It is one of the most extensively studied transporters regarding drug resistance and drug-drug interactions. One of the key players affecting pharmacokinetic profiles of many clinically relevant compounds is an active efflux transporter, P-glycoprotein (Pgp) which is ubiquitously present in living systems from bacteria to humans. Dose dependent efficacy of pyridostigmine pretreatment and time-dependent protection by physostigmine and pyridostigmine using maximum sign-free dose against inhaled sarin aerosols on rats have been reported. These symptoms are likely to be augmented by other stress factors like physical exercise in hyperthermic and hypothermic conditions. A number of studies indicate that the drug was used to protect soldiers against nerve gas exposure during Persian Gulf War (PGW) but the veterans complained of various side effects ascribed to pyridostigmine although it was suggested as “symptom-free dose.” So, controversy hovers around the efficacy of PB with respect to its dosage. Pyridostigmine bromide (PB) is a quarternary ammonium compound which has been approved as a pretreatment drug against toxic OP compounds. Introduction Organophosphorous (OP) compounds are used as pesticides and were also developed as chemical warfare agents. So, pretreatment with sign-free dose of pyridostigmine bromide offers sufficient protection from stress against organophosphorous DFP exposure as observed from these molecular studies and does not significantly alterP-glycoprotein receptors quantitatively.ġ. In silico docking studies show that the pyridostigmine molecule binds with maximum affinity to asparagine(1235), threonine(1199) and arginine(1229) in the C-terminal half of the P-glycoprotein. Further, sign-free dose of pyridostigmine does not induce genotoxicity as far as chromosomal breakage is concerned. Treatment with high doses (8-16mg/ml) of PB on alternate days for a week caused 10 -20% increase in the receptor count, indicating the toxicity level. Immunohistochemical studies show that drug efflux transporter P-glycoprotein receptors were not quantitatively upregulated by physical stress or hyperthermia or hypothermia or sign-free dosage (0.075 mg/Kg after intramuscular injection) of the xenobiotic pyridostigmine bromide. Total antioxidant status was observed to be more than 50% potentiated with sign-free dose of PB. This study attempts to decipher the level of cellular toxicity imparted by PB pretreatment by assessing drug efflux transportation of the PB or DFP and possible genotoxicity with respect to chromosomal aberrations, in addition to total antioxidant status (TAS) of blood under such circumstances. The effects of carbamate (pyridostigmine bromide, PB) pretreatment prior to physiological stress and organophosphorous compound, DFP (diisopropylfluorophosphate) exposure have been investigated on rats. Soldiers are exposed to multiple stress conditions adverse psychological, physico-chemical and environmental conditions during warfare which can result in significant physical and chemical alterations in the biological system.
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