Chelation Modeling of a Plutonium-238 Inhalation Incident Treated with Delayed DTPA.

This work describes an analysis, using a previously established chelation model, of the bioassay data collected from a worker who received delayed chelation therapy following a plutonium-238 inhalation. The details of the case have already been described in two publications. The individual was treated with Ca-DTPA via multiple intravenous injections and then nebulizations beginning several months after the intake and continuing for four years.

Modelling DTPA therapy following Am contamination in rats.

A major challenge in modelling the decorporation of actinides (An), such as americium (Am), with DTPA (diethylenetriaminepentaacetic acid) is the fact that standard biokinetic models become inadequate for assessing radionuclide intake and estimating the resulting dose, as DTPA perturbs the regular biokinetics of the radionuclide. At present, most attempts existing in the literature are empirical and developed mainly for the interpretation of one or a limited number of specific incorporation cases. Recently, several approaches have been presented with the aim of developing a generic model, one of which reported the unperturbed biokinetics of plutonium (Pu), the chelation process and the behaviour of the chelated compound An-DTPA with a single model structure.

Chelation therapy with 3,4,3-Li(1,2-HOPO) after pulmonary exposure to plutonium in rats.

Internal exposure to plutonium can occur through inhalation for the nuclear worker, but also for the public if the radionuclide was released into the atmosphere in the context of a nuclear accident or terrorist attack. DieThylenetriaminePentaAcetic acid (DTPA) is currently still the only authorized chelator that can be used to decorporate internalized plutonium. The Linear HydrOxyPyridinOne-based ligand named 3,4,3-Li(1,2-HOPO) remains the most promising drug candidate to replace it in the hopes of improving chelating treatment.

Excretion of Pu-238 during Long-term Chelation Therapy by Repeated DTPA Inhalation.

An individual underwent an extensive diethylenetriaminepentaacetate (DTPA) chelation therapy that started several months after plutonium incorporation, most likely by inhalation of a soluble compound. After receiving multiple intravenous infusions of DTPA, the patient continued the treatment by pulmonary delivery of aerosolized DTPA. The purpose of the present work is to provide and discuss the bioassay data obtained during the DTPA aerosol therapy and compare them with those under the DTPA infusion therapy that have been largely interpreted elsewhere.

Interpretation of Enhanced Fecal and Urinary Plutonium Excretion Data under a 2-y Regular DTPA Treatment Started Months after Intake.

In a worker who had internalized plutonium, most likely through inhalation of a somewhat soluble compound, an extensive diethylenetriaminepentaacetate (DTPA) treatment regimen was initiated several months after contamination. Numerous radiotoxicological analyses were performed in both fecal and urinary specimens collected, sometimes for three consecutive days after DTPA administration. Activity measurements showed the continued effectiveness of DTPA intravenous infusions in removing plutonium from tissues of retention even if the treatment regimen started very belatedly after contamination.

Comparison of Local and Systemic DTPA Treatment Efficacy According to Actinide Physicochemical Properties Following Lung or Wound Contamination in the Rat.

In cases of occupational accidents in nuclear facilities or subsequent to terrorist activities, the most likely routes of internal contamination with alpha-particle emitting actinides, such as plutonium (Pu) and americium (Am), are by inhalation or following wounding. Following contamination, actinide transfer to the circulation and subsequent deposition in skeleton and liver depends primarily on the physicochemical nature of the compound. The treatment remit following internal contamination is to decrease actinide retention and in consequence potential health risks, both at the contamination site and in systemic retention organs as well as to promote elimination.

DTPA-Coated Liposomes as a New Delivery Vehicle for Plutonium Decorporation.

Administration of diethylenetriaminepentaacetic acid (DTPA) is the treatment approach used to promote the decorporation of internalized plutonium. Here we evaluated the efficacy of PEGylated liposomes coated with DTPA, primarily designed to prevent enhanced plutonium accumulation in bones, compared to marketed nonliposomal DTPA and liposomes encapsulating DTPA. The comparative effects were examined in terms of reduction of activity in tissues of plutonium-injected rats.

Chelation Treatment by Early Inhalation of Liquid Aerosol DTPA for Removing Plutonium after Rat Lung Contamination.

