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KMID : 0385020030190040221
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Korean Journal of Laboratory Animal Science
2003 Volume.19 No. 4 p.221 ~ p.234
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Four-Week Repeated-Dose Toxicity Study on Combinational Prophylactics, Composed of Physostigmine and Procyclidine, for Organophosphate Poisoning
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Lee Jong-Sung
Huang Zai-Zhi
Kang Hyun-Gu
Park Sun-Hee
Park Cheol-Beom
Park Jong-Il
Kim Wang-Soo
Phi Taek-San
Choi Ehn-Kyoung
Hwang Seock-Yeon
Kang Jong-Koo
Kim Yun-Bae
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Abstract
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The 4-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, 30 or 45 μg/kg/hr) and procyclidine (150, 300 or 450 μg/kg/hr) were implanted intraperitoneally to the dogs for 28 days. The low doses of physostigmine (15 μg/kg/hr) and procyclidne (150 μg/kg/hr) were adopted to match the estimated clinical blood concentrations. Mean blood concentrations of 0.51-0.53 ng/ml, 1.12-1.18 ng/ml and 2.49-2.57 ng/ml for physostigmine, and 21.5-33.5 ng/ml, 105.6-153.1 ng/ml and 357.0-502.0 ng/ml for procyclidine were obtained by low (physostigmine 15 μg/kg/hr plus procyclidine 150 μg/kg/hr), medium (physostigmine 30 μg/kg/hr plus procyclidine 300 μg/kg/hr) and high (physostigmine 45 μg/kg/hr plus procyclidine 450 μg/kg/hr) doses of combinational prophylactics, respectively. In addition, mean 30.9-37.2%, 44.2-51.1% and 69.0-71.2% inhibitions of blood butyrylcholinesterase activity were achieved by the 3-dose levels of physostigmine, respectively. The dogs administered with the combinational prophylactics up to 45 μg/kg/hr of physostigmine plus 450 μg/kg/hr of procyclidine did not induce toxic signs and 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, hepatocytic vacuolar degeneration, and hepatic and splenic capsulitis. Taken together, it is suggested that the combinational prophylactics might not exert considerable adverse effects at clinical doses.
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KEYWORD
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Combinational prophylactics, Physostigmine, Procyclidine, Organophosphate poisoning, Repeated-dose toxicity, Osmotic minipumps
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