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PubMed1994

Choline derivatives and sodium fluoride protect acetylcholinesterase against irreversible inhibition and aging by DFP and paraoxon.

A light addressable potentiometric sensor was used to measure acetylcholinesterase (AChE) activity in order to evaluate the protective effects of quaternary compounds and NaF against enzyme phosphorylation and aging by two organophosphates. The use of the immobilized AChE made possible the quick removal of reagents (i.e., organophosphate, 2-pralidoxime, and protectant), thereby permitting accurate determination of AChE activity before and after phosphorylation and aging. Paraoxon was 15-fold more potent in inhibiting AChE than DFP, while the percent aging following phosphorylation by diisopropylfluorophosphate (DFP) was much higher. Sodium fluoride (NaF), the most effective protectant against phosphorylation and aging, and the quaternary ammonium compounds reduced significantly AChE inhibition by DFP and paraoxon, to similar degrees. Even though the percent AChE activity that was lost to aging was reduced by these agents, aging as a percent of phosphorylated AChE was not reduced. Thus, their major effect was in reducing the percent AChE phosphorylation, which consequently resulted in reduction of total aged AChE. The finding that quaternary ammonium compounds protect against phosphorylation is consonant with the proposed presence of the active site of AChE in an aromatic gorge.

Acetylcholinesterase↗
PubMed1991

HI-6 in man: efficacy of the oxime in poisoning by organophosphorus insecticides.

The efficacy of the oxime HI-6 was studied as a treatment for organophosphorus poisoning. HI-6 was given four times daily as a single intramuscular injection of 500 mg accompanied by atropine and diazepam therapy. Oxime treatment was started on admission and continued for a minimum of 48 h and a maximum of 7 d. HI-6 rapidly reactivated human blood acetylcholinesterase inhibited by dimethoxy organophosphorus compounds, while the dimethoxy-inhibited enzyme was mainly resistant to the treatment by HI-6. Although both HI-6 and pralidoxime chloride reactivated the red blood cell cholinesterase in quinalphos-poisoned subjects, the return of enzyme activities was more rapid following the use of HI-6. The general improvement of poisoned patients, which was sometimes more rapid than the rise of acetylcholinesterase activity, pointed to direct pharmacological effects of HI-6. No undesirable side-effects were noted in patients when HI-6 plasma concentrations were maintained at levels far above the 'therapeutic' concentration for up to 7 d.

Adult↗
PubMed2006

Russian VX: inhibition and reactivation of acetylcholinesterase compared with VX agent.

Organophosphorus compounds such as nerve agents inhibit, practically irreversibly, cholinesterases by their phosphorylation in the active site of these enzymes. Current antidotal treatment used in the case of acute nerve agent intoxications consists of combined administration of anticholinergic drug (usually atropine) and acetylcholinesterase (AChE, EC 3.1.1.7) reactivator (HI-6, obidoxime, pralidoxime), which from a chemical view is a derivative from the group of pyridinium or bispyridinium aldoximes (commonly called "oxime"). Oximes counteract acetylcholine increase, resulting from AChE inhibition. In the human body environment these compounds are powerful nucleophiles and are able to break down the bond between AChE and nerve agent molecule. This process leads to renewal of enzyme functionality -- to its reactivation. The usefulness of oxime in the reactivation process depends on its chemical structure and on the nerve agent whereby AChE is inhibited. Due to this fact, selection of suitable reactivator in the treatment of intoxications is very important. In our work, we have compared differences in the in vitro inhibition potency of VX and Russian VX on rat, pig and human brain, and subsequently we have tested reactivation of rat brain cholinesterase inhibited by these agents using oxime HI-6, obidoxime, pralidoxime, trimedoxime and methoxime. The results showed that no major differences in the reactivation process of both VX and Russian VX-inhibited cholinesterase. The similarity in reactivation was caused by analogous chemical structure of either nerve agent; and that oxime HI-6 seems to be the most effective reactivator tested, which confirms that HI-6 is currently the most potent reactivator of AChE inhibited by nerve agents. The results obtained in our study should be considered in the future development of new AChE reactivators.

Animals↗
PubMed2002

Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents.

