ABSTRACT
PURPOSE: Prussian blue is an antidote indicated for the treatment of internal cesium radioisotope contamination. The French armed forces develop and manufacture some antidotal drugs meeting regulatory, analytical and pharmaceutical requirements in order to submit marketing authorization documentation. Prior to an initial meeting with the French National Agency for Medicines and Health Products Safety (ANSM) in 2011, the authors were following regulatory developments in free cyanide release, active pharmaceutical ingredient (API) synthesis, API specifications, ability of cesium/Prussian blue binding products and collection of pre-clinical data. MATERIALS AND METHODS: Free cyanide release was assessed by ultraviolet-visible (UV-Vis) spectrometry at 615 nm. The kinetics of cesium were evaluated in vitro by flame atomic absorption. Good laboratory practice (GLP) and mutagenic assays were examined in rat studies to assess 'no absorption'. RESULTS: A validated method makes it possible to assess the free cyanide in API according to the published tolerability in humans. The French synthesizer meets good manufacturing practice (GMP) to give a drug that is compliant with all specifications, ensuring its high quality. Two standard mutagenic assays showed mutagenic potential, leading to further tests to obtain more information on any induced chromosomal aberrations. Absorption could be an important factor in determining the risk posed by the drug. CONCLUSION: The French health service provides the country with several antidotal drugs reducing Chemical, Biological, Radiological and Nuclear (CBRN) risks. Using their GMP manufacturing facilities and pharmaceutical expertise, the French armed forces have contributed to developing drugs with marketing authorization, such as pentetate calcium trisodium (Ca-DTPA) for infusion, or under development with the French Alternative Energies and Atomic Energy Commission (CEA), such as Ca-DTPA by inhalation.
Subject(s)
Antidotes/chemistry , Cesium Radioisotopes/poisoning , Ferrocyanides/chemistry , Ferrocyanides/pharmacokinetics , Animals , Cesium/chemistry , Cesium Radioisotopes/adverse effects , Chemistry, Pharmaceutical/methods , Drug Design , France , Humans , Male , Mutagens , Rats , Rats, Sprague-Dawley , Spectrophotometry, UltravioletABSTRACT
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.
Subject(s)
Biohazard Release/prevention & control , Disaster Planning/methods , Ferrocyanides/therapeutic use , Iodine/chemistry , Radioactive Hazard Release , Administration, Cutaneous , Administration, Oral , Adolescent , Adult , Child , Child, Preschool , Databases, Factual , Decision Making , Emergency Medical Services/organization & administration , Europe , Humans , Inhalation Exposure , Iodine/therapeutic use , Middle Aged , Pentetic Acid/chemistry , Radiation Dosage , Radioactive Hazard Release/prevention & controlABSTRACT
Organophosphate compounds, which induce organophosphate poisoning, were originally used as pesticides. But this type of product has also been used as warfare nerve agent like sarin, soman, Russian VX, or tabun. HI-6-dimethanesulfonate is a salt of the oxime HI-6 used in the treatment of nerve-agent poisoning. It is known to be the best re-activator component of inactivated acetyl cholinesterase. HI-6-dimethanesulfonate has shown a higher level of solubility with similar potency to reactivate acetyl cholinesterase and a similar pharmacokinetics profile compared with HI-6 dichloride. HI-6 dimethanesulfonate was tested for its mutagenic and genotoxic potential by use of the standard ICH S2R (1) battery for the evaluation of pharmaceuticals. HI-6-dimethanesulfonate was mutagenic in the Ames test only in the presence of metabolic activation. In the mutation assay at the Tk locus in L5178Y mouse-lymphoma cells, HI-6-dimethanesulfonate showed mutagenic activity both with and without metabolic activation, with a significant increase in small colonies. The effects were in favour of a clastogenic activity. It was concluded that the compound was mutagenic and possibly clastogenic in vitro. In contrast, the in vivo micronucleus test in rat bone-marrow did not demonstrate any genotoxic activity and the Comet assay performed in rat liver did not show any statistically or biologically significant increases in DNA strand-breaks. The results of both in vivo studies performed on two different organs with two endpoints are sufficient to conclude the absence of a genotoxic hazard in vivo and to consider that there is no genotoxic concern in humans for HI-6-dimethanesulfonate.
Subject(s)
DNA Damage , Methyl Methanesulfonate/toxicity , Micronuclei, Chromosome-Defective/chemically induced , Mutagens/toxicity , Oximes/toxicity , Pyridinium Compounds/toxicity , Animals , Bone Marrow Cells/drug effects , Bone Marrow Cells/pathology , Cell Line, Tumor , Comet Assay , Dose-Response Relationship, Drug , Female , Injections, Intraperitoneal , Liver/drug effects , Liver/pathology , Male , Methyl Methanesulfonate/chemistry , Mice , Molecular Structure , Mutagens/chemistry , Oximes/chemistry , Pyridinium Compounds/chemistry , Rats , Rats, Sprague-Dawley , Salmonella typhimurium/drug effects , Salmonella typhimurium/geneticsABSTRACT
A high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) procedure for the simultaneous determination of diazepam from avizafone, atropine and pralidoxime in human plasma is described. Sample pretreatment consisted of protein precipitation from 100microl of plasma using acetonitrile containing the internal standard (diazepam D5). Chromatographic separation was performed on a X-Terra MS C8 column (100mmx2.1mm, i.d. 3.5microm), with a quick stepwise gradient using a formate buffer (pH 3, 2mM) and acetonitrile at a flow rate of 0.2ml/min. The triple quadrupole mass spectrometer was operated in positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges of 1-500ng/ml for diazepam, 0.25-50ng/ml for atropine and 5-1000ng/ml for pralidoxime. The coefficients of variation were always <15% for both intra-day and inter-day precision for each analyte. Mean accuracies were also within +/-15%. This method has been successfully applied to a pharmacokinetic study of the three compounds after intramuscular injection of an avizafone-atropine-pralidoxime combination, in healthy subjects.
