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The influence of organic derivatives of pentavalent phosphorus (phosphoric acid and its salts) on the main physical and mechanical properties of high-density polyethylene was studied. It was established that organophosphorus compounds show a stabilizing and plasticizing effect with respect to polyethylene. [ABSTRACT FROM AUTHOR]

Oxime-type acetylcholinesterase reactivators (oxime-AChER) are used as an adjunct in the treatment for organophosphorus anticholinesterase poisoning. Because of the widespread usage and exposure of organophosphorus compounds (OPCs), its poisoning and fatalities is obvious in pregnant women, embryos and fetuses. OPCs irreversibly inhibit acetylcholinesterase (AChE) at nerve synapses. Furthermore, the role of AChE other than neurotransmission termination has been defined in the literature. The growing evidences show that cholinergic mechanisms are involved during growth and development of other organ systems. In contrary to the fact, the data on the use of oxime-AChER in OPC poisoning in pregnancy are scanty. The present review aimed to comprehend the status of oximes in pregnancy in lieu of the published literature. A thorough literature search was performed in January 2013, using ten popular search engines including Medline/PubMed, Google scholar, etc., using nine standard keywords. The search period was set from 1966 to present. The search did not reveal substantial data. No considerable studies were retrieved which could really demonstrate either the beneficial, harmful or even null effect of oxime-AChER usage in pregnancy. Only eighteen relevant articles were obtained for a period of about 47 years. In the literature, there is no report available to demonstrate the risk of using oxime-AChER in pregnancy for the treatment of OPC poisoning. The study reveals that the use of oxime-AChER in pregnancy is largely un-addressed, inconclusive and based on speculation albeit the incidences of OPC poisoning are quite prevalent. Well-designed studies are warranted for a tangible conclusion. [ABSTRACT FROM AUTHOR]

The aim of this prospective study design is to understand the audiological parameters in central and peripheral auditory pathway in organophosphorus compound (OPC) poisoning, within the setting of Tertiary care/Medical College Hospital we studied Distortion Product Oto Acoustic Emission (DPOAE) and brain evoked response audiometry (BERA) in 25 patients with OPC poisoning with respiratory failure and 75 patients without respiratory failure. The results showed that DPOAE was absent in 17 patients with respiratory failure and 51 patients without respiratory failure. BERA showed significant prolongation in wave I, wave III and wave V latencies in both the groups. In conclusion, the current study has demonstrated significant changes in the auditory pathway both in peripheral and central with OPC exposure. The damage induced by these agents has been suggested as a combination of oto- and neurotoxicity with or without respiratory failure. Otolaryngologist should be alert to the toxic properties of OPC and conduct a comprehensive audiological assessment even in the conditions of deliberate poisoning. [ABSTRACT FROM AUTHOR]

A dimeric organophosphorus hydrolase (OPH; EC 3.1.8.1; 72 kDa) was isolated from wild-type bacteria, analyzed for its 16s rRNA sequence, purified, and immobilized on gold nanoparticles (AuNPs) to form the transducer part of a biosensor. The isolated strain was identified as Pseudomonas aeruginosa. The AuNPs were characterized by transmission electron microscopy and localized surface plasmon resonance. Covalent binding of OPH to the AuNPs was confirmed by spectrophotometry, enzymatic activity assays, and FTIR spectroscopy. Coumarin 1, a competitive inhibitor of OPH, was used as a fluorogenic probe. The bioconjugates quench the emission of coumarin 1 upon binding, but the addition of paraoxon results in an enhancement of fluorescence that is directly proportional to the concentration of paraoxon. The gold-OPH conjugates were then used to determine paraoxon in serum samples spiked with varying levels of paraoxon. The method works in the 50 to 1,050 nM concentration range, has a low standard deviation (with a CV of 5.7-11 %), and a detection limit as low as 5 × 10 M. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Context Numerous studies demonstrated a limited efficacy of clinically used oximes in case of poisoning by various organophosphorus compounds. A broad spectrum oxime antidote covering all organophosphorus nerve agents and pesticides is still missing and effective (bio-)scavengers have not yet been marketed. Objective. The interactions of the available and clinically approved hydroxyethyl starch, dextran and lipid emulsions with organophosphorus nerve agents and pesticides were investigated in order to provide an in vitro base for the evaluation of these compounds in human organophosphorus poisoning. Materials and methods. The degradation kinetics of organophosphorus compounds by the glucose derivatives and lipid emulsions were investigated with an acetylcholinesterase inhibition assay. Results. The incubation of organophosphorus compounds with TRIS-Ca2+ buffer resulted in a time-dependent degradation of the nerve agents with half-lives of 42 min for cyclosarin, 49 min for sarin, 99 min for tabun, 107 min for soman 19 h for malaoxon and 54 h for VX. In contrast, incubation with all tested compounds resulted in a stabilisation of the organophosphorus compounds. Discussion. Our results suggest that binding of lipophilic organophosphorus compounds could result in a reduced spontaneous and enzyme-induced degradation of the toxic compounds. Conclusion. High dose lipid emulsions and glucose derivatives stabilised organophosphorus compounds in vitro. [ABSTRACT FROM AUTHOR]

