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PubMed2005

Ultrastructural effects of acute organophosphate poisoning on rat kidney.

We investigated the ultrastructural effects of the organophosphate compound methamidophos and treatment with atropine and pralidoxime (2-PAM) on rat kidneys. Male Wistar albino rats were assigned to four groups. Group 1 received 30 mg/kg methamidophos, the LD50 for this compound in rats, via oral gavage. Group 2 received only physiologic saline. Group 3 rats received 30 mg/kg methamidophos and were treated with 2-PAM and atropine via intraperitoneal injection when cholinergic symptoms were noted. Group 4 served as a control, and received physiologic saline in equivalent volumes and routes to Group 3. Kidney tissues were prepared for electron microscopic studies. No ultrastructural changes were detected in Group 1 after acute poisoning with methamidophos and in Group 3 treated with antidotes after poisoning. Acute organophosphate poisoning and antidotal treatment in this model are not associated with histopathological changes in the rat kidney but the models with different organophosphate compounds, by administrating the different dosages, may be more illuminative in explaining the effects of these chemicals in kidney.

Acute Disease↗
PubMed2006

In vitro potency of H oximes (HI-6, HLö-7), the oxime BI-6, and currently used oximes (pralidoxime, obidoxime, trimedoxime) to reactivate nerve agent-inhibited rat brain acetylcholinesterase.

The efficacy of H oximes (HI-6, HLö-7), the oxime BI-6, and currently used oximes (pralidoxime, obidoxime, trimedoxime) to reactivate acetylcholinesterase inhibited by two nerve agents (tabun, VX agent) was tested in vitro. Both H oximes (HI-6, HLö-7) and the oxime BI-6 were found to be more efficacious reactivators of VX-inhibited acetylcholinesterase than pralidoxime and obidoxime. On the other hand, their potency to reactivate tabun-inhibited acetylcholinesterase was low and did not reach the reactivating efficacy of trimedoxime and obidoxime. Thus, none of these compounds can be considered to be a broad-spectrum reactivator of nerve agent-inhibited acetylcholinesterase in spite of high potency to reactivate acetylcholinesterase inhibited by some nerve agents. More than one oxime may be necessary for the antidotal treatment of nerve agent-exposed individuals.

Acetylcholinesterase↗
PubMed2002

Reactivation kinetics of acetylcholinesterase from different species inhibited by highly toxic organophosphates.

Standard treatment of poisoning by organophosphates (OP) includes the administration of an antimuscarinic agent, e.g. atropine, and of an acetylcholinesterase (AChE) reactivator (oxime). The presently available oximes, obidoxime and pralidoxime (2-PAM), are considered to be insufficient for highly toxic OPs, e.g. sarin. In the past decades numerous oximes were prepared and tested for their efficacy in OP poisoning, mostly in animal experiments. However, data indicate that the reactivating potency of oximes may be different in humans and animal species, which may hamper the extrapolation of animal data to humans and may pose a problem in the drug licensing of new compounds. In order to provide data for a better evaluation of the reactivating potency of oximes, experiments were undertaken to determine the reactivation rate constants of several oximes with human, rabbit, rat and guinea-pig AChE inhibited by the OPs sarin, cyclosarin and VX. The results show marked differences among the species, depending on the inhibitor and on the oxime, and indicate that the findings from animal experiments need careful evaluation before extrapolating these data to humans.

Acetylcholinesterase↗
PubMed2002

Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials.

BACKGROUND: Acute organophosphorus (OP) pesticide poisoning is widespread in the developing world. Standard treatment involves the administration of intravenous atropine and an oxime to counter acetylcholinesterase inhibition at the synapse, but the usefulness of oximes is uncertain. AIM: To assess the evidence on the use of oximes in OP poisoning. DESIGN: Systematic review. METHODS: We searched Medline, Embase, and Cochrane databases (last check 01/02/02) for 'organophosphate' or 'oxime' together with 'poisoning' or 'overdose'. We cross-referenced from other articles, and contacted experts to identify unpublished studies. A Web search engine [www.google.com] was also used, with the keywords 'organophosphate', 'oxime', and 'trial' (last check 01/02/02). RESULTS: We found two randomized controlled trials (RCTs) involving 182 patients treated with pralidoxime. The RCTs found no benefit with pralidoxime, and have been used to argue that pralidoxime should not be used in OP poisoning. DISCUSSION: The RCT authors must be congratulated for attempting important studies in a difficult environment. However, their studies did not take into account recently clarified issues regarding outcome, and their methodology is unclear. A generalized statement that pralidoxime should not be used in OP poisoning is not supported by the published results. Oximes may well be irrelevant in the overwhelming self-poisoning typical of the tropics, but a large RCT comparing the current WHO-recommended pralidoxime regimen (>30 mg/kg bolus followed by >8 mg/kg/h infusion) with placebo is needed for a definitive answer. Such a study should be designed to identify any patient subgroups that might benefit from oximes.

