Disposition kinetics of 2-pyridine aldoxime methochloride in Bubalus bubalis.
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Animals↗
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Reactivation kinetics of diethylphosphoryl acetylcholine esterase.
The kinetics of reactivation of diethylphosphorylated acetylcholine esterase by pyridine-2-aldoxime methochloride has been studied using the approach of following the course of the hydrolysis of acetylcholine during the reactivation of the phosphorylated enzyme by the reactivator [Tsou, C.-L. (1965) Acta Biochem. Biophys. Sin. 5, 398-417]. Equations are derived based on the scheme of the formation of a complex between the phosphorylated enzyme and the reactivator and the rate of dissociation of this complex is not necessarily faster than the dephosphorylation and regeneration of the active enzyme. The regenerated enzyme then reacts with the substrate through an acetyl-enzyme intermediate as generally depicted. The equation obtained for product formation during the course of reactivation contains two exponential terms and this is in accord with the experimentally observed biphasic reaction. By making the assumption that the dissociation of the phosphorylated enzyme-reactivator complex is much faster than the dephosphorylation reaction, the above equation can be simplified to a form containing only one exponential term. By following the course of the reactivation reaction with the conventional approach of taking aliquots and assaying for enzyme activity recovery, it would appear likely that one would miss the initial stage of this biphasic reaction.
Acetylcholinesterase↗
The influence of ionic strength on the interaction of quaternary drugs with mammalian acetylcholinesterase in relation to possible regulatory effects.
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Acetylcholinesterase↗
Oximes and atropine in sarin poisoning.
Three oximes, monoisonitrosoacetone (MINA), pyridine-2-aldoxime methiodide (PAM) and diacetylmonoxime (DAM), have been examined in combination with atropine as antidotes in sarin poisoning. When treatment was administered 15 min. before sarin, atropine enhanced the protective effect of MINA and DAM 2 to 3 times and of PAM 9 to 10 times in mice and rats. In mice, rats, and guinea-pigs, atropine increased by no more than 2 times the protective effect of all three oximes when given 30 sec. after sarin. Atropine given to monkeys 1 min. after sarin raised the LD50 approximately 3 times. When given in conjunction with MINA or DAM, the LD50 of sarin was raised 7 to 14 times.
Animals↗
Protection against the lethal effects of organophosphates by pyridine-2-aldoxime methiodide.
The mechanism responsible for the protection against lethal organophosphate poisoning by pyridine-2-aldoxime methiodide (P-2-AM) was studied in the mouse. Two types of organophosphates were used: ethyl pyrophosphate (TEPP), E 600, Ro 3-0340, and Ro 3-0422 which form with true cholinesterase a diethylphosphoryl enzyme (1) and DFP, D 600, and Ro 3-0351 which form with true cholinesterase a diisopropylphosphoryl enzyme (2).In vitro and under the experimental conditions used more than 50% reactivation of (1) was obtained within 1 hr. by concentrations of P-2-AM ranging from 0.5 to 1x10(-5) M; 30 times higher concentrations of the oxime were required to achieve the same effect with (2). In vivo reactivation of phosphorylated true cholinesterases in blood amounted to 10 to 24% within the first 30 min. if 25 mg./kg. P-2-AM was injected (i.p.) 5 min. before a sublethal dose of TEPP, E 600, Ro 3-0340, or Ro 3-0422 and reactivation reached a maximum within 1 to 2 hr. after the injection of the oxime. P-2-AM was more effective when given 30 min. after the organophosphate. The effect of 25 mg./kg. P-2-AM on the phosphorylated true cholinesterase in brain (experiments with TEPP and E 600) was negligible. A dose of 25 mg./kg. P-2-AM had no consistent effect on the phosphorylated true cholinesterases in blood and brain of mice injected with sublethal doses of DFP, D 600, or Ro 3-0351.The protection by 25 mg./kg. P-2-AM against lethal doses of TEPP, E 600, Ro 3-0422, and Ro 3-0340 was greater than that obtained with 50 mg./kg. atropine sulphate, but the degree of protection was determined by the organophosphate itself and not its dialkylphosphoryl group. Protection by 25 mg./kg. P-2-AM against lethal doses of DFP, D 600, and Ro 3-0351 was negligible. The antidotal effect of P-2-AM was potentiated by atropine. Mice which were injected with atropine and P-2-AM were protected to a greater extent against DFP than against Ro 3-0422, and protection against DFP was only slightly less than protection against TEPP. This is difficult to reconcile with a specific action of P-2-AM on phosphorylated cholinesterases.
