• Journal of the Korea Institute of Military Science and Technology
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• v.14 no.5
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• pp.920-931
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• 2011

Nerve agents are irreversible inhibitors of the cholinesterase enzyme. Exposure causes a progression of toxic signs, including hypersecretions, fasciculations, tremor, convulsions, respiratory distress, epileptiform seizures, brain injuries and death. A combined regimen of prophylaxis and therapy is the most effective medical countermeasure for dealing with the threat of nerve agent poisoning to military personnel. In this paper, the author investigated the updated technologies regarding various pre- and post-treatment drugs for nerve agents detoxification which are under development in several countries including Korea. Some characteristics of active ingredients in the formulations of drugs, their action mechanisms, and effectiveness were analyzed. Additionally, part of experimental data on the transdermal patch studied in ADD using beagle dogs was introduced.

• Toxicological Research
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• v.16 no.3
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• pp.195-200
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• 2000

Antidotal efficacy of physostigmine plus procyclidine, the combinational prophylactics for organophosphate poisoning, was evaluated in rats and guinea pigs. To assess the dose-response relation-ship in rats, various doses (0.3-6.0mg/kg) of procyclidine in combination with a fixed dose (0.1mg/kg) of physostigmine were pretreated subcutaneously 30 min prior to subcutaneous exposure to nerve-agents. Physostigmine alone exerted protection ratios of 2.44, 1.20, 1.50, 1.50 and 2.20 folds for tabun, sarin, soman, cyclosarin and V-agent, respectively. Interestingly, coadmnistration of procyclidine with physostigmine exhibited remarkable synergistic effects in a dose-dependent manner, leading to 4.00~8.00 folds for tabun, 2.15-8.50 folds for sarin, 1.92~507 folds for so man, 2.15~2.90 folds for cyclosarin, and 2.71~10.50 folds for V-agent. On the contrary, a low effect (l.65 fold) was achieved with the traditional antidotes atropine (17.4 mg/kg) plus 2-pralidoxime (30 mg/kg) treated immediately after soman poisoning. Noteworthy, the combinational prophylactics markedly potentiated the effect of atropine plus 2-pralidoxime to 6.13 and 12.27 folds with 1.0 and 3.0 mg/kg of procyclidine, respectively, against soman poisoning. In guinea pigs, the physostigmine plus procyclidine prophylactics exerted protective effects of 3.00~4.70 folds against soman intoxcation, which were much higher at low doses (0.3~1.0 mg/kg) of procyclidine than those in rats. Taken together, it is proposed that the combinational prophylactics composed oj physostigmine and procyclidine could be a promising antidote regimen for the poisoning with organophosphates possessing diverse properties.

• Journal of the Korea Institute of Military Science and Technology
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• v.19 no.1
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• pp.119-126
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• 2016

The US Army used MARK-1 composed of atropine autoinjector and 2-PAM autoinjector as a medical countermeasure against nerve agent poisoning. Recently, it has been being replaced by the ATNAA(Antidote Treatment Nerve Agent AutoInjector) for improvement the convenience in use and rapid detoxification effect. ATNAA(FDA approval, NDA 21-175, 2002. 1. 17) is a multi-chambered autoinjector that sequentially delivers atropine and 2-PAM through a single needle to allow Warfighters to survive against lethal exposure to nerve agents. In this paper, our group investigated the case of FDA approval of ATNAA in a point of the various data required by FDA guideline, thereby making it easy to meet the KFDA guideline for the approval of the prototype our group has been developed. The purpose of this study is to provide a reference for efficient research activities to minimize time and cost. Additionally, the purpose of this study is to provide a reference for the planning for the development of similar drug.

• Journal of the Korea Institute of Military Science and Technology
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• v.16 no.2
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• pp.218-224
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• 2013

Organophosphorus compounds are irreversible inhibitors of cholinesterase enzyme. Exposure causes a progression of toxic signs, including hypersecretion, tremor, convulsion, respiratory distress, epileptiform seizure, brain injuries and death. To protect brain injuries, administration of diazepam as a neuroprotectant is now considered essential for severely exposed nerve agent casualties. However, studies have shown diazepam to provide less than total protection against the neuropathological consequences of nerve agent exposure. In this context, extensive studies have been carried out to find out effective alternative drugs to protect brain from epileptiform seizures induced by organophosphate compounds intoxication. It has been reported that a combination of carbamate and anticholinergic or antiglutamatergic can be a very effective medical countermeasure in dealing with the threat of organophosphorous poisoning. In this study, experimental animals including rats and guinea pigs were implanted with microelectrodes on their brain sculls, and treated with various centrally acting drugs such as physostigmine and procyclidine prior to soman challenge, and then its electroencephalography(ECoG) was monitored to see anticonvulsant effects of the drugs. It was found that seizure activities in ECoG were not always in proportion to clinical signs induced by soman intoxication, and that combinative pretreatment with physostigmine plus procyclidine effectively stopped the seizures induced by organophosphorous poisoning.

• Journal of Microbiology and Biotechnology
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• v.31 no.1
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• pp.144-153
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• 2021

Organophosphorus nerve agents (OPNAs), including both G- and V-type nerve agents such as sarin, soman, tabun and VX, are extremely neurotoxic organophosphorus compounds. Catalytic bioscavengers capable of hydrolyzing OPNAs are under development because of the low protective effects and adverse side effects of chemical antidotes to OPNA poisoning. However, these bioscavengers have certain limitations for practical application, including low catalytic activity and narrow specificity. In this study, we generated a fusion-hybrid form of engineered recombinant human paraoxonase 1 (rePON1) and bacterial organophosphorus hydrolase (OPH), referred to as GV-hybrids, using a flexible linker to develop more promising catalytic bioscavengers against a broad range of OPNAs. These GV-hybrids were able to synergistically hydrolyze both G-type OPNA analogs (paraoxon: 1.7 ~ 193.7-fold, p-nitrophenyl diphenyl phosphate (PNPDPP): 2.3 ~ 33.0-fold and diisopropyl fluorophosphates (DFP): 1.4 ~ 22.8-fold) and V-type OPNA analogs (demeton-S-methyl (DSM): 1.9 ~ 34.6-fold and malathion: 1.1 ~ 4.2-fold above) better than their individual enzyme forms. Among the GV-hybrid clones, the GV7 clone showed remarkable improvements in the catalytic activity toward both G-type OPNA analogs (kcat/Km (106 M-1 min-1): 59.8 ± 0.06 (paraoxon), 5.2 ± 0.02 (PNPDPP) and 47.0 ± 6.0 (DFP)) and V-type OPNA analogs (kcat/Km (M-1 min-1): 504.3 ± 48.5 (DSM) and 1324.0 ± 47.5 (malathion)). In conclusion, we developed GV-hybrid forms of rePON1 and bacterial OPH mutants as effective and suitable catalytic bioscavengers to hydrolyze a broad range of OPNA analogs.

• Journal of The Korean Society of Clinical Toxicology
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• v.7 no.2
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• pp.172-175
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• 2009

Zipeprol dihydrochloride is a non-opioid mucolytic, antitussive agent and it is frequently prescribed for respiratory symptoms such as cough and sputum. The main pharmacologic mechanisms of zipeprol are inhibition of superior laryngeal nerve stimulation and direct antagonism for stimulation of the bronchial receptors, which might have an effect for the drug's mucolytic action. Many cases of drug abuse with zipeprol have occurred world-wide due to the hallucinogenic effect of the drug. In Korea, zipeprol was reported to be the most commonly abused drug among young people for the 1990s. Zipeprol associated death was first reported since 1991 and 69 cases of death related to zipeprol abuse were further reported during 8 years (between 1991 and 1998). In addition to the hallucinogenic effect, dyspnea, extrapyramidal symptoms, seizure, cerebral edema have been reported as the signs and symptoms of toxic zipeprol overdose. However, zipeprol abuse is not common for old age people and non drug abusers. We report here on a fatal case of acute zipeprol poisoning in an eighty five year old drug addicted woman.