Exploring the fate of inhaled monoclonal antibody in the lung parenchyma by microdialysis.

Therapeutic antibodies (Abs) are emerging as major drugs to treat respiratory diseases, and inhalation may provide substantial benefits for their delivery. Understanding the behavior of Abs after pulmonary deposition is critical for their development. We investigated the pharmacokinetics of a nebulized Ab by continuous sampling in lung parenchyma using microdialysis in non-human primates. We defined the optimal conditions for microdialysis of Ab and demonstrated that lung microdialysis of Ab is feasible over a period of several days. The concentration-profile indicated a two-phase non-linear elimination and/or distribution of inhaled mAbX. Lung exposition was higher than the systemic one over a period of 33 hours and above MabX affinity for its target. The microdialysis results were supported by an excellent relationship with dosages from lung extracts.

Development of a drug delivery system for efficient alveolar delivery of a neutralizing monoclonal antibody to treat pulmonary intoxication to ricin.

The high toxicity of ricin and its ease of production have made it a major bioterrorism threat worldwide. There is however no efficient and approved treatment for poisoning by ricin inhalation, although there have been major improvements in diagnosis and therapeutic strategies. We describe the development of an anti-ricin neutralizing monoclonal antibody (IgG 43RCA-G1) and a device for its rapid and effective delivery into the lungs for an application in humans. The antibody is a full-length IgG and binds to the ricin A-chain subunit with a high affinity (KD=53pM). Local administration of the antibody into the respiratory tract of mice 6h after pulmonary ricin intoxication allowed the rescue of 100% of intoxicated animals. Specific operational constraints and aerosolization stresses, resulting in protein aggregation and loss of activity, were overcome by formulating the drug as a dry-powder that is solubilized extemporaneously in a stabilizing solution to be nebulized. Inhalation studies in mice showed that this formulation of IgG 43RCA-G1 did not induce pulmonary inflammation. A mesh nebulizer was customized to improve IgG 43RCA-G1 deposition into the alveolar region of human lungs, where ricin aerosol particles mostly accumulate. The drug delivery system also comprises a semi-automatic reconstitution system to facilitate its use and a specific holding chamber to maximize aerosol delivery deep into the lung. In vivo studies in monkeys showed that drug delivery with the device resulted in a high concentration of IgG 43RCA-G1 in the airways for at least 6h after local deposition, which is consistent with the therapeutic window and limited passage into the bloodstream.

Effect of formulation on the stability and aerosol performance of a nebulized antibody.

Most monoclonal antibodies (mAbs) are administered to patients intravenously to ensure high bioavailability as rapidly as possible. The airways, however, are an attractive delivery route for mAbs for the treatment of lung diseases, making it possible to increase their concentration in the target organ while limiting their systemic passage. Several challenges must be overcome for translation into clinical practice. For example, the drug and device must be paired for the efficient and reliable deposition of a pharmacologically active and safe mAb in the lung region of interest. Mesh nebulizers appear to be the most effective aerosol-producing devices for delivering large amounts of biopharmaceutical while limiting protein instability during nebulization. We used metrological and analytic methods to analyze the effect of both antibody concentration and surfactant addition on aerosol performance and antibody integrity. These two factors had a limited effect on aerosol performance, but affected antibody aggregation. The addition of surfactants to antibody formulations at concentrations appropriate for lung administration markedly reduced the formation of medium or large aggregates, as shown by dynamic light scattering and fluorescence microscopy. Aggregation was also dependent on the type of mesh nebulizer, highlighting the need to optimize drug and device together.

Postural control adjustments during progressive inclination of the support surface in children.

One of the most important postural challenges in daily life is to continuously correct the destabilizing torque due to gravity that accelerates the body further away from the upright position. This study examined children's (7.9 years old) (n=7) and adults' (n=10) capacity to generate continuous corrective torque during a progressive perturbation. The experimental task was to maintain an upright quiet standing on a platform that gradually and slowly toes-down tilted to a maximum of 14° without visual cues. The vertical forces applied on the platform and the electromyograms from the tibialis anterior and the gastrocnemius were measured. The results showed that children had a different postural response to the perturbation than adults. When the platform was stationary before the inclination, children shifted their body weight backward whereas adults had a more balanced distribution of their weight. During the inclination, children applied a stronger forward force, suggesting a larger postero-anterior displacement of their body weight. Muscular activities were higher in children for both the tibialis anterior and the gastrocnemius, and their tibialis anterior activation profile was different. In conclusion, this study showed that in children aged from 7 to 10 years old neuromuscular responses were not mature enough to generate continuous postural corrective torque in response to the perturbation.

Preparative study regarding the implementation of a muscular fatigue model in a virtual task simulator.

Muscle fatigue is considered as one of the major risk factors for developing musculoskeletal disorders. The aim of this project was to select an adequate fatigue assessment model for an implementation in Dassault Systemes digital human modeling software. A review of existing MET models has been done resulting in a decision to use the extended Ma's model (2010). In this project, only shoulder and elbow joints have been tested and more subjects will be necessary for further validation. The model has been compared to several endurance time (ET) static studies. Two dynamic experiments were also performed by two different subjects. The results showed that because of the inter-individual variability, a simple prediction curve or value, can't well predict individual measured ET (or task failure). There is a need for a chart representation which also shows standard deviation (SD) range. Considering the SD range, the results were included in the prediction. Thus, this range may help the human factors expert to nuance the prediction results while considering environment factors and some realities specific to the industry.

Perceived safety and biomechanical stress to the lower limbs when stepping down from fire fighting vehicles.

Injuries related to emergency vehicles represent 19% of compensated work accidents for fire fighters, 37% of which occur while stepping down from their vehicles. This study compared the impact forces, the use of upper limbs and the perception of danger of fire fighters as they step down from five different locations on fire trucks. The results show that stepping down from the crew cab facing the street produces impact forces averaging 3.2 times the subject's body weight, but is also perceived as the safest way to descend in one of the two groups of fire fighters that participated in the study. Stepping down from the same location, but facing the truck, produced significantly less impact force and a better distribution of the energy over time. This may be achieved through better control of the descending leg, ankle flexion, and the use of grab bars. A re-design of the access to emergency vehicles should take into account both the safety needs and reduction in biomechanical stress of fire fighters.