Acetylcholinesterase↗
The toxicity of 2-hydroxyiminomethyl-N-methylpyridinium methanesulphonate (P2S).
The toxicity of 2-hydroxyiminomethyl-N-methylpyridinium methanesulphonate (P2S) has been determined in a number of species by various routes. It is approximately equally toxic in the rat, mouse, and guinea-pig. It is much more toxic in the dog. Atropine influences the toxicity of P2S differently in different species. From the results obtained attempts have been made to assess the maximum safe dose which can be given intramuscularly to man.
Animals↗
The effect of some oximes in sarin poisoning.
The effects of monoisonitrosoacetone (MINA), diacetylmonoxime (DAM) and pyridine-2-aldoxime methiodide (P2AM) upon the cholinesterase of sarin poisoned rats have been studied. Monoisonitrosoacetone and diacetylmonoxime given before sarin protected blood and brain cholinesterase from inhibition. Monoisonitrosoacetone given after the appearance of signs of poisoning caused a rapid reactivation of brain cholinesterase. Diacetylmonoxime, at an equimolar dose, produced only a slight increase in enzyme activity, and pyridine-2-aldoxime methiodide, the best reactivator in vitro, reactivated blood but not brain cholinesterase. There is a relationship between protection and reactivation of brain cholinesterase and prevention and alleviation of signs of poisoning.
Animals↗
Potentiation of the response of frog rectus muscle to acetylcholine by isopropyl methyl phosphonofluoridate and its modification by pyridine-2-aldoxime methiodide.
Pyridine-2-aldoxime methiodide (P2AM) was used to study the relation between the recovery of cholinesterase activity of isolated frog rectus abdominis muscle and the change of isotonic response to acetylcholine after previous treatment with the anticholinesterase, isopropyl methyl phosphonofluoridate (sarin). Addition of P2AM to muscle which had been incubated with sarin produced an 88% decrease in potentiation to acetylcholine. This was accompanied by 71% and 35% recoveries of the cholinesterase activity of the intact and finely ground muscle respectively compared with controls from the contralateral muscle. Following pre-treatment with sarin, a two-hour rinsing with acetylcholine (3 mug./ml.) produced a 61% decrease in potentiation to acetylcholine accompanied by 24% and 4.5% recoveries of cholinesterase activity in intact and in ground muscle respectively. Since control experiments showed absence of uncombined sarin in the muscle after rinsing with acetylcholine solution, the results indicate a greater effectiveness of P2AM and acetylcholine in reactivating superficially situated cholinesterase of the frog rectus abdominis as compared with enzyme within the interior of the muscle.
Acetylcholine↗
2-Hydroxyiminomethyl-N-methylpyridinium methanesulphonate and atropine in the treatment of severe organophosphate poisoning.
The soluble methanesulphonate of the oxime 2-hydroxyiminomethyl-N-methylpyridinium (P2S) has been used to treat animals poisoned with sarin or ethyl pyrophosphate. The effect of the size of the dose, and its time of administration in relation to poisoning, have been examined. This oxime is very efficient in conjunction with atropine when given either before or after poisoning. About 30 mg./kg. seems to be the optimum therapeutic dose of the methanesulphonate. The significance of this optimum is discussed in relation to the treatment of accidental poisoning by organophosphate insecticides in man.
Animals↗
Maximal inhibition of cholinesterase in the central nervous system.