Acute Disease↗
PubMed1994

Emergency care of insecticide poisonings.

Insecticide poisoning is an increasing event which requires a thorough knowledge base for diagnosis and management. Awareness of the importance of decontamination is fundamental not only in the prehospital care phase but also in the emergency department. A thorough knowledge of the essentials of emergency and critical care is indispensable for the management and support of ventilatory and circulatory functions. Specific antidotal therapy utilizing atropine and pralidoxime is usually necessary in the immediate care of acute cases. In addition, use of pralidoxime after acute exposure may contribute to a beneficial outcome. Appropriate laboratory determinations in the acute phase are necessary parameters for successful outcomes. The use of cholinesterase determinations for diagnostic and prognostic purposes is discussed.

Antidotes↗
PubMed1998

Neurophysiological monitoring of pharmacological manipulation in acute organophosphate (OP) poisoning. The effects of pralidoxime, magnesium sulphate and pancuronium.

OBJECTIVES: The neuromuscular transmission failure in acute organophosphate (OP) poisoning occurs because of the irreversible inactivation of the enzyme acetylcholinesterase located in the neuromuscular junction, and is distinguished neuroelectrophysiologically by single electrical stimulus-induced repetitive responses and either a decremental or a decrement-increment response upon high-rate repetitive nerve stimulation (RNS). Understandably, the administration of pharmacological agents with actions at different sites in the neuromuscular junction would alter the neuroelectrophysiological findings in acute OP poisoning. METHODS: The effect of several pharmacological agents including pralidoxime (10 patients), magnesium sulphate (4 patients) and pancuronium (7 patients) on the neuroelectrophysiological abnormalities was studied in 21 patients with acute OP poisoning. RESULTS: Pralidoxime administration produced neurophysiological amelioration in 11 out of 15 occasions. In those cases where it produced a beneficial effect, pralidoxime administration was continued and its neuroelectrophysiological effects were studied daily. The efficacy of pralidoxime administration was demonstrated by neuroelectrophysiological testing for a maximum of 6 days after poisoning. Three types of neuroelectrophysiological responses to pralidoxime were noted: (i) lack of neuroelectrophysiological improvement (two patients); (ii) initial improvement with subsequent lack of improvement (two patients); and (iii) initial improvement with subsequent normalisation of neuromuscular transmission (5 patients). Normalisation of the electrodiagnostic tests and the failure of pralidoxime to ameliorate the neuromuscular transmission abnormalities were neuroelectrophysiological indications for the discontinuation of pralidoxime treatment. The administration of magnesium sulphate (MgSO4.7H2O, 4 g intravenous) resulted in a decrease in the CMAP amplitude, loss of the repetitive response and conversion of the decrement-increment response at high-rate RNS to an incremental response. Repetitive responses and the decremental response at high-rate RNS also disappeared after the administration of pancuronium (0.5 mg intravenous) to 6 patients. However, in one case where pancuronium administration was preceded by pralidoxime, there occurred a dramatic worsening of the neuromuscular transmission defect. CONCLUSIONS: While the administration of all 3 agents-- pralidoxime, magnesium sulphate and pancuronium-- resulted in the reversion of the neuroelectrophysiological defects, only pralidoxime is contended to be therapeutically useful. The therapeutic benefit due to its administration is limited by a short duration of action, and hence it is recommended that it should be administered for a longer period of time under neuroelectrophysiolgical guidance.

Acute Disease↗
PubMed1995

A comparison of trimedoxime, obidoxime, pralidoxime and HI-6 in the treatment of oral organophosphorus insecticide poisoning in the rat.

This study summarizes the results of examination of acute oral toxicity of 26 organophosphorus insecticides in rats. The effectiveness of trimedoxime, obidoxime, pralidoxime and HI-6, given with atropine and diazepam, was tested in the treatment of poisoning with 2 LD50 of the insecticides. It was shown that the oximes were potent antidotes in poisoning with phosphate insecticides. Obidoxime, pralidoxime and HI-6 had low effectiveness in the treatment of poisoning with phosphonates and phosphorothiolates. However, none of the oximes was an effective antidote in poisoning with dimethoate and pyridafenthion. Trimedoxime was the most effective oxime in the treatment of insecticide poisoning, being successful especially at the lowest tested doses.

