Lorke et al., (Citation2008a) have published a study that was performed to assess the therapeutic efficacy of new K-oximes on the mortality of rats exposed to DFP using several dosing groups; this study supplemented earlier work by the same group (Lorke et al., Citation2008b). Both papers refer to DFP, an OP compound that is generally used as a model compound but is neither used as insecticide nor as a nerve agent. It is well known that the in vitro and in vivo efficacy of oximes is strongly dependent on the OP compound (Worek et al., Citation2004; Eddleston et al., Citation2005). Hence, the therapeutic effect of oximes in DFP poisoning does not necessarily imply a comparable therapeutic effect in poisoning by other OP compounds, especially when animal survival without detailed analysis is used as the decisive parameter. A special feature of DFP poisoning in the experimental set-up used is the comparably low rate of inhibition (Eyer et al., Citation2003; Worek et al., Citation2007) and the high affinity of the oximes to AChE. In such a situation, a protective effect that is not indicative for therapeutic reactivation would have been assessed. It is known that the individual reactions occurring during inhibition, aging and reactivation may follow very different kinetics (CitationWorek et al., 2004). This is important as it is known that even small changes in the active site lead to enormous changes in reaction kinetics. In any case, a human AChE source such as red blood cells would be preferable as a suitable surrogate parameter for the synaptic enzyme. Hence, detailed knowledge of the different reaction kinetics would be valuable to allow thorough PK-PD-modelling (Eyer et al., Citation2003; Worek et al., Citation2007). Based on such results it would be possible to compare appropriate oxime concentrations, which then have to be subjected to an adequate safety analysis. Such data could be confirmed in well designed studies using a limited number of animals. Furthermore, due to large species difference, specific data for the investigated species should be worked up to allow reasonable interspecies comparison. Based on these results a more detailed approach, considering also aging kinetics and persisting poison load would be possible. Then, an extrapolation to the human situation could be performed and an adequate comparison with the clinical situation would be possible. In conclusion, in order to extrapolate the effectiveness of new oximes to human OP-insecticide and nerve agent poisoning, a huge amount of additional data are necessary.
References
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- Eyer F, Meischner V, Kiderlen D, Thiermann H, Worek F, Haberkorn M et al. Human parathion poisoning. A toxicokinetic analysis. Toxicol Rev 2003;22:143–63.
- Lorke DE, Hasan MY, Nurulain SM, Kua K, Schmitt A, and Petroianu GA. Efficacy of two new asymmetric bispyridinium oximes (K-27 and K-48) in rats exposed to diisopropylfluorophosphate: comparison with pralidoxime, obidoxime, trimedoxime, methoxime, and HI-6”, Clinical Toxicology, 2008a. DOI: 10.1080/15376510802312365 URL:http://dx.doi.org/10.1080/15376510802312365 Accessed 16 January 2009
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