Evaluation of antidotal effects of adamantyl derivative Tamorf in soman poisoning.
The nerve agent soman, a powerful inhibitor of acetylcholinesterase (AChE; EC 3.1.1.7), causes an array of toxic effects in the central nervous system. Adamantyl tenocyclidine derivative Tamorf (1-[2-(2-thienyl)-2-adamantyl] morpholine), a compound with potential activity at the N-methyl-D-aspartate (NMDA) receptors and with neuroprotective properties, is effective against convulsions and brain lesions related to soman poisoning. The objective of this study was to evaluate the antidotal potency of Tamorf (2.5 mg kg(-1)), which was tested alone as a pretreatment or in combination with atropine (10.0 mg kg(-1)) as a therapy in rats poisoned with two different sub-lethal doses of soman (1/4 and 1/2 of LD50). The effect of Tamorf was compared with carbamate physostigmine (0.1 mg kg(-1)). The study also determined the possible genotoxic effects of Tamorf and physostigmine, especially primary DNA damage in white blood cells, liver and brain tissue. Tamorf administered 5 min before poisoning stopped soman-induced seizures, was successful against sub-lethal doses of soman and protected AChE activity in the brain (P = 0.0014, P = 0.0019), and in plasma (P = 0.0464, P = 0.0405). Compared with Tamorf, physostigmine was slightly effective in the elimination of soman-induced poisoning in rats. The pharmacological effect of Tamorf and atropine was less effective as therapy, but did not increase soman toxicity (P > 0.05 for all interactions). The results obtained indicate that Tamorf and physostigmine are not genotoxic to rats in the concentrations tested. Treatment with Tamorf seems to be a good alternative for current pretreatment in soman poisoning. Its antidotal mechanism is complex and is based on combined biochemical and receptor properties.
Lucić Vrdoljak
A
A
Institute for Medical Research and Occupational Health, Zagreb, Croatia. alucic@imi.hr
Radić
B
B
Garaj-Vrhovac
V
V
Kopjar
N
N
Zlender
V
V
D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D000931:Antidotes / Q000627:therapeutic use*; D001921:Brain / Q000201:enzymology; D002619:Chemical Warfare Agents / Q000506:poisoning; D002800:Cholinesterase Inhibitors / Q000506:poisoning; D020552:Comet Assay; D007962:Leukocytes / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011041:Poisoning / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D012999:Soman / Q000506:poisoning*
C508955:1-(2-(2-thienyl)-2-adamantyl) morpholine; D000927:Anticonvulsants; D000931:Antidotes; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D009025:Morpholines; D018696:Neuroprotective Agents; D012999:Soman; D000110:Acetylcholinesterase; D000218:Adamantane