Therapy Of Organophosphate Poisoning Research Articles

Effect of Sodium Bicarbonate in Rats Acutely Poisoned with Dichlorvos

The development of effective antidotes against organophosphates such as dichlorvos has been a persistent challenge over the past decades. Therapy of organophosphate poisoning is based on the administration of atropine and oxime as standard antidotes. The present study was undertaken to evaluate the ability of sodium bicarbonate to improve protective effects of standard antidotes in rats poisoned with dichlorvos. The aim of this experiment was to establish the correlation between protective effects and biochemical parameters relevant for acid-base status. In order to examine the protective effect of both standard antidotes and their combinations, groups of experimental animals were poisoned subcutaneously with increasing doses of dichlorvos. Immediately thereafter, rats were treated with atropine 10 mg/kg intramuscularly, oximes 10 mg/kg intramuscularly and sodium bicarbonate 3 mmol/kg intraperitoneally. These antidotes were administered either as single doses or in combinations. In the biochemical part of the experiments, rats were poisoned with dichlorvos 1.3 LD(50) (10.64 mg/kg) subcutaneously and immediately thereafter treated with atropine 10 mg/kg intramuscularly, oximes (trimedoxime or obidoxime) 10 mg/kg intramuscularly and sodium bicarbonate 3 mmol/kg intraperitoneally either as single doses or in combinations. Parameters relevant for acid-base status were measured 10 minutes after the administration of antidotes. The results of our study indicate that addition of sodium bicarbonate to standard antidotes significantly improves protective effects of atropine, obidoxime and trimedoxime. Correlation between protection and biochemical outcome is clearly evident when sodium bicarbonate is being added to atropine.

Modern strategies in therapy of organophosphate poisoning

Considering the various microscopic reactions as well as toxicokinetic and pharmacokinetic principles in therapy of organophosphate poisoning, the administration of obidoxime by an initial bolus dose followed by continuous infusion appears rational. Using this protocol, six patients each with parathion or oxydemeton methyl poisoning were treated. In parathion poisoning, reactivation was possible up to 7 days. At paraoxon concentrations >0.1 μM obidoxime only partially reactivated acetylcholinesterase (AChE) of erythrocytes in vivo although reactivation could be assessed in vitro, which roughly fitted theoretical calculations. AChE-inhibitory material was detected up to 5 days. Cholinergic signs soon subsided when AChE was above 20% of normal, and atropine plasma levels could be kept below 7 ng/ml. In one patient brain damage persisted. Oxydemeton methyl poisoning responded to obidoxime therapy only when the oxime was instituted shortly after poisoning. Out of six patients one died. No intermediate syndrome and no signs of permanent hepatic dysfunction were found in the 12 patients.

Therapy of organophosphate poisoning in the rat by direct effects of oximes unrelated to ChE reactivation

Isolated rat diaphragm preparations treated with soman or with the irreversible and oxime resistant cholinesterase (ChE) inhibitor S27 showed a considerable recovery of neuromuscular transmission (NMT) during incubation with the (bis)pyridinium oximes HI-6, HGG-12, P2S and obidoxime. In the soman-treated preparations this NMT recovery was predominantly caused by reactivation of acetylcholinesterase (AChE) but in the S27-treated preparations it was caused by a direct (pharmacological) effect unrelated to enzyme reactivation. Atropinized rats were artificially ventilated after injection with 3 x LD50 soman for 3 h and then treated with HI-6, i.e. at a time when oxime reactivation of soman inhibited ChE is no longer possible. Nevertheless, these rats started to breathe spontaneously and 50-60% survived more than 24 h, whereas all control animals (saline instead of HI-6) died within 10 min after artificial ventilation was terminated. In such animals no significant reactivation of ChE activity at various time intervals following HI-6 treatment was found, either in the diaphragms or in the brains. There was a significant amount of NMT (50%) in vitro in diaphragms obtained from these animals. This NMT did not improve in vitro in the presence of HI-6 and was not inhibited by soman administered to the medium. It is concluded that in this case the NMT found was based on synaptic adaptation to the continued inhibition of ChE and that the survival of the animals might be due to a combination of this synaptic adaptation and central direct effects of HI-6.

On the mechanism whereby HI-6 improves neuromuscular function after oxime-resistant acetylcholinesterase inhibition and subsequent impairment of neuromuscular transmission

Experiments were performed to elucidate the mechanism of action by which the oxime HI-6 causes a recovery of neuromuscular function after oxime-resistant inhibition of acetylcholinesterase by the organophosphate S27 (see 2.4). In the presence of HI-6 (1–3 mM), the ability of isolated rat diaphragm muscle strips to sustain tetanic contractions after inhibition by S27 was markedly improved, as was the electrophysiological response to indirect tetanic stimulation. At lower concentrations (0–1 mM), HI-6 reduced the amplitude of the miniature endplate potentials and their decay time constant in a dose-dependent manner without having any effect on the resting membrane potential. In addition, HI-6 dose dependently increased the quantal content. It is likely that these post- and presynaptic effects of HI-6 are responsible for the improvement of muscle contractions after inhibition of acetylcholinesterase and they could well be of value in the therapy of organophosphate poisoning.