The rise of various neurodegenerative disorders are somewhat correlating with the worldwide application of multiple anthropogenic toxicants. Though different possible targets were revealed to date, for example, for organophosphorus compounds (OPs), plenty of questions remain. Several decarboxylases (aromatic amino acid decarboxylase, AADC; histidine decarboxylase, HDC; glutamate decarboxylase, GAD) catalyze the biosynthesis of neurotransmitters and neuromodulators and contain pyridoxal phosphate (PLP) as a cofactor. In the current work, 18 OPs which have different neurotoxicity (chemical warfare agents and pesticides) and can penetrate through the blood–brain barrier, were selected. Then, their possible interaction with these decarboxylases in both apo- and holoforms was revealed using computer modeling methods (molecular docking and dynamics). The main amino acid residues of the enzymes responsible for binding OPs have been identified. Individual substances that are most dangerous from the point of view of a possible negative effect on the activity of several decarboxylases were revealed among studied OPs. Glyphosate should be of special interest, since it is not highly toxic towards serine hydrolases, but may prove to be a strong inhibitor for decarboxylases. Holo-AADC could be the most inhibition-prone enzyme among all those investigated. [Display omitted] • Decarboxylases were assessed as targets for organophosphorus compounds (OPs). • Effect of individual OPs on different human decarboxylases varies. • OPs compete with cofactor, substrates and inhibitors of decarboxylases in silico. • Glyphosate may be a strong inhibitor of most human decarboxylases. [ABSTRACT FROM AUTHOR]

To obtain fiber materials with pronounced chemical-biological protection, metal (Zn or Ta) nanoparticles were jointly applied with polyelectrolyte complexes of enzymes and polypeptides being their stabilizers. Computer modeling revealed the preferences between certain polyelectrolyte partners for N-acyl-homoserine lactone acylase and hexahistidine-tagged organophosphorus hydrolase (His6-OPH) possessing the quorum quenching (QQ) behavior with bacterial cells. The combinations of metal nanoparticles and enzymes appeared to function better as compared to the combinations of the same QQ-enzymes with antibiotics (polymyxins), making it possible to decrease the applied quantities by orders of magnitude while giving the same effect. The elimination of Gram-positive and Gram-negative bacterial cells from doubly modified fiber materials notably increased (up to 2.9-fold), whereas His6-OPH retained its hydrolytic activity in reaction with organophosphorus compounds (up to 74% of initially applied activity). Materials with the certain enzyme and Zn nanoparticles were more efficient against Bacillus subtilis cells (up to 2.1-fold), and Ta nanoparticles acted preferentially against Escherichia coli (up to 1.5-fold). Some materials were proved to be more suitable for combined modification by metal nanoparticles and His6-OPH complexes as antimicrobial protectants. [ABSTRACT FROM AUTHOR]