The cholinesterase-inhibiting organophosphorus compounds referred to as nerve agents (soman, sarin, tabun, GF agent, and VX) are particularly toxic and are considered to be among the most dangerous chemical warfare agents. Included in antidotal medical countermeasures are oximes to reactivate the inhibited cholinesterase. Much experimental work has been done to better understand the properties of the oxime antidotal candidates including the currently available pralidoxime and obidoxime, the H oximes HI-6 and Hlö-7, and methoxime. There is no single, broad-spectrum oxime suitablefor the antidotal treatment of poisoning with all organophosphorus agents. If more than one oxime is available, the choice depends primarily on the identity of the responsible organophosphorus compound. The H oximes appear to be very promising antidotes against nerve agents because they are able to protect experimental animals from toxic effects and improve survival of animals poisoned with supralethal doses. They appear more effective against nerve agent poisoning than the currently used oximes pralidoxime and obidoxime, especially in the case of soman poisoning. On the other hand, pralidoxime and especially obidoxime seem sufficiently effective to treat poisonings with organophosphorus insecticides that have relatively less toxicity than nerve agents.

Animals↗
PubMed1999

Toxicology cart for stocking sufficient supplies of poisoning antidotes.

Within a three-month period, the University of New Mexico Health Sciences Center (UNMHSC) encountered three toxicological emergencies in which antidotes were either unavailable or inadequately stocked. Patient A was a patient with ethylene glycol intoxication. The emergency department (ED) physician ordered a 10% ethanol infusion. The pharmacy staff was unable to locate the commercially available solution and had to compound the infusion, resulting in a delay in administration of the antidote. Patient B was a patient at an outside hospital with organophosphate exposure whose transfer to our ED was requested by the other hospital. The pharmacy staff was unable to locate the pralidoxime needed to treat this patient; therefore; the patient was not transferred. It was later discovered that the pralidoxime had been stored in a location inconsistent with the storage policy for this medication. Patient C was a patient with severe rattlesnake envenomation. The pharmacy staff could locate only half of the antivenin needed to treat this patient. In each of these three cases, it was necessary to compound the required medication or to obtain it from other local facilities. These cases underscore the need for pharmacies to stock adequate amounts of poisoning antidotes in one immediately accessible location. A similar problem with understocking of poisoning antidotes exists throughout the United States.

Antidotes↗
PubMed2000

Long circulating liposomes encapsulating organophosphorus acid anhydrolase in diisopropylfluorophosphate antagonism.

These studies are focused on antagonizing organophosphorous (OP) intoxications by a new conceptual approach using recombinant enzymes encapsulated within sterically stabilized liposomes to enhance diisopropylfluorophosphate (DFP) degradation. The OP hydrolyzing enzyme, organophosphorous acid anhydrolase (OPAA), encapsulated within the liposomes, was employed either alone or in combination with pralidoxime (2-PAM) and/or atropine. The recombinant OPAA enzyme, from the ALTEROMONAS: strain JD6, has high substrate specificity toward a wide range of OP compounds, e.g., DFP, soman, and sarin. The rate of DFP hydrolysis by liposomes containing OPAA (SL)* was measured by determining the changes in fluoride-ion concentration using a fluoride ion-selective electrode. This enzyme carrier system serves as a biodegradable protective environment for the OP-metabolizing enzyme (OPAA), resulting in an enhanced antidotal protection against the lethal effects of DFP. Free OPAA alone showed some antidotal protection; however, the protection with 2-PAM and/or atropine was greatly enhanced when combined with (SL)*.

Animals↗
PubMed1995

Interaction of phosphamidon with neuropathy target esterase and acetylcholinesterase of hen brain.

Phosphamidon (PSM) is an organophosphorus insecticide widely used in agriculture. This study was undertaken to examine the interaction of PSM with acetylcholinesterase (AChE) and neuropathy target esterase (NTE) of hen brain in vitro and in vivo. PSM was a potent inhibitor of AChE, with an I50 of 2.9 microM and second-order rate constant (ka) of 1.2 x 10(4) M-1 min-1 at 37 degrees C. PSM-inhibited AChE aged rapidly (t1/2 = 1.9 h). Pyridinium oximes pralidoxime, trimedoxime, obidoxime and HI-6 were effective reactivators of PSM-inhibited AChE, providing up to 75% reactivation. PSM was one of the weakest inhibitors of NTE among organophosphorus compounds, with an I50 of 19 mM and ka of 1.8 M-1 min-1 at 37 degrees C. Inhibited NTE did not reactivate spontaneously and KF-induced reactivation was not obtained even at the earliest tested moments, so it was not clear whether aging of PSM-inhibited NTE occurred very quickly or the KF molecule could not affect the stability of phosphoryl-NTE bond. From the ratio of kas for NTE and AChE (0.00015) it was predicted that delayed neuropathic effects of PSM in vivo would appear only at doses far above the acute LD50. The LD50 value of PSM p.o. for hens was 9 mg/kg. Hens were treated with a single oral dose of PSM, combined with standard antidotal treatment which included atropine, physostigmine, pralidoxime and anticonvulsant midazolam. Doses of 90 and 250 mg/kg caused up to 27% and 45% NTE inhibition 48 h after poisoning, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed2002

Organophosphate intoxication as a consequence of mouth-to-mouth breathing from an affected case.

