Physostigmine pretreatment with

Philippens IHCHM, Vanwersch RAP, Groen B, Olivier B, Bruijnzeel PLB, Melchers BPC. Subchronic physostigmine pretreatment in marmosets absence of side effects and effectiveness against soman poisoning with negligible postintoxication incapacitation. Toxicological Sciences 53 84-91, 2000a. 

A third approach to protection against excessive AChE inhibition lies in pretreatment with reversible inhibitors of the enzyme to prevent binding of the irreversible organophosphate inhibitor. This prophylaxis can be achieved with pyridostigmine or physostigmine but is reserved for situations in which possibly lethal poisoning is anticipated, eg, chemical warfare. Simultaneous use of atropine is required to control muscarinic excess. 

Tuovinen, K., Harminen, O. (1999). Protection of mice against soman by pretreatment with eptastigmine and physostigmine. Toxicology 139 233 1. 

The concept of using carbamates as pretreatment which protects against OP intoxication was first mooted in 1956 by Koster who demonstrated that cats pretreated with a small dose of eserine (physostigmine) survived poisoning by supralethal doses of diisopropylphosphorofluori-date (DFP) (Koster, 1956). Subsequently, Berry and Davies (1970) demonstrated the effectiveness of a combination of atropine and carbamate pretreatment against soman poisoning. At that time, it was not considered that pretreatments with substances such as atropine, with marked actions on the central nervous system, would be acceptable for human use. For this reason, effort was concentrated upon pretreatment with pyridostigmine, a quaternary carbamate, which would not be expected to cross the blood-brain barrier and affect the central nervous system. 

FUTURE PROSPECTS PRETREATMENT WITH PHYSOSTIGMINE AND HYOSCINE... 

Figure 2. Duration of loss of posture and performance of a visually guided reaching task in marmosets pretreated with pyridostigmine or physostigmine/hyoscine, and challenged with (a) sarin or (b) soman.

Pharmacokinetics of physostigmine (PHY) was compared after pretreatment with different routs of administration and then soman challenge.Rats were dosed with H-PHY (i.v., 100 i.m., 500 oral, 650 p,g/kg), 5 or 15 min prior to soman (105 p,g/kg S.C. 1.5 LDjq or 35 p,g/kg s.c. 0.5 LD50) treatment and were sacrificed at various times. Pharmacokinetic parameters were determined for PHY using JANA and PC-NONLIN programs. AUC decreased from 1372 to 603 and from 4502 to 1610, indicating 56% and 64% reduction in systemic availability of PHY after i.v. and i.m. dose, respectively, in the presence of soman. Cl increased from 73 to 165 and from 111 to 310 ml min kg in the pretreated rats with i.v. and i.m. PHY, respectively. On the other hand, systemic availability of PHY increased by about 100% (an increase in AUC from 152 to 312), and total Cl decreased from 4254 to 2080 ml min kg after oral pretreatment with PHY. In the presence of soman, hepatic Cl decreased from 31.85 to 29.9 ml min kg and intrinsic Cl from... 

Harris, L.W., Heyl, W.C., Stitcher, D.L., and Moore, R.D., The effect of atropine and/or physostigmine on cerebral acetylcholine in rats poisoned with soman, LifeScL, 22,907,1978. Harris, L.W., Stitcher, D.W., and Heyl, W.C., The effects of pretreatments with carbamates, atropine and mecamylamine on survival and on soman induced alterations in rat and brain acetylcholine. Life Scl, 26, 1885, 1980. 

The time to death of animals given a mixture of spirolides was increased after pretreatment with physostigmine [46]. Conversely, the time to death was decreased when atropine or other acetylcholine antagonists were given before administration of spirolide [46]. 

Tuovinen, K., Hanninen, O., 1999. Protection of mice against soman by pretreatment with eptastigmine and physostigmine. Toxicology 139, 233-241. Tuovinen, K., Kaliste-Korhonen, E., Raushel, F.M., et al., 1999. Success of pyridostigmine, physostigmine and phosphotriesterase treatments in acute sarin... 

Harris, L.W. et al. Physostigmine (alone and together with adjunct) pretreatment against soman, sarin, tabun and VX intoxication. Drug Chem. Toxicol, 14, 265, 1991. 

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