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The administration of purified human plasma-derived butyrylcholinesterase (HuBuChE) as a pretreatment has been demonstrated to enhance survival and protect against decreased cognitive function after exposure to organophosphorus poisons (OPs). Based on efficacy data obtained with guinea pigs and non-human primates and the lack of behavioral side effects, plasma-derived HuBuChE has been granted investigational new drug status by the US Food and Drug Administration. The recent availability of a recombinant form of HuBuChE (rHuBuChE) from the milk of transgenic goats has now allowed us to determine the pharmacokinetics of that material in guinea pigs and use it as a therapy following exposure to the VX. The rHuBuChE was expressed as a dimer and following intramuscular (i.m.) administration had more a rapid adsorption and clearance profile in guinea pigs than the plasma-derived material. Based on those data, we administered rHuBuChE i.m. 1 h after a percutaneous exposure of guinea pigs to either 2xLD50 or 5xLD50 of VX. Post-exposure therapy with rHuBuChE provided improved survival at both challenge levels, 90% and 33% respectively versus 20% or 0% respectively for animals that did not receive therapy. These studies showed that BuChE can be efficacious as a therapy against percutaneous exposure to VX., Published in Chemico-Biological Interactions, n187 p249-252, 2010. Sponsored in part by the Joint Program Executive Office for Chemical and Biological Defense (JPEO-CBD).

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Background: Several organophosphorous compounds (OPs) are now being tested therapeutically. Cholinesterase inhibition, which in large doses makes these agents effective pesticides, may also be useful in other doses for treating dementia. Metrifonate, for example, has been used to treat schistosomiasis and is undergoing trials for the treatment of primary degenerative dementia. Material/Methods: Here we report the characterization of newly synthesized OPs from the group of phosphobetaines [β-(triphenylphosphonio)ethyl carboxylate, PB] and of alpha-aminophosphoryl compounds [N,N′- bis(dihexylphosphinoylmethyl)-1,4-diaminocyclohexane, AP] according to their toxic and genotoxic properties determined in prokaryotic and eukaryotic test systems. Results: The absence of toxicity towards Gram-negative bacteria and of genotoxicity in Ames mutagenicity assay and in SOS-chromotest did not exclude the cytotoxic effect of PB towards NIH3T3 mouse fibroblasts, which supports the notion of an extremely diverse interspecies response to OPs. In contrast, AP demonstrated toxic properties detected by antibacterial effect as well as by the inhibition of the proliferation and respiration of fibroblasts. The enzymatic transformation of the compound is necessary to reveal the genotoxic properties of AP. The role of mammalian microsomal enzymes and of bacterial C-P lyase in the formation of AP genotoxic metabolites is under discussion. Conclusions: Neither toxicity nor genotoxicity of PB was found in bacterial tests. Cytotoxic and mutagenic effects of AP were detected. The data contribute to the investigation of the biological activity of novel organophosphates which could be useful for the future development of OP-based therapeutics.

Background: Several organophosphorous compounds (OPs) are now being tested therapeutically. Cholinesterase inhibition, which in large doses makes these agents effective pesticides, may also be useful in other doses for treating dementia. Metrifonate, for example, has been used to treat schistosomiasis and is undergoing trials for the treatment of primary degenerative dementia. Material/Methods: Here we report the characterization of newly synthesized OPs from the group of phosphobetaines [β-(triphenylphosphonio)ethyl carboxylate, PB] and of alpha-aminophosphoryl compounds [N,N′- bis(dihexylphosphinoylmethyl)-1,4-diaminocyclohexane, AP] according to their toxic and genotoxic properties determined in prokaryotic and eukaryotic test systems. Results: The absence of toxicity towards Gram-negative bacteria and of genotoxicity in Ames mutagenicity assay and in SOS-chromotest did not exclude the cytotoxic effect of PB towards NIH3T3 mouse fibroblasts, which supports the notion of an extremely diverse interspecies response to OPs. In contrast, AP demonstrated toxic properties detected by antibacterial effect as well as by the inhibition of the proliferation and respiration of fibroblasts. The enzymatic transformation of the compound is necessary to reveal the genotoxic properties of AP. The role of mammalian microsomal enzymes and of bacterial C-P lyase in the formation of AP genotoxic metabolites is under discussion. Conclusions: Neither toxicity nor genotoxicity of PB was found in bacterial tests. Cytotoxic and mutagenic effects of AP were detected. The data contribute to the investigation of the biological activity of novel organophosphates which could be useful for the future development of OP-based therapeutics.

Metal species in solid and liquid materials can be extracted by supercritical carbon dioxide containing a suitable ligand. This in-situ chelation/supercritical fluid extraction technique offers several advantages over conventional solvent extraction including minimisation of organic liquid waste generation and exposure of personnel to organic vapours. Using this technique, metal species can be removed from solid materials directly using supercritical carbon dioxide as a solvent. Several ligand systems including dithiocarbamates, beta-diketones, organophosphorous reagents and macrocyclic compounds have been tested for metal extraction in supercritical carbon dioxide., Metal species in solid and liquid materials can be extracted by supercritical carbon dioxide containing a suitable ligand. This in-situ chelation/supercritical fluid extraction technique offers several advantages over conventional solvent extraction including minimisation of organic liquid waste generation and exposure of personnel to organic vapours. Using this technique, metal species can be removed from solid materials directly using supercritical carbon dioxide as a solvent. Several ligand systems including dithiocarbamates, beta-diketones, organophosphorous reagents and macrocyclic compounds have been tested for metal extraction in supercritical carbon dioxide.