Administration, Oral↗
PubMed1976

[Prevention of abnormalities induced by 2 organophosphate insecticides (parathion and bidrin) in quail embryos].

When Quail embryos, injected with bidrin at the unincubated stage, are treated with nicotinamide, beak and leg abnormalities are prevented, but niacin has no beneficial effect on the axial deformities caused by both parathion and bidrin. In contrast, vertebral defects are greatly reduced by giving pralidoxim, an antidote known and used in organophosphorus intoxications. But this compound has no effect on beak and leg damage caused by bidrin. Two other cholinesterase reactivators, diacetylmonoxime and monoisonitrosoacetone have any effect on organophosphorus abnormalities and have no antiteratogenic action either on the beak and legs or on the vertebral column. From these observations the multiple causes of teratogenic effects induced by organophosphorus compounds are evident. Both aspects of teratogenesis, one related to the nicotinamide level, and the other related to the physiology of the cholinergic system are discussed.

Abnormalities, Drug-Induced↗
PubMed1998

The pharmacokinetics of continuous infusion pralidoxime in children with organophosphate poisoning.

OBJECTIVE: To define the pharmacokinetics of continuous infusion pralidoxime in organophosphate-poisoned children. STUDY DESIGN: Open-label study in 11 children and adolescents poisoned with organophosphates or carbamates. Serial blood samples were obtained during continuous pralidoxime infusion and after the drug was stopped. RESULTS: Patients were treated for 12-43 hours. Steady-state concentrations were (mean +/- SD) 22.2 +/- 12.3 mg/L. Volume of distribution ranged from 1.7 to 13.8 L/kg and was significantly higher in the more severely poisoned subjects. Elimination half-life was 3.6 +/- 0.8 hours, and clearance was 0.88 +/- 0.55 L/h/kg. After initiation of continuous infusion pralidoxime, only 1 patient required any additional atropine to control recurrent muscarinic symptoms. All patients exhibited complete clinical recovery. CONCLUSIONS: The pharmacokinetics of pralidoxime in poisoned children following continuous intravenous infusion are widely variable and differ from those previously reported in both healthy and poisoned adults. A loading dose of 25-50 mg/kg is recommended followed by a continuous infusion of 10-20 mg/kg/h. A loading dose of 50 mg/kg may be appropriate in more severely poisoned patients.

Adolescent↗
PubMed2006

Acetylcholinesterase inhibition: does it explain the toxicity of organophosphorus compounds?

The hypothesis that acetylcholinesterase (AChE) inhibition is the mechanism of toxicity of organophosphorus (OP) compounds was examined by mathematically modeling the in vivo lethal effects of OP compounds and determining the amount of variation in OP toxicity that is explained by AChE inhibition. Mortality dose-response curves for several OP compounds (i.e., VX, soman, cyclosarin, sarin, tabun, diisopropylfluorophosphate and paraoxon) exhibited steep probit slopes (> 9.6) in guinea pigs. Steep probit slopes were also observed when the mortality dose-response curves for soman were examined in mice, rats, rabbits and non-human primates. The consistently steep probit slopes of the dose-response curves for highly toxic OP compounds suggested that these compounds have a single specific mechanism of toxicity regardless of the OP compound or the species in which it was tested. Regression analysis indicated that 93% of the 3,280-fold variation in the median lethal doses (i.e., LD(50)) of OP compounds in rats was explained by the variation in their in vitro rate constants for inhibition of AChE. Conversely, 91% of the 23-fold variation in the ability of the oximes pralidoxime and obidoxime to protect against the toxicity of OP compounds in guinea pigs was explained by the variation in the in vitro ability of oximes to reactivate OP-inhibited AChE. The best explanation for this variety of observations was that the primary mechanism of in vivo toxicity for highly toxic OP compounds is the inhibition of AChE, and the residual unexplained variation in OP toxicity that might be explained by other mechanisms represents < 10% of the total variation in OP toxicity.

Animals↗
PubMed1997

Reappraisal of indications and limitations of oxime therapy in organophosphate poisoning.

