Effects of phenytoin, ketamine, and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate

Abstract

Toxic manifestations of acetylcholinesterase inhibitors (AChE-I) include muscle twitching and muscle fiber necrosis, in addition to muscarinic manifestations of acetylcholine excess. The AChE-Is pinacolyl methylphosphonofluoridate (soman) or diisopropylphosphorofluoridate (DFP) were administered to rats to produce spontaneous muscle fiber discharges. Soman produced discharges that arose primarily from the central nervous system (CNS), while those due to DFP were generated from the peripheral nerves as well as the CNS. Three drugs were tested for their potential to reduce muscle fiber discharges: atropine methyl nitrate (AMN), ketamine, and phenytoin. Ketamine caused a significant decrease in discharges of CNS origin, while AMN and phenytoin had no effect. For muscle fiber discharges of peripheral origin, all three drugs produced a significant drop in muscle fiber discharges, but phenytoin showed slightly more efficacy than the others. AChE-I-induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different AChE-Is. Treatment for the toxicity of AChE-Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system (PNS) where AChE-Is exert their effects. By attenuating the effects of AChE-Is at specific CNS or PNS sites, the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each AChE-I.

Evaluation of antidotal effects of adamantyl derivative Tamorf in soman poisoning

“…There are reports on the adjuvant therapeutic effects of phencyclidine (PCP), for example derivative ketamine (Schuh, 1975;Cohen et al, 1974;Clinton et al, 1988;Mion et al, 2003), thienyl phencyclidine (TCP, tenocyclidine) and some of their derivatives in the medical treatment of soman poisoning (McDonough and Shih, 1993;Lallement et al, 1994;Carpentier et al, 1994;Lallement et al, 1998a;Gabrielewitz et al, 1980). The structure-activity of PCP has been discussed in terms of its 3-ring system: an aromatic ring producing an area of negative charge, a basic heterocyclic nitrogen ring bearing a localized positive charge and a cycloalkyl ring which is lipophilic in character (Vaupel et al, 1984).…”

Protective Effects of Aerosolized Scopolamine Against Soman-Induced Acute Respiratory Toxicity in Guinea Pigs

“…It has been previously shown that ketamine protects against GD-induced neuropathology, while anesthetic doses of barbiturate increase GD toxicity. 60 –64 It also has been reported that intramuscular treatment of scopolamine protects against CWNA exposure. 35 , 36 , 41–45 , 65…”

“…It has been previously shown that ketamine protects against GD-induced neuropathology, while anesthetic doses of barbiturate increase GD toxicity. [60][61][62][63][64] It also has been reported that intramuscular treatment of scopolamine protects against CWNA exposure. 35,36,[41][42][43][44][45]65 In addition to the CNS anticholinergic effects, the mechanism of protection by aerosolized scopolamine may involve antisecretory effects and reduction in copious airway secretion and respiratory toxicity and peripheral nervous system effects.…”

Chemical and biological weapons. Implications for anaesthesia and intensive care †

“…Although it increases oropharyngeal secretions (as do nerve agents), in vitro studies have shown that ketamine protects AChE; the in vivo signi®cance of this is not known. 27 The second phase, or`intermediate syndrome', 107 begins after the cholinergic phase and lasts 4±18 days depending on the de novo resynthesis rate of AChE (usually 1% of preexposure AChE function is recovered per day). This phase is characterized by muscle weakness, particularly of the diaphragm, and is associated with respiratory failure and cranial nerve palsies.…”