Organophosphorus (OP) compounds represent an important group of chemical warfare nerve agents that remains a significant and constant military and civilian threat. OP compounds are considered acting primarily via cholinergic pathways by binding irreversibly to acetylcholinesterase, an important regulator of the neurotransmitter acetylcholine. Many studies over the past years have suggested that other mechanisms of OP toxicity exist, which need to be unraveled by a comprehensive and systematic approach such as genome-wide gene expression analysis. Here we performed a microarray study in which cultured human neural cells were exposed to 0.1 or 10 μM of VX for 1 h. Global gene expression changes were analyzed 6, 24, and 72 h post exposure. Functional annotation and pathway analysis of the differentially expressed genes has revealed many genes, networks and canonical pathways that are related to nervous system development and function, or to neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In particular, the neuregulin pathway impacted by VX exposure has important implications in many nervous system diseases including schizophrenia. These results provide useful information valuable in developing suitable antidotes for more effective prevention and treatment of, as well as in developing biomarkers for, VX-induced chronic neurotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: As standard therapy of intoxication with organophosphorus (OP) compounds is still insufficient, developing new treatment strategies is urgently required. For evaluating potential of OP detoxification of several compounds correctly, different toxicodynamic impact of OP enantiomers has to be considered thoroughly. It has already been demonstrated that β-cyclodextrin (β-CD) derivatives with attached nucleophilic substituent iodosobenzoic acid (IBA) can be regarded as potent OP scavengers due to an accelerating effect on decay of different OP. Herein, six CD derivatives permethylated or not on CD torus as well as differently attached nucleophilic substituent IBA derivative were investigated regarding detoxification of GF as an OP model substance. Acceleration of GF detoxification could be detected for all compounds with highest rate constants for propylene chain linked nucleophilic substituents on CD derivative. In addition, fast initial binding of GF on CD could be observed and is ascribed to formation of CD complexes. Furthermore, terminal plateau phase was detected of about 1% of each enantiomer reflecting the necessity of a quantitative determination at low concentrations. Moreover, this molecular depot formation may represent an additional detoxification pathway for OP. [Copyright &y& Elsevier]

Abstract: Current treatments of organophosphorus nerve agents poisoning are imperfect, and more efficient medical countermeasures need to be developed. Chemical scavengers based on β-cyclodextrin displayed promising results, but further investigations have to be performed to evaluate the possibility of application of substituted cyclodextrins as potential detoxification agents. Herein, five new cyclodextrins scavengers were synthesized. New optimal conditions for regioselectively monosubstitution of β-cyclodextrin at O-2 position were then studied to access to key intermediates. After these optimizations, a new series of three permethylated derivatives was developed, and two compounds bearing an α-nucleophilic group via a three carbon atoms linker were prepared. The ability of these five scavengers to detoxify nerve agents (cyclosarin, soman, tabun and VX) was evaluated by a semi-quantitative biological assay. All the modified cyclodextrins significantly decreased the inhibitory effect of chemical warfare G agents on acetylcholinesterase activity. For this purpose, we showed that the specific interactions between the organophosphorus compound and the oligosaccharidic moiety of the scavenger played a pivotal role in the detoxification process. [Copyright &y& Elsevier]

Abstract: Organophosphorus compounds (OPs) are widely used as pesticides because of their ability to inhibit the activity of acetylcholinesterase (AChE) in the nervous system. Thus, AChE is generally used as a biosensor for pesticide detection. Due to the instability of AChE a more stable enzyme would be desirable for robust applications. We investigated the sensitivity of a thermostable carboxylesterase from the archaeon Archaeoglobus fulgidus (AFEST) to seven selected OPs. The IC50 of dichlorvos against AFEST (50.8±2.6nM) was 10-fold lower than that of the commercially obtained AChE, indicating that AFEST had higher sensitivity. Its sensitivity for the other OPs was lower than AChE. To enhance the sensitivity of AFEST to OPs, site-directed mutations were introduced in the cap domain of AFEST. The sensitivity of mutant N44S/S48V was enhanced toward all seven OPs compared to the wild-type and was higher than AChE for four OPs, including paraoxon (3.3±0.01nM), dichlorvos (28.0±0.6nM), profenofos (43.0±1.0nM), and diazinon (3.0±0.2nM). The half-lives of AFEST and the mutant N44S/S48V at 37°C were over 15 d. The interactions between the enzymes and select OPs were investigated by molecular docking. The results demonstrated that AFEST and the mutant N44S/S48V have the potential to be biosensor for OP detection. [Copyright &y& Elsevier]

