trimedoxime-bromide and Organophosphate-Poisoning

The use of organophosphorus pesticides results in toxicity risk to non-target organisms. Organophosphorus compounds share a common mode of action, exerting their toxic effects primarily via acetylcholinesterase (AChE) inhibition. Consequently, acetylcholine accumulates in the synaptic clefts of muscles and nerves, leading to overstimulation of cholinergic receptors. Acute cholinergic crisis immediately follows exposure to organophosphate and includes signs and symptoms resulting from hyperstimulation of central and peripheral muscarinic and nicotinic receptors. The current view of the treatment of organophosphate poisoning includes three strategies, i.e. the use of an anticholinergic drug (e.g., atropine), cholinesterase-reactivating agents (e.g., oximes) and anticonvulsant drugs (e.g., benzodiazepines). Oximes, as a part of antidotal therapy, ensure the recovery of phosphylated enzymes via a process denoted as reactivation of inhibited AChE. However, both experimental results and clinical findings have demonstrated that different oximes are not equally effective against poisonings caused by structurally different organophosphorus compounds. Therefore, antidotal characteristics of conventionally used oximes can be evaluated regarding how close the certain substance is to the theoretical concept of the universal oxime. Pralidoxime (PAM-2), trimedoxime (TMB-4), obidoxime (LüH-6), HI-6 and HLö-7 have all been demonstrated to be very effective in experimental poisonings with sarin and VX. TMB-4 and LüH-6 may reactivate tabun-inhibited AChE, whereas HI-6 possesses the ability to reactivate the soman-inhibited enzyme. An oxime HLö-7 seems to be an efficient reactivator of AChE inhibited by any of the four organophosphorus warfare agents. According to the available literature, the oximes LüH-6 and TMB-4, although relatively toxic, are the most potent to induce reactivation of AChE inhibited by the majority of organophosphorus pesticides. Since there are no reports of controlled clinical trials on the use of TMB-4 in human organophosphate pesticide poisoning, LüH-6 may be a better option.

Topics: Acetylcholinesterase; Antidotes; Chemical Warfare Agents; Cholinesterase Reactivators; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Insecticides; Obidoxime Chloride; Organophosphate Poisoning; Organothiophosphorus Compounds; Oximes; Pralidoxime Compounds; Sarin; Trimedoxime

For over 60 years, researchers across the world have sought to deal with poisoning by nerve agents, the most toxic and lethal chemical weapons. To date, there is no efficient causal antidote with sufficient effect. Every trialed compound fails to fulfil one or more criteria (e.g. reactivation potency, broad reactivation profile). In this recent contribution, we focused our attention to one of the promising compounds, namely the bis-pyridinium reactivator K203. The oxime K203 is very often cited as the best reactivator against tabun poisoning. Herein, we provide all the available literature data in comprehensive and critical review to address whether K203 could be considered as a new drug candidate against organophosphorus poisoning with the stress on tabun. We describe its development from the historical point of view and review all available in vitro as well as in vivo data to date. K203 is easily accessible by a relatively simple two-step synthesis. It is well accommodated in the enzyme active gorge of acetylcholinesterase providing suitable interactions for reactivation, as shown by molecular docking simulations. According to a literature survey, in vitro data for tabun-inhibited AChE are extraordinary. However, in vivo efficiency remains unconvincing. The K203 toxicity profile did not show any perturbations compared to clinically used standards; on the other hand versatility of K203 does not exceed currently available oximes. In summary, K203 does not seem to address current issues associated with the organophosphorus poisoning, especially the broad profile against all nerve agents. However, its reviewed efficacy entitles K203 to be considered as a backup or tentative replacement for obidoxime and trimedoxime, currently only available anti-tabun drugs.

Topics: Acetylcholinesterase; Antidotes; Molecular Docking Simulation; Nerve Agents; Obidoxime Chloride; Organophosphate Poisoning; Organophosphates; Oximes; Pyridinium Compounds; Trimedoxime

Beside the key inhibition of acetylcholinesterase (AChE), involvement of oxidative stress in organophosphate (OP)-induced toxicity has been supported by experimental and human studies. On the other hand, according to our best knowledge, possible antioxidant properties of oximes, the only causal antidotes to OP-inhibited AChE, have been examined only by a few studies. Thus, we have determined the effect of four conventional (obidoxime, trimedoxime, pralidoxime, asoxime) and two promising experimental oximes (K027, K203) on dichlorvos (DDVP)-induced oxidative changes in vivo. Wistar rats (5/group) were treated with oxime (5% LD

