Toxicokinetics of soman in cerebrospinal fluid and blood of anaesthetized pigs

Abstract

The toxicokinetics of the four stereoisomers of the nerve agent C(+/-)P(+/-)-soman was analysed in cerebrospinal fluid (CSF) and blood in anaesthetized, spontaneously breathing pigs during a 90-min period after injection of soman. The pigs were challenged with different intravenous (i.v.) doses of C(+/-)P(+/-)-soman corresponding to 0.75-3.0 LD50 (4.5, 9.0 and 18 microg/kg in a bolus injection and 0.45 microg/kg per min as a slow infusion). Artificial ventilatory assistance was given if, after soman intoxication, the respiratory rate decreased below 19 breaths/min. Blood samples were taken from a femoral artery and CSF samples from an intrathecal catheter. The concentrations of the soman isomers were determined by gas chromatography coupled with high resolution mass spectrometry. All four isomers of soman were detected in both blood and CSF samples. The relatively non-toxic C(+/-)P(+) isomers disappeared from the blood stream and CSF within the first minute, whereas the levels of the highly toxic C(+/-)P(-) isomers could be followed for longer, depending on the dose. Concurrently with the soman analyses in blood and CSF, cholinesterase (ChE) activity and cardiopulmonary parameters were measured. C(+/-)P(-) isomers showed approx. 100% bioavailability in CSF when C(+/-)P(+/-)-soman was given i.v. as a bolus injection. In contrast, C(+/-)P(-) isomers displayed only 30% bioavailability in CSF after slow i.v. infusion of soman. The ChE activity in blood decreased below 20% of baseline in all groups of pigs irrespective of the soman dose. The effect of soman intoxication on the respiratory rate, however, seems to be dose-dependent and the reason for ventilatory failure and death. Artificial ventilation resulted in survival of the pigs for the time-period studied.

Chromatographic resolution, characterisation and quantification of VX enantiomers in hemolysed swine blood samples

“…In case of sarin and soman injection the less toxic (+)-P isomers are either not detectable (sarin) or only transiently detectable (soman) [20][21][22][23][24][25].…”

Swine models in the design of more effective medical countermeasures against organophosphorus poisoning

“…Lumbar puncture sites can also be used with (Lips et al, 2005) or without laminectomies (Heinritzi and Schillinger, 1996;Garcia Aguado et al, 2000). From our experience and that of others (Göransson-Nyberg et al, 1998), it is very difficult to obtain clean CSF samples from any of the routes described above.…”

Development and application of procedures for the highly sensitive quantification of cyclosarin enantiomers in hemolysed swine blood samples

“…The short residence time of (−)-GF, compared to other nerve agents, e.g. soman [18], may be due to a relatively rapid hydrolysis (enzymatic and nonenzymatic) of GF in blood in vivo [19] and to consumption of GF by repeated reactivation-inhibition cycles of GF-inhibited acetylcholinesterase and butyrylcholinesterase in the presence of the reactivator HI 6 (Fig. 6).…”