1 In vitro studies with human erythrocyte acetylcholinesterase (AChE) and the mouse diaphragm model were performed to unravel the various microscopic reaction parameters that contribute to the dynamic equilibrium of AChE inhibition, ageing and reactivation. These data may help to define more precisely the indications and limitations of oxime therapy in organophosphate (OP) poisoning. 2 Diethylphosphoryl-AChE resulting from intoxications with parathion, chlorpyrifos, chlorfenvinphos, diazinon and other OPs is characterized by slow spontaneous reactivation and low propensity for ageing. This kind of phosphorylated enzyme is particularly susceptible to reactivation by oximes. 3 None of the oximes tested (pralidoxime, obidoxime, HI 6 and HLö 7) can be regarded as a universally suitable reactivator. Obidoxime turned out to be the most potent and most efficacious oxime in reactivating AChE inhibited by various classes of OP insecticides and tabun. Obidoxime, however, was inferior to HI 6 against soman, sarin, cyclosarin and VX. Pralidoxime was generally less potent. 4 The kinetic data of reactivation established for diethylphosphoryl-AChE of human red cells indicate that the usually recommended dosage to attain a plasma concentration of 4 micrograms/ml does not permit exploitation of the full therapeutic potential of the oximes, in particular of pralidoxime. However, in suicidal mega-dose poisoning, oximes, even at optimal plasma concentrations, may be unable to cope with the fast re-inhibition of reactivated AChE in the first days following intoxication. 5 It is suggested that oximes be administered by continuous infusion following an initial bolus dose as long as reactivation can be expected and until permanent clinical improvement is achieved.

Acetylcholinesterase↗
PubMed1992

Plasma concentrations of pralidoxime methylsulphate in organophosphorus poisoned patients.

Using pharmacokinetic data from healthy human volunteers in a bicompartmental pharmacokinetic model, a repeated dose scheme for pralidoxime methylsulphate (Contrathion) was developed producing plasma levels remaining above the assumed "therapeutic concentration" of 4 mg.l-1. Using the same data, it was found that a concentration of 4 mg.l-1 could also be obtained by a loading dose of 4.42 mg.kg-1 followed by a maintenance dose of 2.14 mg.kg-1.h-1. In order to study the pharmacokinetic behaviour of pralidoxime in poisoned patients, this continuous infusion scheme was then applied in nine cases of organophosphorus poisoning (agents: ethyl parathion, ethyl and methyl parathion, dimethoate and bromophos), and the pralidoxime plasma levels were determined. The mean plasma levels obtained in the various patients varied between 2.12 and 9 mg.l-1. Pharmacokinetic data were calculated, giving a total body clearance of 0.57 +/- 0.27 l.kg-1.h-1 (mean +/- SD), an elimination half-life of 3.44 +/- 0.90 h, and a volume of distribution of 2.77 +/- 1.45 l.kg-1.

Dose-Response Relationship, Drug↗
PubMed2004

A comparison of the efficacy of a bispyridinium oxime--1,4-bis-(2-hydroxyiminomethylpyridinium) butane dibromide and currently used oximes to reactivate sarin, tabun or cyclosarin-inhibited acetylcholinesterase by in vitro methods.

The efficacy of a bispyridinium oxime 1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide, called K033, and of currently used oximes (pralidoxime, obidoxime, oxime HI-6), to reactivate acetylcholinesterase inhibited by various nerve agents (sarin, tabun cyclosarin) was tested by in vitro methods. The new oxime K033 was found to be a more efficacious reactivator of sarin or cyclosarin-inhibited acetylcholinesterase than pralidoxime and obidoxime but it did not reach the efficacy of oxime HI-6 in the case of the inhibition of acetylcholinesterase by sarin or cyclosarin. On the other hand, oxime K033 was more efficacious than oxime HI-6 in reactivating tabun-inhibited acetylcholinesterase. Thus, oxime K033 seems to be a relatively efficacious broad spectrum acetylcholinesterase reactivator and, therefore, could be useful if no information about the type of nerve agent used was available.

Acetylcholinesterase↗
PubMed2004

In vitro reactivation of acetylcholinesterase using the oxime K027.

The ability of a new bisquaternary oxime, K027 (1-[4-hydroxyiminomethylpyridinium]-3-[carbamoylpyridinium] propane dibromide), to reactivate the enzyme acetylcholinesterase (AChE) inhibited by the nerve agents Tabun, sarin and VX was evaluated. Its reactivation potency was compared to the AChE reactivators pralidoxime (2-PAM), obidoxime and HI-6; K027 seems a good reactivator of organophosphates-inhibited AChE. Its reactivation potency is lower compared to the other oximes for reactivation of sarin-inhibited AChE, but it is sufficient to significantly increase the activity of sarin-inhibited AChE. Its reactivation ability is comparable to obidoxime for reactivation of VX- and tabun-inhibited AChE and is higher than the reactivation potency of HI-6, for tabun-inhibited AChE. HI-6 is currently regarded the most promising reactivator of organophosphates-inhibited AChE.

