Direct lung delivery of a dry powxer formulation, of DTPA with improved aerosolization properties : effect on lung and systemic decorporation of plutonium

International audienceDTPA, an actinide chelating agent, has demonstrated its ability to complex plutonium (Pu) and to facilitate its urinary excretion after internal contamination. This process, known as decorporation is crucial to diminish the burden of Pu in the body. The ability to deliver a chelating agent directly to the alveolar region may increase its local concentration as compared to systemic delivery and therefore increase the extent of decorporation. Second, inhalation offers the potential for needle-free, systemic delivery of small molecules and would be convenient in case of nuclear accident as a first pass emergency treatment. To benefit from the improvement of inhalation technology, we have formulated DTPA into porous particles by spray-drying with dl-Leucine, DPPC and ammonium bicarbonate. The optimized particles possess a volume mean geometric diameter around 4.5 μm and crumpled paper morphology. The in vitro aerodynamic evaluation shows that about 56% of the powder should deposits in the lungs, with about 27% in the alveolar region, an improvement as compared with the micronized powder available with the Spinhaler®. After pulmonary administration to rats contaminated with PuO2, a 3-fold increase of the Pu urinary excretion was observed, but the dissolution of PuO2 in the lungs was not enhanced

Intracellular Pu Decorporation in Rat by Different DTPA Formulations

Cellular internalisation of DTPA appears negligible. Thus, a fast urinary excretion of Pu-DTPA is observed after treatments, but a slow excretion also occurs, explained by Pu-DTPA retention within the interstitium (2.5% of Pu-DTPA, half-life 1 week). One day after 14C-DTPA i.v., 1-2% of the activity was retained in perfused soft tissues, demonstrating its cellular internalisation, whereas blood DTPA was 0.025%. Encapsulation of DTPA has been proposed to improve its cellular internalisation, and a nearly total liver decorporation was obtained using stealth® 100 nm-liposomes. This study estimates intracellular decorporation of Pu by different DTPA formulations. First, a biokinetic study was performed after Pu-DTPA i.v., to help interpretation of decorporation data. About 99% of Pu was excreted via urines for the first 3 days, followed by residual excretion. Similar Pu activities were measured in skeleton, liver, kidneys and urine of day 7 (0.1%). These values, quite different than those measured after Pu-citrate i.v., demonstrated the great stability of Pu-DTPA, in extra and intracellular environments. When DTPA solutions were given i.v., 1 hour after Pu-citrate i.v., both fast and slow excretion (half-life 3-4 days) of Pu-DTPA were observed. The ratio between fast and slow excretions increased with DTPA dosage and, at similar dosage, this ratio was much lower after pulmonary insufflation of dry DTPA powder than after i.v.. Therefore, fast excretion depends on DTPA concentration in blood, whereas slow excretion, associated with intracellular DTPA, depends on total DTPA administered. This was confirmed after specific liver or lung contamination. Then, most of the urinary decorporation involved a slow process observed for 1 month. Moreover, half-life of slow excretion appeared to vary depending on tissues. In a last experiment, a treatment was performed 1 day before Pu-citrate i.v. (30 and 300µmol.kg-1). A decorporation similar to a standard treatment (30µmol.kg-1, i.v. at+1h) was observed for the highest dosage (~50%), whereas a 25 % decorporation was obtained for the lowest dosage. Altogether, these results underline the importance of intracellular DTPA in the decorporation process which will be discuss in terms of modelling and radioprotection

Modélisation de la décorporation du Pu/am par le dtpa

A new tool has been developed to optimize DTPA efficacy as concerns reduction of effective dose after 239Pu wound. For example, the simulations show, for moderately soluble compounds (type M), a 1/3 decrease of effective dose is obtained after repeated early treatment (24 i.v. for 4 months), whereas a decrease by a factor 5 can be reached if treatments continue for 5 years at 2 week interval. By contrast, for poorly soluble compounds (type S), negligible efficacy is observed after early treatments, and a 3 time decrease of dose is obtained for treatments performed at 2 week interval for 50 years. Some of the hypotheses retained for modelling DTPA decorporation are validated from new experimental data published recently, and structure of a new model which can be applied both to Pu and Am is reported, taking into account urinary and faecal excretion, structure being suitable for different doses of DTPA and using various galenic forms. © 2009 EDP Sciences.Un nouvel outil a été développé pour optimiser l’efficacité des traitements par le DTPA après blessure, sur la base d’une réduction de la dose efficace engagée. Les simulations montrent, notamment, que pour du 239Pu modérément soluble (type M), des traitements précoces (24 i.v.) étalées sur 4 mois permettent une réduction d’un tiers de la dose, alors que leur prolongement sur 5 ans, avec un intervalle de 2 semaines, peut diminuer la dose d’un facteur 5. En revanche, pour des composés peu solubles (type S), l’efficacité des traitements précoces est négligeable et un gain dosimétrique d’un facteur 3 n’est atteint que pour des traitements effectués 2 fois par mois durant 50 ans. Certaines des hypothèses retenues pour la modélisation ont été validées par les résultats d’expérimentations animales récemment publiés. Enfin, la structure d’un nouveau modèle applicable à la fois au Pu et à l’Am est rapportée, structure tenant compte de la décorporation urinaire et fécale de ces actinides et qui pourrait être adapté à différentes posologies et formes galéniques de DTPA

Socio-economic characterisation of agriculture models

Analyses of transition towards a more sustainable agriculture often identify two different pathways that can be linked to either strong or weak sustainability. In this interdisciplinary work, we aim at overcoming this narrow choice between these two alternatives, by offering a socio-agronomic characterisation of multiple agriculture models that currently coexist in Western economies. We use an agronomic typology of farming systems based on the role of exogenous inputs and endogenous ecosystem services in agricultural production, and on the degree of embeddedness of farming systems within local/global food systems. This typology identifies six agriculture models that we analyse in socio-economic terms. We then clarify the structuring principles that organise these models, and the social values underpinning their justification. This analysis enables us to discuss the efficiency conditions of political instruments