Soman respiratory effects

Pyridostigmine bromide studies have been performed in dogs, guinea pigs, monkeys, rabbits, rats, and mice. Diarrhea, salivation, tremors, and respiratory failure were seen prior to death. Side effects of the drug are related to muscarinic and nicotinic effects. Toxicity is also related to cholinergic stimulation. Effectiveness of pretreatment to reduce lethality after exposure to nerve agents (in particular, soman) is dependent on the administration of atropine and pralidoxime, postexposure. 

Lipp JA (1976). Effect of atropine upon the cardiovascular system during soman-induced respiratory depression. Arch Int Pharmacodynam Ther, 220, 19-27. 

There are only a few reports in the open literature on the effect of oximes in nerve agent-exposed humans. Pralidoxime chloride was very effective in reactivating erythrocyte AChE in individuals exposed to sublethal intravenous or oral VX while this oxime was substantially less effective in humans exposed to IV sarin (Sidell and Groff, 1974). Accidental sarin exposure by inhalation resulted in an initial progressive deterioration (coma, apnea) of the patient despite atropine and 2-PAM treatmentand substantial recovery of erythrocyte AChE activity (Sidell, 1974). It took several hours until the patient s condition improved. Sidell also reported an accidental oral soman exposure. A lethal dose of diluted soman splashed into and around the mouth of an individual, resulting in coma, bronchoconstriction and respiratory depression, which was successfully treated with repeated atropine injections. 2-PAM (2 g IV) had no effect on inhibited erythrocyte AChE. 

In an attempt to understand the mechanism whereby diazepam was efficacious, Johnson and co-workers (Johnson and Lowndes, 1974 Johnson and Wilcox, 1975) showed diazepam to counteract the over-activity normally associated with skeletal and heart muscle following soman intoxication. It was also shown, however, that diazepam enhances the respiratory depression produced by soman in the pentobarbitone-anaesthetized rabbit. Boskovid (1981) found that atropine and diazepam increased approximately threefold the survival time of rats poisoned with soman, when given 1 min after poisoning. In addition, there are several pharmacodynamic studies of oximes by the same author, in which diazepam (and frequently atropine) were included, but it is often difficult to separate out the effects of the diazepam from the other drugs used (e.g. BoSkovid etal, 1984). 

As in the case of s.c. toxicokinetics, the kinetics of C(+)P(-)- and C(—)P(—)-soman were described mathematically as a discontinuous process, with an equation for the exposure period and an equation for the post-exposure period. In view of the limited number of data points during exposure, the absorption phase was described with a mono-exponential function. In order to describe the exposure phase of C(+)P(-)-soman, lag times of 2 and 4 min were selected for the 8-min exposures to 0.8 and 0.4 LCtjo, respectively. These lag times correspond with the earliest time points at which this stereoisomer could be detected. Toxicokinetic parameters derived from the various calculated concentration-time curves are given in Table 2.6. There were no measurable effects of the exposures on the respiratory minute volume (RMV) and respiratory frequency (RF). 

Kassa, J., and Fusek, J. (1997). Effect of Panpal pretreatment and antidotal treatment (HI-6 plus henaciyzine) on respiratory and citxiuiatory function in soman-poisoned rats. Hum. Exp. Toxicol. 16. 563-569. 

The effectiveness of pyridostigmine pretreatment may not be conclusive evidence against the importance of central mechanisms in respiratory arrest it appears that there is at least partial permeability of the blood-brain barrier to polar compounds such as pyridostigmine, specifically in the regions of the fourth ventricle and brainstem, where respiratory centers are located. In addition, an increase in blood-brain barrier permeability occurs rapidly after soman administration.1314 The key observation... 

Subsequent to the acute cholinergic manifestations of OP toxicity in humans, and approximately 24-96 hours after exposure, the onset of an "intermediate syndrome" which includes ocular effects has been recognised more recently for some OPs (Senanayake and Karalliedde, 1987 Karademir et aL, 1990). The associated clinical signs, which are characteristically different from those seen in OP-induced delayed pol)meuropathy, are paralysis and weakness of proximal limbs, respiratory, neck and cranial muscles, including those innervated by the oculomotor nerve. The occurrence of myopathy in rats exposed to diisopropylfluorophosphate, paraoxon or soman (Wecker et aL, 1978 Vanneste and Lison, 1993) resembled the features of the "intermediate syndrome". The severity and duration of the myopathy in rats appeared directly related to the degree of inhibition of AChE. 

The nerve agent soman causes loss of muscle control and death from respiratory failure. Evidence of the effectiveness of pyridostigmine bromide as a pretreatment for exposure to soman was obtained primarily from studies in monkeys and guinea pigs. This evidence shows that administration of the drug before exposure to soman, together with atropine and pralidoxime administered after exposme, increases survival. The FDA believes... 

Kim, Y.-B., Cheon, K.-C., Hu, G.-H., et al., 2002. Effects of combinational prophylactics composed of physostigmine and procyclidine on soman-induced lethality, seizures and brain injuries. Env. Toxicol. Pharmacol. 11, 15-21. Kubin, L., Fenik, V., 2004. Pontine cholinergic mechanisms and their impact on respiratory regulation. Resp. Physiol. Neurobiol. 143, 235-249. 

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