Ira Katz

There is an increase in pressure necessary to drive xenon insufflation due to increased flow resistance that results from the elevated density and viscosity of xenon-oxygen mixtures. It had been suggested that these higher pressures could be clinically relevant, though results from animal experiments demonstrate otherwise. Numerical simulations in a healthy adult morphology were performed to investigate how these elevated pressures are distributed within the respiratory tract and patient interface as a function of gas concentration, flow rate and endotracheal tube size. The results confirm that there is indeed an increase in pressure needed to drive xenon anesthesia compared to air or oxygen ventilation and that the differences occurred primarily across the endotracheal tube and were found to be much less significant within the lung itself. For all parameters studied, pressure differences between xenon-oxygen and air or oxygen ventilation were found to be negligible in the acinus fo...

Medical air (MA) is widely used in hospitals, often manufactured onsite by compressing external ambient air and supplied through a local network piping system. Onsite production gives rise to a risk of impurities that are governed by the same pharmacopoeia purity standards applicable to commercially produced MA. The question to be addressed in this paper is how to assess if a lack of purity poses a medical problem? The MA produced onsite at a major Canadian hospital was monitored for carbon dioxide (CO) and other impurity gases at high frequency (one per minute) over a two-month period. The average CO concentration was 255 ppm. The United States Pharmacopeia (USP) threshold of 500 ppm was exceeded during 1% of the total study period, and the average while exceeding the threshold was 526 ppm. The maximum concentration was 634 ppm. To our knowledge, there is only one study that evaluated the effects suffered by respiratory patients of elevated nitric oxide in MA; thus, it is not clear...

The chemically inert noble gases display a surprisingly rich spectrum of useful biological properties. Relatively little is known about molecular mechanisms behind these effects. It is clearly not feasible to conduct large numbers of pharmacological experiments on noble gases to identify activity. Computational studies of binding of noble gases and proteins can address this paucity of information and provide insight into mechanisms of action. We employed bespoke computational grid calculations to predict the positions of energy minima in the interactions of noble gases with diverse proteins. The method was validated by quantifying how well simulations could predict binding positions in 131 diverse protein x-ray structures containing 399 Xe and Kr atoms. We found excellent agreement between calculated and experimental binding positions of noble gases. 94% of all crystallographic xenon atoms were within 1 Xe VdW diameter of a predicted binding site and 97% lay within 2 VdW diameters. ...

The 21st Congress for the International Society for Aerosols in Medicine included, for the first time, a session on Pulmonary Delivery of Therapeutic and Diagnostic Gases. The rationale for such a session within ISAM is that the pulmonary delivery of gaseous drugs in many cases targets the same therapeutic areas as aerosol drug delivery, and is in many scientific and technical aspects similar to aerosol drug delivery. This article serves as a report on the recent ISAM congress session providing a synopsis of each of the presentations. The topics covered are the conception, testing, and development of the use of nitric oxide to treat pulmonary hypertension; the use of realistic adult nasal replicas to evaluate the performance of pulsed oxygen delivery devices; an overview of several diagnostic gas modalities; and the use of inhaled oxygen as a proton magnetic resonance imaging (MRI) contrast agent for imaging temporal changes in the distribution of specific ventilation during recover...

The noble gases represent an intriguing scientific paradox. They are extremely inert chemically but display a remarkable spectrum of clinically useful biological properties. Despite a relative paucity of knowledge of their mechanisms of action, some of the noble gases have been used successfully in the clinic. Studies with xenon have suggested that the noble gases as a class may exhibit valuable biological properties such as anaesthesia; amelioration of ischemic damage; tissue protection prior to transplantation; analgesic properties; and a potentially wide range of other clinically useful effects. Xenon has been shown to be safe in humans, and has useful pharmacokinetic properties such as rapid onset, fast wash out etc. The main limitations in wider use are that: many of the fundamental biochemical studies are still lacking; the lighter noble gases are likely to manifest their properties only under hyperbaric conditions, impractical in surgery; and administration of xenon using con...