We report three cases of organophosphate (OP) poisoning. One patient was a 19-year-old woman who drank OP compounds in an attempt at suicide. The other two patients became intoxicated on the way to the hospital during mouth-to-mouth breathing. The first patient died in the emergency department, and the other two were taken to the ICU. There, they were treated with atropine and pralidoxime. Three days later, all symptoms and signs had disappeared, and they were discharged from the hospital satisfactorily.

Adult↗
PubMed2001

A clinico-epidemiological study of organophosphorus poisoning at a rural-based teaching hospital in eastern Nepal.

Thirty-seven patients with severe organophosphorus poisoning (OPP) presented to the emergency ward of BP Koirala Institute of Health Sciences between January 1995 and December 1996. The mean age of patients was 26.9 years. There were 17 (46%) males and 20 (54%) females, with male:female ratio being 1:1.2.Twenty-three (62%) patients were unmarried with 16 (46%) of them students. The most common reason for poisoning was suicide--32 patients (86.5%). The most commonly involved compound was Metacid (methyl-parathion)--23 (62%) patients. Ninety per cent of the patients presented within 2 h of ingestion. All patients were managed with intravenous atropine. Pralidoxime was given to patients with nicotinic symptoms and mechanical ventilation initiated in patients with respiratory distress. The mean dose of atropine used in the first 24 h and during the hospital stay was 30.6 mg and 136.7 mg, respectively. The mean duration of treatment was 5.5 days (range 2-20 days). Two patients developed intermediate syndrome and the overall mortality among hospitalized patients was 8%.

Adolescent↗
PubMed1998

Effects of various drugs including organophosphorus compounds (OPC) and therapeutic compounds against OPC on DRL responding.

The effects of various drugs were assessed in rats responding under a Differential-Reinforcement-of-Low-Rate 30-s (DRL 30-s) schedule. Atropine, scopolamine, and CEB-1957 (a new muscarinic blocker) increased response rate and decreased reinforcement rate, while methylatropine only decreased reinforcement rate. Physostigmine decreased response and reinforcement rates, when pyridostigmine had few effect on DRL responding. The irreversible acetylcholinesterase (AChE) inhibitors organophosphorus compounds (OPC) soman and sarin, injected at one-third of the LD50 did not consistently alter DRL performance, suggesting that they produce few behavioral effects in the rat when administered at subtoxic doses. Three oximes--pralidoxime, pyrimidoxime, and HI-6--decreased both response and reinforcement rates. Mecamylamine had few consistent effects on performance, and nicotine, d-amphetamine, diazepam, and the wakening drug modafinil increased response rate and decreased reinforcement rate. These two latter drugs also increased the number of very premature responses. These results, taken together, indicate that a DRL schedule is a useful tool to bring to light the existence of psychotropic effects of a drug. The explanation of drug-induced alterations of DRL performance, in terms of effects on cognition or on mood, is also discussed.

Animals↗
PubMedDate not supplied

Five oximes (K-27, K-33, K-48, BI-6 and methoxime) in comparison with pralidoxime: survival in rats exposed to the organophosphate paraoxon.