Occupational contamination is a potential health risk associated with plutonium inhalation. DTPA remains the chelating drug of choice to decorporate plutonium. In this study, plutonium was found to be more effectively removed from lungs by a single inhalation of nebulized DTPA solution at only 1.

Americium biodistribution in rats after wound contamination with different physicochemical forms in the presence or absence of plutonium: analyses using STATBIODIS.

Americium (Am) biodistribution data obtained after wound contamination in rats were analysed to evaluate and quantify the influence of different physicochemical forms of Am in the presence or absence of plutonium (Pu). The biodistribution data were individual Am daily urinary excretion and tissue retention. The data were analysed with STATBIODIS, a statistical tool developed in the laboratory and based on the R language.

Delivery of DTPA through Liposomes as a Good Strategy for Enhancing Plutonium Decorporation Regardless of Treatment Regimen.

In this study, we assessed the efficacy of unilamellar 110-nm liposomes encapsulating the chelating agent diethylenetriaminepentaacetic acid (DTPA) in plutonium-exposed rats. Rats were contaminated by intravenous administration of the soluble citrate form of plutonium. The comparative effects of liposomal and free DTPA at similar doses were examined in terms of limitation of alpha activity burden in rats receiving various treatment regimens.

Decorporation Approach after Rat Lung Contamination with Plutonium: Evaluation of the Key Parameters Influencing the Efficacy of a Protracted Chelation Treatment.

While the efficacy of a protracted zinc (Zn)- or calcium (Ca)-diethylenetriaminepentaacetic acid (DTPA) treatment in reducing transuranic body burden has already been demonstrated, questions about therapeutic variables remain. In response to this, we designed animal experiments primarily to assess both the effect of fractionation of a given dose and the effect of the frequency of dose fraction, with the same total dose. In our study, rats were contaminated intravenously with plutonium (Pu) then treated several days later with Ca-DTPA given at once or in various split-dose regimens cumulating to the same total dose and spread over several days.

Decorporation of Pu/Am Actinides by Chelation Therapy: New Arguments in Favor of an Intracellular Component of DTPA Action.

Diethylenetriaminepentaacetic acid (DTPA) is currently still the only known chelating drug that can be used for decorporation of internalized plutonium (Pu) and americium (Am). It is generally assumed that chelation occurs only in biological fluids, thus preventing Pu/Am deposition in target tissues. We postulate that actinide chelation may also occur inside cells by a mechanism called "intracellular chelation".

Medical countermeasures after a radiological event: an update from the CATO project.

Purpose: As part of the European project 'CBRN crisis management: Architecture, Technologies and Operational Procedures' (CATO), an open Toolbox is in development that will address the needs of all stakeholders from first responders to decision makers. A database on chemical, biological, radiological and nuclear (CBRN) threats, including information on medical countermeasures, will be integrated in this Toolbox.

Results And Conclusions: After a radiological accident, review of national and international recommendations for the major countermeasures (stable iodine, Prussian Blue, and diethylenetriaminepentaacetic acid [DTPA]) showed that discrepancies in treatment protocols and open questions remain: How to proceed in case of repeated release of radioiodines? Which dosage for Prussian Blue? For which radionuclides is DTPA really effective? This paper brings elements to answer these questions.

Decorporation approach following rat lung contamination with a moderately soluble compound of plutonium using local and systemic Ca-DTPA combined chelation.

Decorporation efficacy of prompt pulmonary delivery of DTPA dry powder was assessed following lung contamination with plutonium nitrate and compared to an intravenous injection of DTPA solution and a combined administration of both DTPA compounds. In addition, efficacy of a delayed treatment was assessed. In case of either early or late administration, insufflated DTPA was more efficient than intravenously injected DTPA in reducing the plutonium lung burden due to its high local concentration.

Plutonium behavior after pulmonary administration according to solubility properties, and consequences on alveolar macrophage activation.

The physico-chemical form in which plutonium enters the body influences the lung distribution and the transfer rate from lungs to blood. In the present study, we evaluated the early lung damage and macrophage activation after pulmonary contamination of plutonium of various preparation modes which produce different solubility and distribution patterns. Whatever the solubility properties of the contaminant, macrophages represent a major retention compartment in lungs, with 42 to 67% of the activity from broncho-alveolar lavages being associated with macrophages 14 days post-contamination.

