Protection by a transdermal patch containing physostigmine and procyclidine of soman poisoning in dogs.
The prophylactic efficacy of a combinational patch system containing physostigmine and procyclidine against soman intoxication was evaluated using dogs. Female beagle dogs (body weights 9-10 kg) were shaved on the abdominal side, attached with a matrix-type patch (7x7 cm) containing 1.5% of physostigmine plus 6% procyclidine for 2 days, and challenged with subcutaneous injection of serial doses (2-10 LD50) of soman. Separately, in combination with the patch attachment, atropine (2 mg/dog) plus 2-pralidoxime (600 mg/dog) or atropine plus 1-[([4-(aminocarbonyl)pyridinio]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium (HI-6, 500 mg/dog) were injected intramuscularly 1 min after soman poisoning. The LD50 value of soman was determined to be 9.1 microg/kg, and high doses (> or = 1.4 LD50) of soman induced salivation, emesis, defecation and diarrhea, tremors and seizures, and recumbency of dogs, leading to 100% mortality in 24 h. The prophylactic patch, which led to mean 18.5-18.8% inhibition of blood cholinesterase activity by physostigmine and mean 7.9-8.3 ng/ml of blood concentration of procyclidine, exerted a high protection ratio (4.7 LD50), in comparison with relatively-low effects of traditional antidotes, atropine plus 2-pralidoxime (2.5 LD50) and atropine plus HI-6 (2.7 LD50). Noteworthy, a synergistic increase in the protection ratio was achieved by the combination of the patch with atropine plus HI-6 (9 LD50), but not with atropine plus 2-pralidoxime (5 LD50). In addition, the patch system markedly attenuated the cholinergic signs and seizures induced by soman, especially when combined with atropine plus HI-6, leading to elimination of brain injuries and physical incapacitation up to 6 LD50 of soman poisoning. Taken together, it is suggested that the patch system containing physostigmine and procyclidine, especially in combination with atropine and HI-6, could be a choice for the quality survival from nerve-agent poisoning.
Kim
Wang-Soo
WS
Biomedical Section, Agency for Defense Development, Yuseong P.O. Box 35-1, Daejeon 305-600, Republic of Korea.
Cho
Young
Y
Kim
Jee-Cheon
JC
Huang
Zai-Zhi
ZZ
Park
Sun-Hee
SH
Choi
Ehn-Kyoung
EK
Shin
Sunhee
S
Nam
Sang-Yoon
SY
Kang
Jong-Koo
JK
Hwang
Seock-Yeon
SY
Kim
Yun-Bae
YB
D000279:Administration, Cutaneous; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004285:Dogs; D005260:Female; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010091:Oximes; D010830:Physostigmine / Q000008:administration & dosage / Q000494:pharmacology*; D011352:Procyclidine / Q000008:administration & dosage / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology; D012999:Soman / Q000506:poisoning*
D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D010091:Oximes; D011726:Pyridinium Compounds; D001285:Atropine; D012999:Soman; D010830:Physostigmine; D011352:Procyclidine; C022870:asoxime chloride