Oximes are cholinesterase reactivators used in organophosphorus poisoning. Clinical experience with pralidoxime (PRX) and other oximes is disappointing and their routine use has been questioned. In addition it is known that not all oximes are equally effective against all existing organophosphorus compounds. There is a demand for broad-spectrum reactivators with a higher efficacy than PRX. Based on our previous in vitro work the protection conferred by the various new oximes against inhibition by paraoxon as quantified by the IC(50) shift (nM increase in the IC(50) of the inhibitor per microM oxime present) is: 0.3 (PRX), 0.4 (methoxime; MMC-4), 1 (K-33), 1.2 (BI-6), 1.5 (K-48) and 3.7 (K-27). The purpose of the study was to quantify in vivo the extent of oxime-conferred protection, using paraoxon (POX) as a cholinesterase inhibitor and to test whether in vitro efficacy translates to protection from mortality. There were seven groups of six rats in each cycle of the experiment. Group 1 (G1) received 1 micromol POX (approximately LD(75)), the other groups (G2-G7) received 1 micromol POX + of one the six reactivators. The animals were monitored for 48 h and the time of mortality was recorded. The procedure was repeated five times (cycles). All substances were applied i.p. The experiments were repeated using 2, 3, 5 and 10 micromol POX. Mortality data were compared and hazards ratios (relative risks) ranked using the Cox proportional hazards model using POX dose and group (reactivator) as time-independent covariables. The relative risk of death estimated by Cox analysis (95% CI) in oxime treated animals when compared with untreated animals, adjusted for POX dose (high/low) was K-27: 0.26 (0.19-0.35); K-48: 0.34 (0.25-0.45); methoxime: 0.38 (0.29-0.50); BI-6: 0.53 (0.41-0.69); PRX: 0.70 (0.54-0.91); K-33: 0.82 (0.63-1.07). It is concluded that K-27 and K-48 are the most promising new oximes. The compounds with the best results in vitro also confer the best protection in vivo. Further testing using methyl- and propyl-organophosphates are needed.

Animals↗
PubMedDate not supplied

Dose-response effects of atropine and HI-6 treatment of organophosphorus poisoning in guinea pigs.

HI-6 (1-2-hydroxyiminomethyl-1-pyridino-3-(4-carbamoyl-1-pyridino -2- oxapropane dichloride) has been evaluated as an oxime alternative to pralidoxime, and toxogonin in the treatment of organophosphorus (OP) poisoning. The dose response effects of atropine (ATR) and HI-6 were investigated to more fully explore the interaction of these compounds in the treatment of OP poisoning. ATR, HI-6 and various combinations of the two drugs were evaluated against lethal poisoning by soman (GD) and tabun (GA) in guinea pigs. The effect of adjunctive diazepam treatment on the efficacy of atropine and HI-6 against soman was also investigated. Animals of either sex were challenged s.c. with OP and treated i.m. 1 min later with ATR and/or HI-6. When used, diazepam was injected immediately after ATR+HI6. LD50s of each treatment were calculated from probit models based on 24-hour survival against 5 levels of nerve agent and 6 animals per challenge level. A protective index (PI) was calculated by dividing the nerve agent LD50 in the presence of treatment by the LD50 in the absence of treatment. Treatment with HI6 alone had little effect on the toxicity of either OP. Treatment with ATR alone was more effective than HI-6 alone and was significantly more effective against soman than against tabun. When used in combination atropine and HI-6 had a strong synergistic effect against both agents. The dose of atropine used with HI-6 was critical in determining the efficacy of HI-6 against either agent. The slopes of the dose-lethality curves were minimally affected by the dose of ATR or HI-6. Adjunctive treatment with diazepam enhanced the efficacy of HI-6 and atropine against soman. It is concluded that 1) ATR has a large effect on the efficacy of HI-6 against OP poisoning, 2) the dose of ATR must be carefully selected in studies investigating the efficacy of HI-6 against OP poisoning, 3) the effective dose of ATR in the guinea pig is approximately 16 mg/kg, and 4) diazepam is a useful adjunct to atropine and HI-6.

Animals↗
PubMed2006

HPLC analysis of K-48 concentration in plasma.

K-48 is a new oxime-type compound to be used as an enzyme reactivator in the treatment of exposure to organophosphorous compounds. Plasma concentration of K-48 can be determined using reversed-phase HPLC. Analysis using octyl silica stationary phase and ultraviolet-absorbance detection is fast and simple. K-48 displays a relatively high dose-normalized area under the curve as compared to pralidoxime, which might be beneficial for an antidote. After i.m. administration of 50 mumol K-48, the time course of the concentration can be approximated by a straight line between 15 and 120 min meaning the elimination follows zero-order kinetics.

Animals↗
PubMedDate not supplied

A review of organophosphate poisoning.

Many organophosphate compounds are pesticides widely used for the control of insect vectors. They are not ideal agents because they lack target vector selectivity, and have caused severe toxicity and even death in humans and domestic animals. Their toxicity has been recognised since the 1930s, when they were also developed for use as chemical warfare agents. The mechanism of action of organophosphates has been determined in some depth; the understanding of the toxic effects resulting from the inhibition of cholinesterase activity, causing accumulation of acetylcholine at nerve endings has played a major part in providing a rationale for specific antidote treatment using atropine and oximes. However, the most suitable oxime for reactivation of cholinesterases has still not been established with certainty, although pralidoxime is widely recommended. Chronic toxicity, particularly the neuropathic effects, merits further study because it contributes substantially to the long term morbidity in cases of severe acute, or chronic, exposure. Prevention of potentially toxic organophosphate exposure, particularly amongst employees in industries manufacturing or using the compounds and in the most susceptible groups of the population, such as the young and the elderly, should be sought wherever possible. Government authorities should be encouraged to control organophosphate product licensing, manufacture, storage, import, methods of use and delivery, food contamination and disposal.