Preferential decorporation of americium by pulmonary administration of DTPA dry powder after inhalation of aged PuO(2) containing americium in rats.

After inhalation of plutonium oxides containing various percentages of americium in rats, we identified an acellular transient pulmonary compartment, the epithelial lining fluid (ELF), in which a fraction of actinide oxides dissolve prior to absorption and subsequent extrapulmonary deposit. Chelation therapy is usually considered to be poorly efficient after inhalation of actinide oxides. However, in the present study, prompt pulmonary administration of diethylenetraminepentaacetic acid (DTPA) as a dry powder led to a decrease in actinide content in ELF together with a limitation of bone and liver deposits.

Drosophila translational elongation factor-1gamma is modified in response to DOA kinase activity and is essential for cellular viability.

Drosophila translational elongation factor-1gamma (EF1gamma) interacts in the yeast two-hybrid system with DOA, the LAMMER protein kinase of Drosophila. Analysis of mutant EF1gamma alleles reveals that the locus encodes a structurally conserved protein essential for both organismal and cellular survival. Although no genetic interactions were detected in combinations with mutations in EF1alpha, an EF1gamma allele enhanced mutant phenotypes of Doa alleles.

Acute and persisting Th2-like immune response after fractionated colorectal gamma-irradiation.

Aim: To investigate if an immune imbalance may account for the development and progression of chronic radiation enteritis. We analyzed the Th1/Th2 immune response profile early and 6 mo after fractionated colorectal irradiation.

Methods: A rat model of fractionated colorectal gamma-irradiation (4-Gy fractions, 3 fractions per week) was designed to investigate the effects of cumulative dose on inflammatory mediators (cytokines and chemokines) and immune response (Th1/Th2 profile and immunosuppressive mediator IL-10) during acute (early) response and 6 mo after the end of fractionated irradiation (chronic response).

Activation of alveolar macrophages after plutonium oxide inhalation in rats: involvement in the early inflammatory response.

Alveolar macrophages play an important role in the distribution, clearance and inflammatory reactions after particle inhalation, which may influence long-term events such as fibrosis and tumorigenesis. The objectives of the present study were to investigate the early inflammatory events after plutonium oxide inhalation in rats and involvement of alveolar macrophages. Lung changes were studied from 3 days to 3 months after inhalation of PuO2 of different isotopic compositions (70% or 97% 239Pu) and initial lung deposits (range 2.

Reduction of peroxisome proliferation-activated receptor gamma expression by gamma-irradiation as a mechanism contributing to inflammatory response in rat colon: modulation by the 5-aminosalicylic acid agonist.

Radiation-induced intestinal injuries, including inflammation and immune response, remain a limiting factor in the effectiveness of pelvic radiotherapy and in the patient's quality of life during and after treatment. Peroxisome proliferation-activated receptor (PPAR) agonists are now emerging as therapeutic drugs for various inflammatory diseases that are characterized by impaired PPAR expression. The purpose of this study was to investigate the profile of PPAR expression in rat colonic mucosa 3 and 7 days after abdominal gamma-irradiation (10 Gy).

Caffeic acid phenethyl ester modifies the Th1/Th2 balance in ileal mucosa after gamma-irradiation in the rat by modulating the cytokine pattern.

Aim: To pharmacologically modulate Th polarization in the ileum exposed to ionizing radiation by using the immuno-modulatory/apoptotic properties of Caffeic Acid Phenethyl Ester (CAPE).

Methods: Rats received CAPE (30 mg/kg) treatment ip 15 min prior to intestinal 10 Gy gamma-irradiation and once a day for a 6 d period after irradiation. Expression of genes implicated in Th differentiation in ileal mucosa (IL-23/IL-12Rbeta2), Th cytokine responses (IFN-gamma, IL-2, IL-4, IL-13), Th migratory behaviour (CXCR3, CCR5, CCR4), Th signalling suppressors (SOCS1, SOCS3), transcription factor (T-Bet, GATA-3) and apoptosis (FasL/Fas, TNF/TNFR, XIAP, Bax, caspase-3) was analyzed by RT-PCR 6 h and 7 d post-irradiation.