Abstract: Monodisperse molecularly imprinted polymers (MIPs) for diphenyl phosphate (DPP) and 1-naphthyl phosphate (1-NapP) have been prepared by a multi-step swelling and polymerization method using 4-vinylpyridine as a functional monomer, glycerol dimethacrylate as a crosslinker and cyclohexanol or 1-hexanol as a porogen. The retention and molecular-recognition properties of these MIPs for organophosphorus compounds were evaluated by HPLC using a mixture of phosphate buffer and acetonitrile as an eluent. In addition to shape recognition, hydrogen bonding and hydrophobic interactions could play an important role in the retention and molecular recognition of DPP and 1-NapP. Furthermore, the MIPs were applied to the separation of adenosine and adenosine phosphates (AMP, ADP and ATP). These phosphates were retained on the MIPs according to the number of phosphate groups in the molecule and were well separated from one another. Hydrogen bonding and hydrophobic interactions seemed to affect the retention and recognition of adenosine phosphates in low acetonitrile content, while hydrophilic interactions affected these properties in high acetonitrile content. Finally, the MIPs were applied to the trapping of phosphopeptides. The MIPs non-selectively trapped phosphopeptides, which have phosphorylated tyrosine, serine or threonine in the sequences, and successfully trapped four phosphopeptides in tryptic digests of bovine α-casein. [Copyright &y& Elsevier]

The reactivation of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) by oximes is inadequate in case of different OP nerve agents. This fact led to the synthesis of numerous novel oximes by different research groups in order to identify more effective reactivators. In the present study, we investigated the reactivation kinetics of a homologous series of bispyridinium bis-oximes bearing a ( E)-but-2-ene linker with tabun-, sarin-, and cyclosarin-inhibited human AChE. In part, marked differences in affinity and reactivity of the investigated oximes toward OP-inhibited human AChE were recorded. These properties depended on the position of the oxime groups and the inhibitor. None of the tested oximes was equally effective against all used OPs. In addition, the data indicate that a ( E)-but-2-ene linker decreased in most cases the reactivating potency in comparison to oximes bearing an oxybismethylene linker, e.g., obidoxime and HI-6. The results of this study give further insight into structural requirements for oxime reactivators, underline the necessity to investigate the kinetic interactions of oximes and AChE with structurally different OP inhibitors, and point to the difficulty to develop an oxime reactivator which is efficient against a broad spectrum of OPs. [ABSTRACT FROM AUTHOR]

Abstract: Inhibition of acetylcholinesterase (AChE) is the main toxic mechanism of organophosphorus compounds (OP) and reactivation of OP-inhibited AChE by oximes is a mainstay of antidotal treatment. The inadequate efficacy of clinically used oximes led to the synthesis of numerous new compounds in the past decades to identify more effective reactivators. Despite of extensive in vitro reactivation studies the structural features for the development of effective oximes are not well understood. In the present study we investigated the kinetic interactions of a homologous series of bispyridinium monoximes bearing C1 to C12 alkylketone groups on the second pyridinium ring with native and cyclosarin-inhibited human AChE. We observed a correlation of the length of the alkyl side chain with an up to 20-fold increased affinity towards native AChE. The effect of the alkyl side chain on the affinity and reactivity towards phosphonylated AChE was moderate, except of a markedly reduced reactivity of C10 and C12 oximes. In comparison to the reference oxime HI-6 all HGG oximes had a lower reactivating potency and these oximes are not considered as promising compounds for the reactivation of cyclosarin-inhibited AChE. [Copyright &y& Elsevier]

