Article

An in vitro comparative study on the reactivation of nerve agent-inhibited guinea pig and human acetylcholinesterases by oximes.

Department of Molecular Pharmacology, Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
Biochemistry (Impact Factor: 3.19). 11/2007; 46(42):11771-9. DOI: 10.1021/bi701002f
Source: PubMed

ABSTRACT The reactivation of nerve agent-inhibited acetylcholinesterase (AChE) by oxime is the most important step in the treatment of nerve agent poisoning. Since the evaluation of nerve agent antidotes cannot be conducted in humans, results from animal experiments are extrapolated to humans. Guinea pig is one of the animal models that is frequently used for conducting nerve agent antidote evaluations. Several investigations have demonstrated that the efficacy of an oxime primarily depends on its ability to reactivate nerve agent-inhibited AChE. If the in vitro oxime reactivation of nerve agent-inhibited animal AChE is similar to that of human AChE, it is likely that the results of an in vivo animal study will reliably extrapolate to humans. Therefore, the goal of this study was to compare the reactivation of guinea pig and human AChEs inhibited by six different G and V type nerve agents. Reactivation kinetic studies with five mono- and bis-pyridinium oximes showed that oxime reactivation of nerve agent-inhibited human AChE in most cases was faster than guinea pig AChE. The most significant enhancement was observed in the reactivation of human AChE inhibited by nerve agents containing bulky side chains GF, GD, and VR, by H-series oximes HLo-7, HI-6, and ICD-585. In these cases, species-related differences observed between the two AChEs, based on the second-order reactivation rate constants, were 90- to over 400-fold. On the other hand, less than 3-fold differences were observed in the rates of aging of nerve agent-inhibited guinea pig and human AChEs. These results suggest that the remarkable species-related differences observed in the reactivation of nerve agent-inhibited guinea pig and human AChEs were not due to differences in the rates of aging. These results also suggest that guinea pig may not be an appropriate animal model for the in vivo evaluation of oxime therapy.

0 Bookmarks
 · 
179 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The reaction of Mn(OAc)2·4H2O with bis(5-phenyl-2H-1,2,4-triazole)-3-yl-disulfane (H2ptds·2H2O) (1) yielded new complex [Mn(ptds)(o-phen)2] (2). It is observed that under similar conditions the reaction of Co(OAc)2 with H2ptds·2H2O (1) leads to thermolysis of the S–S bond of the disulfane to yield [Co(pts)(o-phen)2]·H2O·0.5C2H5OH, with the newly generated organic ligand 5-phenyl-2H-1,2,4-triazole-3-sulfinate, (pts)2−. The ligand H2ptds·2H2O (1), [Mn(ptds)(o-phen)2] (2) and [Co(pts)(o-phen)2]·H2O·0.5C2H5OH (3) crystallized into monoclinic, trigonal and triclinic crystal systems, respectively. The triazole ring nitrogen of the bidentate ligand chelates the Mn(II) center forming a seven membered chelate ring, while N, O donor sites of the resulting triazole sulfinate bond Co(II) to form a five membered chelate. The resulting complexes are paramagnetic and have a distorted octahedral geometry.
    Polyhedron 08/2011; 30(12):1927-1934. · 2.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: The continuous application of organophosphate pesticides in developing countries, in addition to the remaining stock piles of chemical warfare nerve agents and their possible use is a significant threat to the public. Yet, today's options for a treatment of organophosphorus poisonings are still inadequate. Areas covered: This article provides a concise overview of current and future research trying to improve both prophylaxis and treatment of organophosphorus intoxications. The authors provide a summary of current oxime therapy and highlight several new concepts to overcome existing gaps. This overview of therapeutic options is accompanied by two sections on cyclodextrins, related compounds and bioscavengers, which may be used for either prophylaxis or treatment. For both groups, the authors review current drug design and screening approaches, the resulting developments and future challenges. Expert opinion: While the search for one multipotent oxime has been a fruitless endeavor, combination of multiple oximes with complemental and systemic reactivity appears as a valuable concept. Development of potential scavengers, be it cyclodextrins or bioscavengers, is still hampered by insufficient efficacy of these compounds. Future strategies will aim at improving their catalytic efficacy while minimizing immunogenicity.
    Expert Opinion on Drug Discovery 10/2013; · 3.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Reactivation of organophosphate (OP) inhibited acetylcholinesterase (AChE) by oximes is inadequate against various OP nerve agents known till date owing to their diverse structural features. As a consequence, in the past decades widespread research programs have been undertaken independently throughout the world to develop and identify more effective oxime reactivators. The efficacy of oxime reactivators is estimated through different in-vitro and in-vivo models using AChE from various sources against structurally different OPs. In the present study, reactivation kinetics of OP (paraoxon, DFP, sarin and VX) inhibited AChE by xylene linked carbamoyl bis-pyridinum mono-oximes have been described. It was found that the reactivation potency of tested oximes varied with the inhibitors used as 5l (4-carbamoyl-2' hydroxyiminomethyl-1-1'-(1,3-phenylenedimethyl)-bispyridinium dibromide) was found to be the most effective reactivator against paraoxon. In case of DFP, 5k (3-carbamoyl- 2' hydroxyimino-methyl l-1-1'-(1,3-phenylenedimethyl)-bispyridinium dibromide) showed best reactivation while in case of sarin 5e (3-carbamoyl- 2' hydroxyiminomethyl-1-1'-(1,4-phenylenedimethyl)-bispyridinium dibromide) exhibited outstanding reactivation ability in comparison to standard oximes (2-PAM, obidoxime and TMB-4) as indicated by its highest value of second order reactivation rate constant (kr2) 3.26mM(-1)min(-1). The enhanced reactivation efficacy of oximes may be attributed to the optimal length of the xylene linker which facilitates appropriate positioning of carbamoyl function to the peripheral anionic site (PAS) and extending the oxime moiety to the active site of AChE.
    Toxicology 12/2013; · 3.75 Impact Factor

Full-text (2 Sources)

Download
14 Downloads
Available from
Jun 19, 2014