼吸深度,以及添加阳离子剂将DNA凝聚成紧凑有序的复合物。本研究的目的是研究几种经典的以及最新的雾化装置对非复杂DNA结构的影响。采用静电喷雾、超声波喷雾、振动网喷雾、喷射喷雾等方法对不同大小的质粒和粒状DNA进行处理。根据雾化装置和DNA大小的不同,结果变化很大。这也许可以解释基因治疗在肺部分娩时的低效率。更重要的是,这表明选择雾化装置应考虑DNA的大小,以实现最佳的基因输送到肺部。
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引用次数: 47
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Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine
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