Abstract: The standard treatment of poisoning by organophosphorus (OP) nerve agents with atropine and oximes is not sufficiently effective against all types of nerve agents. Alternative therapeutic strategies are required and bispyridinium non-oximes, acting as nicotinic antagonists, were identified as promising compounds. A previous study showed that the di(methanesulfonate) salt of the bispyridinium compound MB327 could restore soman-impaired neuromuscular function in vitro and improve survival of sarin, soman and tabun poisoned guinea pigs in vivo. Here, by using the indirect field stimulation technique, the ability of MB327 to counteract soman-impaired neuromuscular transmission was investigated in human intercostal muscle and rat diaphragm preparations. MB327 restored muscle force in a concentration-dependent manner in both species without reactivating soman-inhibited acetylcholinesterase. The therapeutic effect of MB327 could be washed out, indicating a direct effect at the nicotinic receptor level. Also the ability of MB327 to restore respiratory muscle function could be demonstrated for the first time in rat and human tissue. In combination with previous in vitro and in vivo findings MB327 may be considered a promising compound for the treatment of nerve agent poisoning and further studies are needed to identify optimized drug combinations, concentrations and dosing intervals to provide an effective therapy for OP poisoning. [Copyright &y& Elsevier]

Abstract: There is an ongoing debate whether oximes can effectively counteract the effects of organophosphorus compounds (OP) on brain acetylcholinesterase (AChE) activity and whether there are differences in the kinetic properties of brain and erythrocyte AChE. In order to investigate the kinetics of AChE from different tissues and species the well established dynamically working in vitro model with real-time determination of membrane-bound AChE activity was adapted for use with brain AChE. The enzyme reactor, that was loaded with brain, erythrocyte or muscle AChE, was continuously perfused with substrate and chromogen while AChE activity was on-line analyzed in a flow-through detector. It was possible to determine the Michaelis–Menten constants of human erythrocyte, muscle and brain AChE which were almost identical. In addition, the inhibition kinetics of sarin and paraoxon as well as the reactivation kinetics of obidoxime and HI 6 were determined with human, swine and guinea pig brain and erythrocyte AChE. It was found that the inhibition and reactivation kinetics of brain and erythrocyte AChE were highly comparable in all tested species. These data support the view that AChE from different tissue has similar kinetic properties and that brain AChE is comparably susceptible toward reactivation by oximes. [Copyright &y& Elsevier]

A Quantitative structure-activity relationship study is performed on a set of organophosphorus compounds to reveal structural and quantum-chemical features influencing the toxic effect. The properties derived from the topological analysis of the electron density have been used to model the toxicity data. A multiple linear regression analysis in conjunction with genetic algorithm is used in the study, followed by subsequent validation of the results. Obtained QSAR models are beneficial for virtual screening of toxicity for new compounds of interest. Because toxicity of organophosphorus compounds is dependent on conformational properties, a conformational search has been performed before optimization of geometries. All quantum-chemical calculations are carried out at DFT/B3LYP level of theory with 6-311++G(d,p) basis set. Frequency calculations are performed after full geometry optimization. Ab initio wave functions were obtained for further analysis and evaluation of quantum topological properties of target molecules. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012 [ABSTRACT FROM AUTHOR]

Abstract: Filler nanoparticles pave the way for the development of novel halogen-free flame-retardant polymers. The aim of this study was to investigate the thermal degradability, and in particular, the thermal degradation mechanism of organophosphorus flame-retardant poly(methyl methacrylate) (PMMA) nanocomposites containing nanoclay (NC) and multi-walled carbon nanotubes (CNT). For this purpose, thermogravimetry and direct pyrolysis mass spectrometry analysis were utilized. The onset of degradation was delayed through increased maximum degradation temperature and suppressed mass loss corresponding to initial degradation stage with carbon nanotubes and nanoclays, respectively. Possibility of reactions of melamine and/or melamine derivatives and interactions between carbonyl groups of PMMA and phosphinic acid leading to thermally more stable products was increased owing to the barrier effect of filler nanoparticles. In the presence of NC better flame retarding characteristics was detected as anhydride formation, leading to charring being more effective. [Copyright &y& Elsevier]

