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KMID : 0385020030190040209
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Korean Journal of Laboratory Animal Science
2003 Volume.19 No. 4 p.209 ~ p.220
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Two-Week Dose-Range Finding Study on Combinational Prophylactics, Composed of Physostigmine and Procyclidine, for Organophosphate Poisoning
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Huang Zai-Zhi
Kang Hyun-Gu
Park Sun-Hee
Kang Seong-kwi
Lee Jong-Sung
Park Jong-Il
Kim Wang-Soo
Phi Taek-San
Hwang Seock-Yeon
Kang Jong-Koo
Kim Yun-Bae
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Abstract
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The 2-week repeated-dose toxicity of novel combinational prophylactics, composed of physostigmine and procyclidine, for organophosphate poisoning was investigated in Beagle dogs. Osmotic minipumps containing physostigmine (15, 45 or 90 μg/kg/hr) and/or procyclidine (150, 450 or 900 μg/kg/hr) were implanted intraperitoneally to the dogs for 14 days. As a result, mean 40.1-42.3%, 70.3-73.4% and 87.3-91.7% inhibitions of blood butyrylcholinesterase activity were obtained by low (physostigmine 15 μg/kg/hr plus procyclidine 150 μg/kg/hr), medium (physostigmine 45 μg/kg/hr plus procyclidine 450 /kg/hr) and high (physostigmine 90 μg/kg/hr] plus procyclidine 900 μg/kg/hr) doses of combinational prophylactics, respectively. Interestingly, only high doses of each physostigmine (90 μg/kg/hr) or procyclidine (900 μg/kg/hr) induced severe toxic signs, resulting in death of male dog implanted with pumps containing physostigmine alone. In contrast, the dogs administered with high doses of combinational physostigmine (90 μg/kg/hr) plus procyclidine (900 μg/kg/hr) did not show any toxic signs, indicative of the offset of their side effects each other. In addition, the combinational prophylactics did not exert severe pathological changes, although high concentrations of the drugs slightly enhanced the focal inflammations induced by implantation of pumps containing vehicle, such as adhesion of pumps to omentum, yellowish ascites, capsulitis in spleen, hepatocytic degeneration and thickening of alveolar septa. Taken together, it is confirmed that the maximum tolerable doses of physostigmine and procyclidine are remarkably enhanced up to 90 μg/kg/hr and 900 μg/kg/hr, respectively, by combinational administration, in spite of severe toxic activities of each drug.
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KEYWORD
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Combinational prophylactics, Physostigmine, Procyclidine, Organophosphate poisoning, Repeated-dose toxicity, Osmotic minipumps
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