Synthesis of 4‐{{[(Isopropyloxy)methylphosphoryloxy]imino}methyl}‐1‐methylpyridinium Iodide and Its Characterisation

AbstractOximes are used in the therapy of organophosphate poisoning. They form an interaction product with the organophosphate which is claimed to be more toxic than the organophosphate itself. We have synthesized one of these compounds which would be formed by the reaction of pyridine‐4‐carbaldehyde oxime methiodide with sarin (GB). Thus, reaction of oxime 1 with sarin chloridate (2), yielded 4‐{{[(isopropyloxy)methylphosphoryloxy]‐imino}methyl}‐1‐methylpyridinium iodide (4) which was characterized by NMR spectroscopy and X‐ray crystallography.

Prompt recovery from severe cholinesterase-inhibitor poisoning — Remarks on classification and therapy of organophosphate poisoning

In organophosphate intoxication the assessment of both the degree of severity of poisoning and the initial dose of pralidoxime and atropine are as yet based only on clinical symptoms. We present three patients with clinically severe organophosphate poisoning in whom a prompt recovery from central nervous symptoms occurred after the administration of low doses of atropine and pralidoxime. It is suggested that the true severity of organophosphate intoxication as well as the initial therapy should be determined by the amount ingested, the propensity for aging, and the pharmacodynamic properties of the organophosphorus compound, as well as by the time interval between exposure and initiation of appropriate treatment, as far as these data can be verified in the individual patient.

Device for quantitating tremor activity in mice: Antitremor activity of atropine versus soman- and oxotremorine-induced tremors

A tremor monitor was constructed and tested that quantitates soman- and oxo-tremorine-induced tremors. The device consisted of a force transducer, from which was suspended a plastic beaker containing a mouse. The signal from the force transducer was fed into a tremor monitor, which was essentially a low-pass filter, and quantitated using the Applecounter from Columbus Instruments (Columbus, Ohio) with the data stored on floppy diskette in a personal computer or on a magnetic tape cassette. The tremor monitor demonstrated a dose response relationship to both soman- and oxotremorine-induced tremors and the antagonism of these tremors by various doses of atropine. In addition, the duration of action of a dose of atropine (17.4 mg/kg,ip) normally used in the therapy of organophosphate poisoning was assessed using the atropine antagonism of oxo-tremorine-induced tremors as an indicator. This device permits the unbiased determination of the tremor activity of a drug and allows the use of statistical analysis on the data produced.

Side effects of therapeutic drugs against organophosphate poisoning

The possible side effects of therapeutic drugs against organophosphate poisoning were investigated. First, dose-effect curves were obtained with atropine sulphate (AS), P2S, obidoxime, aprophen, N-methylatropine nitrate and HI-6. The first three drugs are currently used in the therapy of organophosphate poisoning, the others are potentially useful candidates. Automated tests measuring open field behavior, motor coordination and shuttlebox performance, as well as neurophysiological techniques such as the quantified EEG (qEEG) and visual evoked responses were used. The sign-free doses of these compounds were determined; it appeared that open field behavior and the qEEG were the most sensitive methods for these drugs. Subsequently, these two methods were used to investigate the effects of the combinations of AS and P2S, AS and obidoxime or AS and HI-6, each compound given in a sign-free dose. Synergistic or additive effects were found with the combination of AS and P2S, which were smaller with the combination of AS and obidoxime and absent with the combination of AS and HI-6. These results indicate that the untimely use (false alarm, panic) of the current drug combinations may cause undesirable side effects.

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.

On a successfully treated acute oral paraoxone (E 600) poisoning

A case of acute oral suicidal poisoning with paraoxone (E 600) and its treatment are described. The use of cholinesterase-reactivating substances and reanimation procedures achieved full success, even without a high dosage of atropine, in the treatment of that very serious poisoning. The problems concerned with the use of oximes in the therapy of organophosphate poisoning are discussed.

Problems in the treatment with oximes and atropine of rats poisoned by organophosphates

Some of the factors contributing to the failure of TMB-4 (1,3-di(4-hydroxy-iminomethylpyridinium) propane dichloride) and atropine to treat rats poisoned with MBPF (3-methylbutyl-2 methylphosphonofluoridate) have been investigated. The largest doses of oxime that the animal could tolerate produced in the diaphragm concentrations which, according to studies in vitro, would be expected to produce barely enough reactivation of the acetylcholinesterase to restore normal function. Greater reactivation in vitro could be achieved by using much higher concentrations of oxime. The “ageing” of inhibited diaphragm acetylcholinesterase was found to be relatively slow in vivo. The importance of ageing in the therapy of organophosphate poisoning is discussed, with particular reference to poisoning by Soman (3,3-dimethylbutyl-2 methylphosphonofluoridate).