Acetylcholinesterase↗
PubMed1995

Neuroleptic malignant-like syndrome: a complication of acute organophosphate poisoning.

We report a 60-yr-old woman with schizophrenia, who manifested a neuroleptic malignant (NM)-like syndrome after acute organophosphate poisoning (OPP). She attempted suicide by ingesting 40% emulsions of DMTP (S-2,3-dihydro-5-methoxy-2-oxo-1,3,4-thiadizol-3-yl-methyl O,O-dimethyl phosphorodithioate) 100 ml. On admission, she was unconscious and demonstrated convulsions, depressed respiratory movements, miosis and profuse salivation. Plasma cholinesterase concentration (842 IU.L-1) was very low and OPP was diagnosed. She was treated with gastric lavage, atropine and pralidoxime (PAM). By the seventh day after admission, symptoms of OPP disappeared and serum ChE had recovered to a sub-normal level. On the 13th day, she demonstrated coma, high fever (41.0 degrees C) and lead-pipe rigidity. Serum CPK was increased (1631 IU.L-1). Dantrolene sodium iv was administered for three days. Body temperature began to decrease in 24 hr, and her consciousness, muscle rigidity and other neurological symptoms returned to normal by the 16th day after admission. She was discharged from the hospital without sequelae 55 days after admission. We conclude that OPP can predispose to an NM-like syndrome and that dantrolene may be effective in the management.

Atropine↗
PubMedDate not supplied

The reactivating and therapeutic efficacy of oximes to counteract Russian VX poisonings.

Russian VX (O-isobutyl-S-(2-diethylaminoethyl)methylphosphonothioate) is the structural analogue of VX agent. It differs from VX agent (O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothioate) by two alkyl groups. The potency of currently available oximes (pralidoxime, obidoxime, HI-6) to reactivate Russian VX-inhibited acetylcholinesterase and to eliminate Russian VX-induced acute toxic effects was evaluated using in vivo methods. In vivo determined percentage of reactivation of Russian VX-inhibited blood and brain acetylcholinesterase in poisoned rats shows that HI-6 seems to be the most efficacious reactivator of Russian VX-inhibited acetylcholinesterase among currently used oximes in the peripheral compartment, whereas no difference between reactivating efficacy of all tested oximes was observed in the central compartment. The oxime HI-6 was also found to be the most efficacious oxime in the elimination of acute lethal toxic effects in Russian VX-poisoned mice among all studied oximes. Thus, the oxime HI-6 seems to be the most suitable oxime for the antidotal treatment of acute poisonings with Russian VX as in the case of VX, sarin, cyclosarin, and soman poisonings.

Acetylcholinesterase↗
PubMed1983

Brain neuronal RNA metabolism during acute soman toxication: effects of antidotal pretreatments.

Effects of various antidotal treatments on neuronal RNA contents and on soman induced RNA and acetylcholinesterase (AChE) depletion were monitored using quantitative cytochemical techniques. In rats only with antidotes, atropine depressed whereas pralidoxime (2-PAM) elevated RNA contents of both caudate and cerebrocortical (Layer V) neurons. Soman produced a virtually complete inhibition of AChE activity and a moderate decline in neuronal RNA contents. Atropine pretreatment partially restored neuronal RNA levels. Atropine + 2-PAM prophylaxis eventuated in a complete restoration of RNA levels but no reactivation of AChE. Addition of physostigmine to the atropine + 2-PAM treatment regimen resulted in appreciable AChE reactivation but reduced RNA levels. The overall data indicate that: (1) soman-induced neuronal RNA depletion can be completely reversed by antidotal pretreatments; (2) no precise relationship exists between the extents of antidote-induced restoration of RNA and AChE levels; and (3) 2-PAM exerts marked effects on the brain neuronal network which are unrelated to AChE reactivation. It is postulated that effects of soman and antidotes on neuronal RNA metabolism may signify alterations in acetylcholine (ACh) sensitivity and that pharmacologic manipulation of ACh responsiveness during organophosphate cholinesterase poisoning may be a mechanism for additional therapeutic intervention.

Acetylcholinesterase↗