Development of a new drug for the treatment of lung disease is a complex and time consuming process involving numerous disciplines of basic and applied sciences. During the 2015 Congress of the International Society for Aerosols in Medicine, a group of experts including aerosol scientists, physiologists, modelers, imagers, and clinicians participated in a workshop aiming at bridging the gap between basic research and clinical efficacy of inhaled drugs. This publication summarizes the current consensus on the topic. It begins with a short description of basic concepts of aerosol transport and a discussion on targeting strategies of inhaled aerosols to the lungs. It is followed by a description of both computational and biological lung models, and the use of imaging techniques to determine aerosol deposition distribution (ADD) in the lung. Finally, the importance of ADD to clinical efficacy is discussed. Several gaps were identified between basic science and clinical efficacy. One gap...

ABSTRACT This work describes the development of an experimental setup that allows rapid determination of deposition characteristics of aerosols in different carrier gases and different geometries, based on particle size distribution measurements using the laser diffraction method. Isotonic saline solution was nebulized by a vibrating mesh nebulizer. The aerosol was introduced to a humidified gas stream of air or helium-oxygen. The particle size distributions at the inlet and outlet of a mouth-throat model were measured by laser diffractometry. Additionally, the nebulizer output and the deposition mass in the model were determined gravimetrically. The deposited percentage of the nebulizer output was highest in air. The laser diffractometry data showed increasing deposition of larger particles; in the given model particles larger than 9 mum in diameter deposited completely. Compared to the entering particle size distribution, however, the mass fraction in small particles was increased in the distribution leaving the model. The developed setup can be used for a rapid determination of deposition characteristics in different geometries and different gases. The shift towards small particles should be investigated further. Particle shrinkage via evaporation could be one of the reasons despite the humidification of the carrier gas.

... thermistor probe - Ira M Katz and Edward J Shaughnessy Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27706, USA ... A similar concept has been used by McConchie and Bullock (1975) in hot-film anemometry. ...

A mathematical model for inhaled aerosolized drugs is validated by comparisons of predicted particle deposition values with experimental data from adult subject inhalation exposure tests. The model is subsequently used to study the effects of ventilatory parameters on particle deposition patterns within the human lung. By altering breathing profiles, deposition values can be affected regarding quantity delivered and spatial location. Increased tidal volumes and breath-holding times increase deposition in the pulmonary region, while increased inspiratory flow rates increase deposition in the tracheobronchial region. Based upon fluid dynamics considerations (Reynolds numbers), an original method of partitioning the lung is also presented. The model has implications with regard to aerosol therapy, indicating that the efficacies of inhaled pharmacological drugs in the prophylaxis and treatment of airway diseases can be improved by regulating breathing profiles to deposit particles selec...

Analytical estimates of the respirable fractions on inhaled pharmaceutical aerosols are obtained by inertial sampling techniques. The respirable fraction may be defined as that portion of the particle size distribution less than a designated diameter. The diameter size below which particles were considered respirable in these studies was 6.4 microns. In clinical practice, a variety of particle size distributions may be related to a single respirable fraction. Herein, three respirable fractions were each defined by six particle size distributions. The deposition patterns of aerosols exhibiting these particle size characteristics were examined in a mathematical model. The analytically defined respirable fractions were compared with predicted lung deposition values. Under clearly defined breathing conditions, there is a correlation between the nominal respirable fraction and deposition. However, it was concluded that the variations which occur in breathing parameters within patient pop...

The inhalation of insulin for absorption into the bloodstream via the lung seems to be a promising technique for the treatment of diabetes mellitus. A fundamental issue to be resolved in the development of such insulin aerosol delivery systems is their efficiency (measured, for example, in terms of the amount of insulin absorbed in the blood compared to the total amount loaded into an inhalation device). A primary factor that could cause inefficiency of insulin absorption is deposition in the nonalveolated airways with subsequent removal from the lung via mucociliary clearance. Thus, a better understanding of the spatial distribution of insulin particle deposition in the lung can give guidance to the optimization of inhalation therapy. A mathematical model was used to study factors affecting the disposition of aerosolized insulin. The model calculates the trajectories of inhaled particles in the lung and has been validated by data from human subject experiments. Computer simulations...

