Gas transport during in vitro and in vivo preclinical testing of inert gas therapies

Abstract

New gas therapies using inert gases such as xenon and argon are being studied, which require in vitro and in vivo preclinical experiments. Examples of the kinetics of gas transport during such experiments are analyzed in this paper. Using analytical and numerical models, we analyze an in vitro experiment for gas transport to a 96 cell well plate and an in vivo delivery to a small animal chamber, where the key processes considered are the wash-in of test gas into an apparatus dead volume, the diffusion of test gas through the liquid media in a well of a cell test plate, and the pharmacokinetics in a rat. In the case of small animals in a chamber, the key variable controlling the kinetics is the chamber wash-in time constant that is a function of the chamber volume and the gas flow rate. For cells covered by a liquid media the diffusion of gas through the liquid media is the dominant mechanism, such that liquid depth and the gas diffusion constant are the key parameters. The key message from these analyses is that the transport of gas during preclinical experiments can be important in determining the true dose as experienced at the site of action in an animal or to a cell.

Neuroprotection of dopamine neurons by xenon against low-level excitotoxic insults is not reproduced by other noble gases

“…Note that we cannot exclude, however, that favorable PK properties also contributed to the efficacy of xenon. In particular, in this in vitro experimental set-up, the concentrations of xenon at the level of the cell layer and the time necessary to reach these concentrations may be important factors for neuroprotection (Katz et al 2016). Theoretical calculations made with gaseous atmospheres containing noble gases at a concentration of 50%, revealed that xenon was the slowest of all these gases to saturate the culture medium.…”

“…The mathematical model and experimental parameters used to perform calculations have been described in detail in one of our previous papers (Katz et al 2016). In brief, the transport of the Noble gas through the liquid medium to the cells is modeled as a one-dimensional diffusion problem:…”

Gaseous nitric oxide failed to inhibit the replication cycle of SARS-CoV-2 in vitro

“…Exposure of cell to gasses has been designed inspired from previously described methods of NO administration (Miller et al, 2009b) integrating lessons learnt from our models of in vitro gas exposure [ 26 ]. Infected cells were placed within hermetically sealed Plexiglas incubation chambers (220 × 220 × 194mm) with separate gas entry and exit ports allowing a continuous flow of gaseous NO through the chamber.…”

“…Clearly, only a small percentage of this NO will be available to cells. In particular, the solubility of NO in the cell medium (the Ostwald solubility coefficient in water for NO is 0.04128 [ 28 ] ( Table 1 , pg 229) is a ceiling on the potential exposed concentration [ 26 ].…”

A physiologically based model for denitrogenation kinetics

“…This study employs a physiologically based pharmacokinetic model developed by Lockwood 7 for anesthetic gases that has been employed within the Simbiology Toolbox of MATLAB (Mathworks, Natick, MA, USA). 8 The model considers all transport to be perfusion limited, that there is no metabolism, and all excretion is through expiration via the lung. Here we present the partition coefficients for N 2 ( Table 1 ) and a detailed explanation of the compartment consisting of the alveolar gas exchange region of the lung ( Figure 1 ) as these are the results comparable to the published experimental data by Lundin.…”