In experiments on mice treated with pralidoxime iodide (pyridine-2-aldoxime methiodide; PAM) and atropine, the cholinesterase activity in the brain was assayed after poisoning with very high doses of organophosphorous anticholinesterases. Acetylcholine was added to the buffer solution in which the brains were homogenized. This precaution reduced the combination between free inhibitor present in the tissue and active enzyme, and the cholinesterase activity found was below 0.5% of controls. When the experimental data were corrected for spontaneous reactivation in vitro during incubation, the calculated activities in vivo were even less. It is concluded that mice can survive complete inactivation of the cholinesterase in the central nervous system, if enough atropine is given to protect the animals against the toxic effects of the accumulating acetylcholine.
Acetylcholine↗
Phosphorylphosphatase and oximes.
The effects of pralidoxime iodide, 1,1-trimethylenebis(4-formylpyridinium bromide) dioxime and diacetyl monoxime on the activity of phosphorylphosphatase prepared from pig kidney in vitro have been studied. It was found that these oximes, even at high concentrations, did not affect the activity of the enzyme.
Animals↗
Mechanism of the antagonism by pralidoxime and 1,1-trimethylenebis(4-hydroxyiminomethylpyridinium) of the action of echothiphate on the intestine.
Pralidoxime chloride (pyridine-2-aldoxime methochloride; Protopam Chloride) and 1,1'-trimethylenebis(4-hydroxyiminomethylpyridinium bromide) (TMB-4) antagonize the spasm of the isolated or intact small intestine of the rabbit caused by the anticholinesterase, echothiophate iodide (S-2-dimethylaminoethyl OO-diethyl phosphorothiolate methiodide; Phospholine Iodide). In vitro, both oximes also antagonize the spasm caused by acetylcholine. The quantitative relationships have been studied in comparison with the activity of atropine against echothiophate and acetylcholine. Echothiophate-treated intestine which is subjected to a concentration of oxime sufficient to cause 100% restoration of function (but not cholinesterase reactivation) will go back into spasm on washing out both drugs. Strips treated with a high concentration of oxime, sufficient to cause 100% reactivation of cholinesterase, exhibit normal control tone and motility after washing. It is concluded that pralidoxime and 1,1'-trimethylenebis(4-hydroxyiminomethylpyridinium bromide) have an anticholinergic action as well as the ability to reactivate cholinesterase and that this action plays a significant part in the initial recovery of function under the conditions of these experiments.
Animals↗
Differential antagonism of the acutely lethal effects of organophosphates in rats.
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Animals↗
Therapy of organophosphate poisoning: the marmoset as a model for man.
1 The ability of various bis-pyridinium oximes to restore organophosphate-inhibited neuromuscular transmission in vitro was compared in human intercostal and marmoset diaphragm muscles. 2 HI-6 (2-hydroxyiminomethyl-pyridinium-1-methyl-4'-carbamoyl-pyridinium-1'-methyl ether dichloride monohydrate) appeared very effective against VX (O-ethyl S-2-diisopropylaminoethyl methylphosphonothioate) and sarin in both muscles, whereas obidoxim was quite effective against tabun. 3 Against soman, HI-6, HS-6 (2-hydroxyiminomethyl-pyridinium-1-methyl-3'-carbamoyl-pyridinium-1'-methyl ether dichloride dihydrate) and obidoxim had little effect in the human muscle and only slight activity in the marmoset muscle; HGG-12 (2-hydroxyiminomethyl-pyridinium-1-methyl-3'-phenylcarbonyl-pyridinium-1'-methy l ether dichloride) and benzyl-P2A (1-benzyl-2-hydroxyiminomethyl-pyridinium methanesulphonate) were ineffective. 4 Anaesthetized, atropinized marmosets were poisoned with soman (4 X LD50, i.v.) and subsequently treated with HI-6, HS-6 or HGG-12. Only HI-6 and HS-6 were marginally effective in restoring respiration and neuromuscular transmission. 5 Marmoset muscle is a reasonable model for human muscle for the study of organophosphate poisoning and therapy.