Abstract: The impact of organophosphorus compound (OP) intoxication on the activity of central respiratory circuitry, causing acetylcholinesterase (AChE) inhibition and accumulation of acetylcholine in the respiratory brainstem circuits, is not understood. We investigated the central effect of the OP Crotylsarin (CRS) on respiratory network activity using the working heart brainstem preparation, which specifically allows for the analysis of central drug effects without changes in brainstem oxygenation possibly caused by drug effects on peripheral cardio-respiratory activity. Respiratory network activity was determined from phrenic and hypoglossal or vagal nerve activities (PNA, HNA, VNA). To investigate combined central and peripheral CRS effects hypo-perfusion was used mimicking additional peripheral cardiovascular collapse. Systemic CRS application induced a brief central apnea and complete AChE-inhibition in the brainstem. Subsequently, respiration was characterised by highly significant reduced PNA minute activity, while HNA showed expiratory related extra bursting indicative for activation of un-specified oro-pharyngeal behaviour. During hypo-perfusion CRS induced significantly prolonged apnoea. In all experiments respiratory activity fully recovered after 1h. We conclude that CRS mediated AChE inhibition causes only transient central breathing disturbance. Apparently intrinsic brainstem mechanisms can compensate for cholinergic over activation. Nevertheless, combination of hypo-perfusion and CRS exposure evoke the characteristic breathing arrests associated with OP poisoning. [Copyright &y& Elsevier]

Abstract: Standard treatment of organophosphorus (OP) poisoning includes administration of an antimuscarinic (e.g., atropine) and of an oxime-based reactivator. However, successful oxime treatment in soman poisoning is limited due to rapid aging of phosphylated acetylcholinesterase (AChE). Hence, the inability of standard treatment procedures to counteract the effects of soman poisoning resulted in the search for alternative strategies. Recently, results of an in vivo guinea pig study indicated a therapeutic effect of physostigmine given after soman. The present study was performed to investigate a possible pre- and post-treatment effect of physostigmine on soman-inhibited human AChE given at different time intervals before or after perfusion with soman by using a well-established dynamically working in vitro model for real-time analysis of erythrocyte and muscle AChE. The major findings were that prophylactic physostigmine prevented complete inhibition of AChE by soman and resulted in partial spontaneous recovery of the enzyme by decarbamylation. Physostigmine given as post-treatment resulted in a time-dependent reduction of the protection from soman inhibition and recovery of AChE. Hence, these date indicate that physostigmine given after soman does not protect AChE from irreversible inhibition by the OP and that the observed therapeutic effect of physostigmine in nerve agent poisoning in vivo is probably due to other factors. [Copyright &y& Elsevier]

etylcholinesterase (AChE) is the primary target of organophosphorus compounds (OP). The investigation into interactions between AChE, OP and oximes in vitro may be affected by the experimental conditions, e.g. by the buffer system. Hence, it was tempting to investigate the Michaelis-Menten kinetics and the inhibition and reactivation kinetics of paraoxon-ethyl, sarin, soman and VX in the presence of phosphate, MOPS, Tyrode and TRIS buffer with human AChE. Compared to phosphate buffer, the inhibition and reactivation kinetics of human erythrocyte AChE were markedly changed by TRIS and in part by MOPS, whereas Tyrode showed similar results to phosphate buffer. These results indicate an effect of the tested buffers on the properties of AChE, and an interaction between OP and oximes has to be considered for the design of in vitro studies and may impair the comparison of data from different laboratories. In view of the comparability of human in vitro kinetic data determined with phosphate buffer with data from human OP poisoning, it seems to be a suitable buffer for the investigation into interactions between AChE, OP and oximes. [ABSTRACT FROM AUTHOR]