Antidotes↗
PubMed2006

LC-UV and LC-MS evaluation of stress degradation behaviour of avizafone.

It has been known for many years that benzodiazepine compounds effectively antagonize seizures induced by organophosphorous nerve agents. In the event of poisoning, a combination of three drugs is commonly used: an anticholinergic drug (e.g. atropine), an oxime used as cholinesterase reactivator (e.g. pralidoxime or HI-6) and an anticonvulsant (i.e. benzodiazepine). Most of anticholinergics and oximes are freely soluble in water, whereas many benzodiazepines are not. However, a water-soluble prodrug form of diazepam, avizafone, has been adopted by French armed forces for the immediate treatment of nerve agent seizure. The degradation behaviour of this new drug was investigated under different stress degradation conditions (hydrolytic, oxidative, photolytic and thermal) as recommended by International Conference on Harmonization. Successful separation of the active pharmaceutical ingredient from decomposition products formed under stress conditions was achieved using liquid chromatography. The method was validated with respect to specificity, linearity, precision and accuracy.

Chemistry, Pharmaceutical↗
PubMed2003

[A case of mixed poisoning by organophosphate and methanol].

We encountered a case of mixed poisoning by organophosphate and methanol. Each poisoning was comparatively frequent but we reviewed no cases of mixed poisoning of them. A 49-year-old woman was transferred to our hospital because of oral ingestion of organophosphorous compound (about 14 g of fenitrothion) and glass cleaner (about 40 g of methanol) for suicidal purpose. She underwent general antioverdose treatment including gastric lavage, activated charcoal and cathartics. For fenitrothion poisoning, she received atropine and pralidoxime. For methanol poisoning, she was treated with hemodialysis. Three days later, she moved to psychiatric ward from emergency ward without aftereffects and was given a diagnosis of depression.

Cathartics↗
PubMed1990

Decreased brain pathology in organophosphate-exposed rhesus monkeys following benzodiazepine therapy.

Two benzodiazepine compounds, midazolam and diazepam, were administered as adjunctive treatment to soman-exposed rhesus monkeys to evaluate their effects on acute soman intoxication. Monkeys were pretreated orally with pyridostigmine, exposed to soman, and treated i.m. with atropine, pralidoxime chloride (2-PAM), and with midazolam, diazepam or sterile water (control). All monkeys that received the benzodiazepines recovered sooner and exhibited no convulsions. Neuronal degenerative and necrotic lesions were decreased or eliminated in the entorhinal cortex, caudate nucleus, and hippocampus of those animals that received benzodiazepine therapy. These findings support the continued evaluation of drugs with anticonvulsant activity as standard adjunct therapy for soman intoxication.

Animals↗
PubMed1984

Profenofos insecticide bioactivation in relation to antidote action and the stereospecificity of acetylcholinesterase inhibition, reactivation, and aging.

Poisoning signs in chicks administered the organophosphorus insecticide profenofos correlated with in vivo inhibition of brain acetylcholinesterase (AChE) activity. Mixtures of atropine with eserine, pyridinium oximes, or the bispyridinium compound SAD-128 increased the LD50 of coadministered profenofos by up to sevenfold in chicks and fourfold in mice. Atropine and the oximes were less effective as profenofos antidotes, indicating that profenofos-inhibited AChE may undergo rapid aging. Brain AChE from chicks poisoned with profenofos was not reactivated by pralidoxime methanesulfonate, although it was from chicks poisoned with the phosphoramidothiolate, methamidophos. Similarly, eel AChE, inhibited in vitro by bioactivated (-)-profenofos, the most toxic isomer, did not reactivate in contrast to that inhibited by methamidophos, nonbioactivated (-)-profenofos, and (+)-profenofos, with or without bioactivation. It appears that the action of eserine and possibly SAD-128 was due to protecting AChE or cholinergic receptors from profenofos or bioactivated profenofos and that oximes may work in the same way rather than as reactivators due to rapid aging of the inhibited AChE.

Aging↗