A physiologically based pharmacokinetic (PB/PK) model for multiple exposure routes for soman in multiple species

A physiologically based pharmacokinetic (PB/PK) model has been developed in advanced computer simulation language (ACSL) to describe blood and tissue concentration-time profiles of the C(±)P(-) stereoisomers of soman after inhalation, subcutaneous and intravenous exposures at low (0.8-1.0 × LD50), medium (2-3 × LD50) and high (6 × LD50) levels...

Improvements of the fluoride reactivation method for the verification of nerve agent exposure

One of the most appropriate biomarkers for the verification of organophosphorus nerve agent exposure is the conjugate of the nerve agent to butyrylcholinesterase (BuChE). The phosphyl moiety of the nerve agent can be released from the BuChE enzyme by incubation with fluoride ions, after which the resulting organophosphonofluoridate can be...

Retrospective detection of exposure to nerve agents: Analysis of phosphofluoridates originating from fluoride-induced rectivation of phospylated BuChE

The utility was explored of a new approach to detect retrospectively exposure to nerve agents by means of conversion of the inhibitor moiety bound to the active site of the enzyme BuChE in plasma with fluoride ions into a phosphofluoridate which is subsequently analyzed by means of gas chromatography (GC). This quantifies ≥0.01% inhibition of...

Biochemical and behavioral effects of soman vapors in low concentrations

Soman belongs to the most dangerous nerve agents because of the low effectiveness of the presently available antidotes. Soman acts by inhibiting acetylcholinesterase (AChE) both peripherally and centrally, with a subsequent accumulation of neuromediator acetylcholine and other metabolic changes. From the data published in literature it can be...

Toxicokinetics of the nerve agent (±)-VX in anesthetized and atropinized hairless guinea pigs and marmosets after intravenous and percutaneous administration

In continuation of our investigations on the toxicokinetics of the volatile nerve agents C(±)P(±)-soman and (±)-sarin, we now report on the toxicokinetics of the rather nonvolatile agent (±)-VX. A validated method was developed to determine blood levels of (±)-VX by means of achiral gas chromatography at blood levels ≥10 pg/ml. The ratio of the...

Exploring the active center of human acetylcholinesterase with stereomers of an organophosphorus inhibitor with two chiral centers

The stereoselectivity of the phosphonylation reaction and the effects of adduct configuration on the aging process were examined for human acetylcholinesterase (HuAChE) and its selected active center mutants, using the four stereomers of 1,2,2-trimethylpropyl methylphosphonofluoridate (soman). The reactivity of wild type HuAChE toward the P(S)...

Semi-continuous high speed gas analysis of generated vapors of chemical warfare agents

A method is presented for the continuous analysis of generated vapors of the nerve agents soman and satin and the blistering agent sulfur mustard. By using a gas sampling valve and a very short (15 cm) column connected to an on-column injector with a 'standard length' column, the system can either be calibrated or used for performing high speed...

Low level nose-only exposure to the nerve agent soman: Toxicokinetics of soman stereoisomers and cholinesterase inhibition in atropinized guinea pigs

In order to initiate a quantitative basis for the toxicology of low level exposure to nerve agents, the toxicokinetics of soman stereoisomers during nose-only exposure for 5 h to 20 ppb (160 μg/m3) of C(±)P(±)- soman in air were studied in restrained, anesthetized, and atropinized guinea pigs. The concentrations of the toxic C(±)P(-)-soman...

Subchronic physostigmine pretreatment in guinea pigs: Effective against soman and without side effects

The behavioral and neurophysiological effects of the subchronically administered cholinesterase-inhibitor physostigmine (PHY) (0.025 mg/kg/h) either with or without the muscarinergic antagonist scopolamine (SCO) (0.018 mg/kg/h) were determined in guinea pigs. In contrast to a single injection of PHY, subchronic application by osmotic minipumps...

Capillary gas chromatographic analysis of nerve agents using large volume injections

The use of large volume injections has been studied for the verification of intact organophosphorus chemical warfare agents in water samples. As the use of ethyl acetate caused severe detection problems new potential solvents were evaluated. With the developed procedure, the nerve agents sarin, tabun, soman, DFP and VX can be determined in...

Protection of guinea pigs against soman poisoning by pretreatment with p-nitrophenyl phosphoramidates

Several p-nitrophenyl phosphoramidates with the general formula RO(NH2)P(O)OC6H4-p-NO2, in which R = CH2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2CH2CH2CH3, and CH2CH2Cl, as well as (NH2)2P(O)OC6H4-p-NO2 were administered intravenously to guinea pigs as pretreatment compounds for protection against the lethal effects of 1,2,2-trimethylpropyl...

Effects of low doses of cholinesterase inhibitors on behavioral performance of robot-tested marmosets

To investigate at which dose levels undesirable effects started, behavioural performance and several physiological parameters were measured in marmosets (Callithrix Jacchus) after soman (1.75 and 3.5 μg/kg), sarin (3 and 6 μg/kg), physostigmine (10 and 20 μg/kg), and pyridostigmine (200 and 400 μg/kg). Effects on performance were investigated...

Efficacy of HI-6 and HLÖ-7 in preventing incapacitation following nerve agent poisoning

The therapeutic efficacy of the oximes HI-6 and HLo-7 (132.5 μmol/kg), in combination with atropine, in soman- or tabun-intoxicated guinea pigs was compared, particularly with respect to recovery of shuttlebox performance and electroencephalograms (EEGs). After 1.5 x LD50 soman SC, therapy with HI-6 or HLo-7 resulted in survival of 87.5% of the...

Behavioral performance, brain histology, and EEG sequela after immediate combined atropine/diazepam treatment of soman-intoxicated rats

It is known that rats poisoned with near-lethal doses of pinacolyl methylphosphonofluoridate (soman) develop brain lesions, particularly when convulsions are induced. When rats were intoxicated with a LD50 of soman and treated immediately thereafter with a combination of low doses of atropine and diazepam (LOW AS/DZ treatment), large decrements...

On the development of behavioral tolerance to organophosphates IV: EEG and visual evoked responses

Several earlier studies showed that, in contrast with DFP, repeated injections with soman did not lead to behavioral tolerance in rats. The reason for the difference between the effects of these two organophosphate cholinesterase inhibitors was not clear and a neurophysiological approach was undertaken. Four experiments (A, B, C and D) were...

The bispyridinium-dioxime HLö-7. A potent reactivator for acetylcholinesterase inhibited by the stereoisomers of tabun and soman

Purification of (+)-tabun was accomplished by treatment with electric eel acetylcholinesterase (AChE) in order to bind contaminating (-)-tabun, the more potent enantiomer with respect of AChE inhibition. Electric eel AChE inhibited with (-)-tabun and with purified (+)-tabun show similar properties in reactivation reactions with oximes (pH 7.5,...