Abstract: Developing potent detoxification strategies for prophylaxis and therapy against organophosphate (OP) intoxication still represents a challenging task. Clinical application of numerous investigated substances including enzymes and low molecular scavengers like metal ions or nucleophiles could not yet be realised due to profound disadvantages. Presenting a promising attempt, cyclodextrins (CDs) efficiently enhance the degradation of some organophosphorus compounds. The present study examined the in vitro GF degradation mediated by three CDs and a nucleophilic precursor performed by mass spectrometric detection with ammonia chemical ionisation. All four compounds caused a notable enhancement of GF detoxification that was synergistically accelerated in the case of 2-O-(3-carboxy-4-iodosobenzyl)-β-cyclodextrin (IBA-β-CD) with the alpha-nucleophile 2-iodosobenzoic acid (IBA) grafted on the secondary face of β-cyclodextrin (β-CD). In vitro toxicokinetic investigations of CD derivatives are needed to evaluate the effect of slow terminal elimination phase of the more toxic (−)-GF shown for two CD-derivatives underlining the necessity of detecting the complete kinetic course of inactivation. The observed effect of fast high affinity binding (20–30%) represents an additional therapeutic option of an extremely rapid reduction of GF concentration in vivo. Distinctive differences in the course of reaction are detected depending on β-CD-derivatives, allowing a first inference of possible mechanisms and relevance of attached substituents. However, further profound investigation needs to be done to evaluate the basis of a clinical application of substituted CDs as potential detoxification agents. [Copyright &y& Elsevier]

Abstract: Previous in vitro studies showed marked species differences in the reactivating efficiency of oximes between human and animal acetylcholinesterase (AChE) inhibited by organophosphorus (OP) nerve agents. These findings provoked the present in vitro study which was designed to determine the inhibition, aging, spontaneous and oxime-induced reactivation kinetics of the pesticide paraoxon, serving as a model compound for diethyl-OP, and the oximes obidoxime, pralidoxime, HI 6 and MMB-4 with human, Rhesus monkey, swine, rabbit, rat and guinea pig erythrocyte AChE. Comparable results were obtained with human and monkey AChE. Differences between human, swine, rabbit, rat and guinea pig AChE were determined for the inhibition and reactivation kinetics. A six-fold difference of the inhibitory potency of paraoxon with human and guinea pig AChE was recorded while only moderate differences of the reactivation constants between human and animal AChE were determined. Obidoxime was by far the most effective reactivator with all tested species. Only minor species differences were found for the aging and spontaneous reactivation kinetics. The results of the present study underline the necessity to determine the inhibition, aging and reactivation kinetics in vitro as a basis for the development of meaningful therapeutic animal models, for the proper assessment of in vivo animal data and for the extrapolation of animal data to humans. [Copyright &y& Elsevier]

There are classes of microbial enzymes that have the ability to degrade harmful organophosphorus (OP) compounds that are present in some pesticides and nerve agents. To date, the most studied and potentially important OP-degrading enzymes are organophosphorus hydrolase (OPH) and organophosphorus acid anhydrolase (OPAA), which have both been characterized from a number of organisms. Here we provide an update of what is experimentally known about OPH and OPAA to include their structures, substrate specificity, and catalytic properties. Current and future potential applications of these enzymes in the hydrolysis of OP compounds are also addressed. [ABSTRACT FROM AUTHOR]

Abstract: Degradation of organophosphorus compounds was achieved in the presence of purified fungal laccase from Trametes versicolor and a small molecular weight redox mediator (ABTS). This laccase-mediator system (LMS) catalyzed degradation of VX, PhX and VR while had no apparent effect on CVX, ecothiophate or demeton. Inhibition of ABTS oxidation was shown with VX, PhX, VR and CVX. Results with CVX suggest either no degradation subsequent to interaction with the laccase active site or the formation of a new toxic compound. PhX degradation was also monitored by mass spectroscopy, a method that allowed us to identify certain intermediates formed during OP degradation. Altogether, results underline the importance of the OP nitrogen atom at β-position and of its substituents, even though the intimate mechanism of laccase-catalyzed degradation is not yet known. [ABSTRACT FROM AUTHOR]

Abstract: 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. 1h 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. [ABSTRACT FROM AUTHOR]