Topics: Animals; Aryldialkylphosphatase; Biomarkers; Brain; Cholinesterase Inhibitors; Dichlorvos; Male; Malondialdehyde; Obidoxime Chloride; Organophosphate Poisoning; Oxidative Stress; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Superoxide Dismutase; Trimedoxime

The ability of two newly developed oximes (K305, K307) to protect tabun-poisoned rats from tabun-induced inhibition of brain acetylcholinesterase, acute neurotoxic signs and symptoms and brain damage was compared with that of the oxime K203 and trimedoxime. The reactivating and neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose were evaluated. The reactivating efficacy of a newly developed oxime K305 is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime while the ability of the oxime K307 to reactivate tabun-inhibited acetylcholinesterase (AChE) in the brain roughly corresponds to the reactivating efficacy of the oxime K203 and it is slightly lower compared to trimedoxime. In addition, only one newly developed oxime (K307) combined with atropine was able to markedly decrease tabun-induced neurotoxicity although it did not eliminate all tabun-induced acute neurotoxic signs and symptoms. These results correspond to the histopathological evaluation of tabun-induced brain damage. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes (especially trimedoxime) in the treatment of acute tabun poisonings.

Topics: Acetylcholinesterase; Animals; Atropine; Brain; Chemical Warfare Agents; Cholinesterase Reactivators; Humans; Male; Neuroprotective Agents; Neurotoxicity Syndromes; Organophosphate Poisoning; Organophosphates; Oximes; Pyridinium Compounds; Rats, Wistar; Trimedoxime

The ability of two newly developed oximes (K727, K733) to reduce tabun-induced acute neurotoxic signs and symptoms was evaluated and compared with currently available trimedoxime in rats.. The neuroprotective effects of the oximes studied combined with atropine on Wistar rats poisoned with tabun at a lethal dose (380 µg/kg i.m.; 90% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery consisting of 38 measurements of sensory, motor and autonomic nervous functions at 2 hours following tabun challenge.. All tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K727, K733) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of lethal poisoning although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms.. The ability of both novel bispyridinium oximes to decrease tabun-induced acute neurotoxicity was slightly lower than that of trimedoxime. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes such as trimedoxime in the treatment of acute tabun poisonings.

Topics: Animals; Atropine; Cholinesterase Inhibitors; Cholinesterase Reactivators; Male; Muscarinic Antagonists; Nervous System; Neuroprotective Agents; Neurotoxicity Syndromes; Organophosphate Poisoning; Organophosphates; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Trimedoxime

A toxic effect of highly toxic nervous agents is irreversible inhibition of vitally important enzyme acethylcholinesterase (AChE). Inhibition of AChE results in accumulation of acetylcholine (ACh) at the synaptic cleft of the cholinergic neurons, leading to overstimulation of cholinergic receptors. The highly toxic nature of tabun has been known for many years, but there are still serious limitations to the antidotal therapy. In this paper a bispyridinium compound K027 [1-(4-hydroxyiminomethylpyridinium)-3-(-4-carbamoylpyridinium) propane dibromide] was tested as potential antidote in tabun poisoned mice. Oxime TMB-4 was included for comparison. The therapeutic efficacy of applied antidotal regimens was tested as pretreatment given 15 min before tabun poisoning and/or as therapy given 1 min after tabun poisoning. Using oxime K027 (25% of its LD(50)) plus atropine as both, pretreatment and therapy, we showed that this combination can protect mice 8 times better than the therapy alone. Under these experimental conditions we confirmed good antidotal efficacy of K027. Moreover, its low acute toxicity is as much as beneficial effect in contrast to high toxicity of currently used TMB-4.

Topics: Acetylcholinesterase; Animals; Antidotes; Catalytic Domain; Cholinesterase Inhibitors; Male; Mice; Organophosphate Poisoning; Organophosphates; Oximes; Phosphorylation; Pyridinium Compounds; Trimedoxime

Up to now, intensive attempts to synthesize a universal reactivator able to reactivate cholinesterases inhibited by all types of nerve agents/organophosphates were not successful. Therefore, another approach using a combination of two reactivators differently reactivating enzyme was used: in rats poisoned with tabun and treated with combination of atropine (fixed dose) and different doses of trimedoxime and HI-6, changes of acetylcholinesterase activities (blood, diaphragm and different parts of the brain) were studied. An increase of AChE activity was observed following trimedoxime treatment depending on its dose; HI-6 had very low effect. Combination of both oximes showed potentiation of their reactivation efficacy; this potentiation was expressed for peripheral AChE (blood, diaphragm) and some parts of the brain (pontomedullar area, frontal cortex); AChE in the basal ganglia was relatively resistant. These observations suggest that the action of combination of oximes in vivo is different from that observed in vitro.

Topics: Acetylcholinesterase; Animals; Central Nervous System; Cholinesterase Reactivators; Drug Therapy, Combination; Enzyme Activation; Female; Organophosphate Poisoning; Organophosphates; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Trimedoxime

Organophosphorus compounds pose a potential threat to both military and civilian populations. Since post-exposure therapy has its limitations, our research was focused on the possibility of improving pretreatment in order to limit the toxic effects of tabun. We determined the protective index of various combinations of atropine, oximes (K074, K048, and TMB-4), and pyridostigmine given to mice before tabun intoxication. Although the tested oximes showed very good therapeutic efficacy in tabun-poisoned mice, the given pretreatments improved therapy against tabun poisoning. These regimens ensured survival of all animals up to 25.2 LD(50) of tabun. Our results indicate that even pretreatment with atropine alone is sufficiently effective in enhancing the survival of mice poisoned by multiple doses of tabun, if oxime therapy follows. K048 is our oxime of choice for future research, as it shows better protective and reactivating potency.

Topics: Animals; Atropine; Butanes; Chemical Warfare Agents; Cholinesterase Inhibitors; Mice; Organophosphate Poisoning; Organophosphates; Oximes; Protective Agents; Pyridinium Compounds; Survival Rate; Treatment Outcome; Trimedoxime

We studied bispyridinium oxime K203 [(E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide] with tabun-inhibited human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and its antidotal effect on tabun-poisoned mice and rats in vivo. We compared it with oximes K048 and TMB-4, which have proven the most efficient oxime antidotes in tabun poisoning by now. Tabun-inhibited AChE was completely reactivated by K203, with the overall reactivation rate constant of 1806 L mol(-1) min(-1). This means that K203 is a very potent reactivator of tabun-inhibited AChE. In addition, K203 reversibly inhibited AChE (Ki = 0.090 mmol L(-1)) and BChE (K(i) = 0.91 mmol L(-1)), and exhibited its protective effect against phosphorylation of AChE by tabun in vitro. In vivo, a quarter of the LD50 K203 dose insured survival of all mice after the application of as many as 8 LD50 doses of tabun, which is the highest dosage obtained compared to K048 and TMB-4. Moreover, K203 showed high therapeutic potency in tabun-poisoned rats, preserving cholinesterase activity in rat plasma up to 60 min after poisoning. This therapeutic improvement obtained by K203 in tabun-poisoning places this oxime in the spotlight for further development.

Topics: Acetylcholinesterase; Animals; Antidotes; Butyrylcholinesterase; Chemical Warfare Agents; Enzyme Activation; Lethal Dose 50; Male; Mice; Organophosphate Poisoning; Organophosphates; Oximes; Rats; Trimedoxime

The potency of newly developed bispyridinium compounds (K117, K127) to reactivate tabun-inhibited acetylcholinesterase and reduce tabun-induced lethal toxic effects was compared with currently available oximes (obidoxime, trimedoxime, oxime HI-6) by using in vivo methods. A study that determined the percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of newly developed oxime K127 is comparable with obidoxime and trimedoxime in blood but lower than the reactivating potency of trimedoxime and obidoxime in the diaphragm and brain. The potency of another newly developed K117 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in the diaphragm, but it is significantly lower than the reactivating potency of trimedoxime and obidoxime in the blood and brain. The oxime, K127, was also found to be relatively effective in reducing lethal toxic effects in tabun-poisoned mice. Its therapeutic efficacy is consistent with the therapeutic potency of obidoxime. On the other hand, the potency of the oxime, K117, to reduce acute toxicity of tabun is significantly lower compared to trimedoxime and obidoxime. The therapeutic efficacy of K117 and K127 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in the diaphragm and brain. Contrary to obidoxime and trimedoxime, the oxime, HI-6, is not an effective oxime in the reactivation of tabun-inhibited acetycholinesterase and in reducing the lethal effects of tabun. The reactivating and therapeutic potency of both newly developed oximes does not prevail over the effectiveness of currently available obidoxime and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.

Topics: Acetylcholinesterase; Animals; Antidotes; Brain; Cholinesterase Inhibitors; Diaphragm; Male; Mice; