• Journal of Pharmaceutical Investigation
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• v.31 no.3
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• pp.181-184
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• 2001

The purpose of this study was to develop transdermal drug delivery system (TDDS) for the combination of physostigmine and procyclidine. The effects of various pressure sensitive adhesives (PSA) on the percutaneous absorption of procyclidine across hairless mouse skin were evaluated to select an appropriate PSA. In addition, the influences of various vehicles on the percutaneous absorption of procyclidine from PSA matrix across hairless mouse skin were evaluated using flow-through diffusion cell system at $37^{\circ}C$. Physostigmine did not have any influence on the permeation rate of procyclidine. The flux of procyclidine was the highest in silicone and PIB and was relatively lower in SIS, Acryl, and SBS adhesive matrices, however, their use was limited by the crystallization of the drug in the matrix. Among acrylic adhesives, the permeability of procyclidine was the highest from poly (ethylene oxide) grafted acrylic adhesive. Some enhancers show different enhancing effect depending on the drug, however, many of the tested enhancers showed enhancing effect for the permeation of both procyclidine and physostigmine to some extent. $Crovol^{\circledR}$ EP 40 showed the highest enhancing effect on the permeation of both compounds. The size of TDDS to provide required permeation rate was estimated to be $35\;cm^2$ based on available information.

• 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.

• Applied Biological Chemistry
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• v.44 no.3
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• pp.148-152
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• 2001

This study investigated the role of excitatory amino acid systems in the initiation of organophosphate-induced seizures and brain damages in rats through quantitative in vivo microdialysis. Microdialysates were collected from the hippocampus of rat brain, treated with diisopropylfluorophosphate (DFP; 2.67 mg/kg, s.c.) alone, and/or atropine sulfate (15 mg/kg, i.m.) and procyclidine (30 mg/kg, i.m.). The protective effects of atropine, a muscarinic blocker, and/or procyclidine, a N-methyl-D-aspartate and cholinergic antagonist, against DFP were examined. DFP treatment increased the levels of aspartate (Asp) and glutamate (Glu) significantly in the hippocampal persuate with the induction of seizures. Treatment of procyclidine could effectively block the increase of Asp and Glu levels. Atropine treatment showed no significant anticonvulsive effects against DFP-induced seizures. The increases of Asp and Glu levels by DFP were also completely blocked through the combined treatment of atropine and procyclidine. Histopathological findings on the hippocampus confirmed the above results. More effective protection was observed through the treatments of procyclidine alone or of both procyclidine and atropine than atropine alone against DFP-induced brain damage. Procyclidine was shown to be effective in DFP-induced seizures.

• Archives of Pharmacal Research
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• v.24 no.3
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• pp.219-223
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• 2001

Nasal absorption of procyclidine, a synthetic anticholinergic compound, was investigated in Wistar rats and Beagle dogs. The dosing solution was prepared by dissolving$^{14}C$-procyclidme in 50% ethanolic saline. The dosing solution was administered intravenously and intranasally to rats at a dose of 0.6 mg/kg (i.e., $60{\mu}$l/kg in the form of a 1% w/v solution), and intravenously, orally and intranasally to doss at a dose of 0.3 mg/kg(i.e., $6{mu}$l/kg in the form of a 5% w/v solution). Blood samples were taken from an artery of the animals through the catheter for periods of 1200 (for rats) and 1440 min (for dogs), and the radioactivity in the samples was determined by liquid scintillation counting. The nasal bioavailability of Procyclidine in rats and dogs, based on the radioactivity was calculated to be 81.1 and 98.6% respectively. In both rats and dogs, the plasma profiles of procyclidine following nasal administration were very close to those following intravenous administration, leading to nearly superimposable profiles between the two protocols. In dogs, nasal administration resulted in significantly higher plasma concentrations during the first 30 min period compared to oral administration, suggesting the superiority of the nasal route over the oral route in terms of a prompt expression of the pharmacological effect of the drug. The results obtained in this study indicate that procyclidine is rapidly and nearly completely absorbed via the nasal route. In conclusion, nasal administration represents a viable alternative to intravenous administration in the case of procyclidine.

• Toxicological Research
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• v.16 no.3
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• pp.187-193
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• 2000

The antidotal, anticonvulsant and neuroprotective effects of physostigmine and procyclidine. the combinational prophylactics for organophosphate poisoning, were evaluated in rats. In comparison with a low protective effect (1.6 fold) of atropine (15 mg/kg) and 2-pralidoxime (30 mg/kg), the traditional antidotes regimen, a marked protection ratio of 7.3 fold was achieved by combinational pretreatment with physostigmine (0.05 mg/kg) and procyclidine (10 mg/kg), which was superior to that (3.5 fold) with pyri-dostigmine (0.1 mg/kg) and atropine (15 mg/kg). Rats exposed to a high dose (10 mg/kg. 2 X $LD_{50}$) of diisopropylfluorophosphate showed severe epileptiform seizures on electroencephalography, resulting in necrotic and apoptotic brain injuries in discrete brain regions under histopathological and TUNEL immuno-histochemical examinations in 24 hr. Such seizures and excitotoxic brain injuries were fully prevented by pretreatment with physostigmine (0.05 mg/kg) and procyclidine (10 mg/kg). in contrast to a negligible effect of pyridostigmine (0.1 mg/kg) and atropine (15 mg/kg). Taken together, it is proposed that the prophylactics composed of physostigmine and procyclidine could be a promising regimen for the prevention of lethality, seizures and brain injuries induced by organophosphate poisoning.

• Biomolecules & Therapeutics
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• v.9 no.1
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• pp.33-39
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• 2001

Antidotal efficacy of combinational prophylactics composed of physostigmine plus procyclidine, alone or in combination with antidotes such as atropine plus 2-pralidoxime or atropine plus HI-6, was evaluated in rats. Physostigmine (0.1 mg/kg) plus procyclidine (3 mg/kg), pretreated subcutaneously 30 min prior to subcutaneous exposure to organophosphates of militarily importance, exerted protection ratios of 7.2, 6.5, 4.0, 2.9 and 8.0 fold for tabun, saris, soman, cyclosarin and V-agent, respectively. In comparison, low effects (1.7 fold for soman and 1.3 fold for cyclosarin) were achieved with the traditional antidotes atropine (17.4 mg/kg) plus 2-pralidoxime (30 mg/kg) administered intramuscularly immediately after organophosphate, in contrast to high effects (5.5 fold for soman and 160.0 fold for cyclosarin) with atropine (17.4 mg/kg) plus HI-6 (125 mg/kg), although the protection ratio markedly decreased when treatment of antidotes was delayed. Note- worthy, the combinational prophylactics markedly potentiated the effects of antidotes to higher than 5.0 fold in all cases. In addition, the combinational prophylactics fully prevented the seizures and excitotoxic brain injuries induced by a high dose (100 mg/kg, 1.3 LD$_{50}$) of soman. Taken together, it is suggested that the prophylactics composed of physostigmine and procyclidine, in combination with posttreatment antidotes, could be a promising regimen for the prevention of lethality, seizures and brain injuries induced by organophosphates possessing diverse properties.s.

• Proceedings of the PSK Conference
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• 2001.10a
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• pp.191.1-191.1
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• 2001

• 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 the Korea Institute of Military Science and Technology
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• v.24 no.1
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• pp.144-150
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• 2021

This study was designed to evaluate the prophylactic efficacy of a combinational patch system containing physostigmine and procyclidine against sarin and soman using guinea pig. The median lethal dose values of two nerve agents were calculated by a probit analysis of deaths occurring within 24 h. In this study, the values of median lethal dose of sarin and soman were determined to be 33.0 and 26.7 ㎍/kg in guinea-pigs, respectively. The guinea pigs treated with a prophylactic patch(4×5 ㎠) for 24 h were 100 % protected against a challenge of 1.5 LD50. The combinational KMARK-1(atropine and 2-PAM) and prophylactic patch were more effective than a single KMARK-1, a combination of pyridostigmine and KMARK-1 significantly. Epileptiform seizures in the guinea pigs treated with the combinational antidotes led to neuropathological changes, in comparison with intact feature of brain of the animal treated with the patch.