Animals↗
Oral treatment of organophosphate poisoning in mice.
OBJECTIVE: Organophosphates are used as pesticides, herbicides, and chemical warfare agents. Treatment of organophosphate poisoning is with intravenous atropine and pralidoxime in addition to supportive care. This study determined the efficacy of oral agents in preventing death from organophosphate poisoning. METHODS: The organophosphate paraoxon (8 mg/kg) was used in a murine model with lethality at four and 24 hours as an end point. For oral treatment, 15 male Balbc mice were given either atropine sulfate (4 mg/kg), or a combination of atropine sulfate (4 mg/kg) with pralidoxime (100 mg/kg), by oral gavage. A control group of 22 mice received water by oral gavage. Chi-square analysis was used to compare results in the different groups. RESULTS: Of the control group, six of 22 survived to four hours after paraoxon exposure. Of the exposed animals treated with oral atropine, eight of 15 survived to four hours. Of the exposed animals treated with a combination of atropine and pralidoxime, 13 of 15 survived to four hours. All animals surviving to four hours survived to 24 hours. The increased survival of animals in the atropine group relative to the control group was not significant (p = 0.09). Survival was significant in the group treated with atropine and pralidoxime relative to atropine alone (p = 0.02) and to the control group (p = 0.0002). All treated mice surviving at four hours were alive at 24 hours. CONCLUSIONS: Both oral atropine and a combination of oral atropine and pralidoxime improved survival, and combination therapy achieved statistical significance. Generalization of this result to other organophosphate pesticides, other doses of paraoxon, and other species cannot be made without further investigations.
Animals↗
Cardiovascular consequences of organophosphorus poisoning and of antidotes in conscious unrestrained rats.
The cardiovascular effects of two organophosphorus, paraoxon and soman, as well as of antidotes advocated in the treatment of these intoxications have been investigated using a computerized analysis of arterial blood pressure in conscious unrestrained rats. Intravenous administration of paraoxon as well as of soman produced a marked, sustained and dose-related increase in blood pressure associated with a bradycardia. Pyridostigmine, a quaternary carbamate, neither altered blood pressure nor heart rate. Benzodiaxepines, such as diazepam or loprazolam, and atropine induced a dose-dependent tachycardia while pralidoxime decreased heart rate. A complete therapeutic scheme including the intravenous administration of pyridostigmine 10 min. before a postpoisoning therapy made of pralidoxime, diazepam and atropine induced a transient tachycardia, which was followed, after a return to control values, by a second and more stable tachycardia concurrently to a slight hypertension. Postpoisoning therapy alone suppressed the pressor effect of soman within a few minutes after its administration. Afterwards, this therapy reduced the importance of the cardiovascular effects produced by soman. Pyridostigmine pretreatment decreased the protection afforded by postpoisoning therapy in soman-intoxicated rats. These results show that postpoisoning therapy with pralidoxime, diazepam and atropine has a noteworthy efficacy against cardiovascular manifestations of soman intoxications in the rat.
Animals↗
Organophosphate poisoning in pregnancy: a case report.
A 42-year-old pregnant woman (26 weeks of gestation, G(4)P(0+3)) presented at the emergency department with a two-hour history of dizziness, blurred vision and repeated vomiting. These symptoms started during the use of an undiluted insecticide liquid (diazinon 60 EC) while cleaning a small non-aired bathroom. After clinical and laboratory confirmation for organophosphate poisoning (plasma pseudocholinesterase levels 161 U/l), treatment with atropine and pralidoxime was started. She recovered within 7 days and delivered a healthy baby 12 weeks later (Apgar score 9 and 10) by elective cesarean section. The child showed no signs or symptoms of organophospate, atropine or pralidoxime exposure.
Adult↗
Occurrence, diagnosis, and treatment of organophosphate pesticide poisoning in man.
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Adult↗