Persistent/delayed toxic effects of low-dose sarin and pyridostigmine under physical stress (exercise) in mice.

Pyridostigmine bromide, a reversible anticholinesterase drug, was used by military personnel during the Gulf War. They were under physical stress and might have been exposed to low-dose nerve gas, sarin. This study examined the interactions of low-dose sarin and pyridostigmine in exercised mice. Male NIH Swiss mice were treated as follows: 1) Control; 2) Sarin (0.01 mg/kg, sc); 3) exercise; 4) sarin plus exercise; 5) pyridostigmine; 6) pyridostigmine plus exercise; 7) pyridostigmine plus sarin; 8) pyridostigmine plus sarin plus exercise. Exercise was given daily for 10 weeks on treadmill and pyridostigmine and sarin were administered daily during the 5th and 6th weeks only. Respiratory exchange ratio decreased significantly during the dosing period of 5th and 6th weeks in groups 4, 6, and 8. Animals were sacrificed 24 hours after the ten-week exercise, tissues isolated and analyzed. Sarin significantly decreased butyrylcholine esterase (BChE) activity in plasma; AChE activity in platelet, triceps muscle, and striatum; neurotoxic esterase (NTE) activity in platelets, spinal cord, cortex and striatum and malondialdehyde (MDA) levels in sciatic nerve and cord. Sarin plus exercise significantly reduced BChE activity in plasma; acetylcholinesterase (AChE) activity in platelets, muscle, nerve and striatum; NTE activity in platelets, cord, cortex and striatum; and increased creatinine phosphokinase (CK) activity in plasma and MDA levels in cord. Pyridostigmine plus exercise significantly decrease BChE activity in plasma; AChE activity in muscle and enhanced malondialdehyde (MDA) levels in muscle. Pyridostigmine plus sarin significantly decreased NTE activity in platelets, cord, cortex and striatum. Pyridostigmine plus sarin plus exercise significantly altered AChE activity and MDA levels in muscle; and NTE activity in platelets, nerve, cord and cortex. Exercise significantly augmented the changes in plasma CK activity, muscle and nerve AChE activity, platelet NTE activity and cord MDA levels induced by sarin. It is concluded that physical stress (exercise) enhanced the persistent/delayed toxic effects of low-dose sarin and pyridostigmine in specific tissues of mice.

A comparative study of delayed neurotoxicity in hens following repeated administration of organophosphorus compounds.

Hens treated with Mipafox (10 mg/kg, sc), sarin (50 micrograms/kg, sc) or parathion (1 mg/kg, sc) daily for 10 days exhibited severe, moderate and no ataxia respectively on 14th day after the start of exposure. The neurotoxic esterase (NTE) activity was significantly inhibited in the brain, spinal cord and platelets of hens treated with mipafox or sarin whereas no change was noticed with parathion treatment. All three compounds significantly inhibited acetylcholinesterase (AChE) activity in the platelets. Spinal cord of hens treated with mipafox, sarin or parathion showed axonal degeneration heavy, moderate and none respectively. It is concluded that repeated administration of equitoxic doses of mipafox, sarin and parathion to hens are marked, moderate and non-delayed neurotoxic respectively.

Influence of pretreatment of carbamates on dynamic pulmonary mechanics in rats exposed to sarin aerosols.

The effect of pretreatment of two carbamates, pyridostigmine and physostigmine on dynamic pulmonary mechanics has been studied in rats exposed to sarin aerosols. Sign-free dose of pyridostigmine (0.075 mg/kg, i.m.) or physostigmine (0.1 mg/kg, i.m.) did not significantly alter the parameters of the dynamic pulmonary mechanics 20 min after treatment. However, sarin (51.2 mg/m3, for 15 min) depressed the respiratory rate, air flow and minute volume and enhanced the transthoracic pressure and tidal volume. Pretreatment with carbamates 20 min prior to sarin exposure significantly modified or counteracted the above induced changes. It is concluded that the protective effect of carbamates is mainly due to the correction of respiratory changes caused by sarin aerosols in rats.