A mathematical model of aerosol deposition has been developed for drug delivery protocols and used successfully to simulate inhalation exposure tests with human subjects. Therefore, we have used the validated model to address the delivery of inhaled pharmaceuticals as a function of disease-induced changes in airway structure. Clinical data from the literature had suggested that progressive lung disease associated with cystic fibrosis (CF) could compromise the successful administration of pharmacologic drugs used in its treatment, hence it was studied. We described the lungs of patients inflicted with CF by different morphologies (representing the processes of airway obstruction, infection and inflammation) than healthy (control) subjects. Affected ventilatory parameters were also examined to demonstrate their effects upon drug disposition. Particle distributions were computed on a generation-by-generation basis. Deposition patterns were dramatically affected by CF-produced alteratio...

Asthma presents serious medical problems of global proportions. Clinical data suggest that the disease occurs preferentially at regions designated by large (0 </= I </= 5), central (6 </= I </= 11), and small (12 </= I </= 16) airways, where I defines branching generations within lungs. Our straightforward hypothesis, therefore, was that the efficacies of pharmacologic drugs proposed for the treatment and prophylaxis of asthma would be enhanced via their targeted delivery to appropriate sites. Hence, we have developed a mathematical model describing the behavior and fate of inhaled aerosols. Original algorithms have been derived to detail the physical manifestation of asthma as distinct components of smooth muscle constriction and inflammation. We have conducted a systematic analysis of the relative effects of morphology, ventilation, and particle size on aerosol deposition. Different intensities of asthma were simulated by reducing airway diameters by prescribed amounts. To show the real clinical applications of modeling, we have also simulated the performance of a popular nebulizer. Regarding therapeutic implications, it is clear that disease-induced changes in airway morphologies have pronounced effects on the administration of inhaled drugs. Likewise, ventilation affects both the total aerosol mass deposited and its relative spatial distribution among airways. By formulating these effects, the computer code allows drugs (e.g., bronchodilators for constriction, steroids for inflammation) to be selectively deposited. We suggest, therefore, that the code can be used in a complementary manner with clinical studies and can be integrated into aerosol therapy regimens.

A computational fluid dynamics software package (FIDAP) has been employed to obtain three-dimensional flow data, which are used herein to calculate the trajectories of fluid particles. Our computations have demonstrated that the flow fields inside the larynx are very complex including eddies in the lumen and reverse motion along the surface. The effects of such flow fields will be to increase the residence times of entrained drug particles. Our computations have also demonstrated that the larynx has pronounced effects on the motion of air in the trachea.

Nonhuman primates may be used as human surrogates in inhalation exposure studies to assess either the (1) adverse health effects of airborne particulate matter or (2) therapeutic effects of aerosolized drugs and proteins. Mathematical models describing the behavior and fate of inhaled aerosols may be used to complement such laboratory investigations. For example, the optimal conditions, in terms of ventilatory parameters (e.g., breathing frequency and tidal volume) and aerosol characteristics (e.g., geometric size and density), necessary to target drug delivery to specific sites within the respiratory tract may be estimated a priori with models. In this work a mathematical description of the rhesus monkey (Macaca mulatta) lung is presented for use with an aerosol deposition model. Deposition patterns of 0.01- to 5-microm-diameter monodisperse aerosols within lungs were calculated for 3 monkey lung models (using different descriptions of alveolated regions) and compared to human lung results obtained using a previously validated mathematical model of deposition physics. Our findings suggest that there are significant differences between deposition patterns in monkeys and humans. The nonhuman primates had greater exposures to inhaled substances, particularly on the basis of deposition per unit airway surface area. However, the different alveolar volumes in the rhesus monkey models had only minor effects on aerosol dosimetry within those lungs. By being aware of such quantitative differences, investigators can employ the respective primate models (human and nonhuman) to more effectively design and interpret the results of future inhalation exposure experiments.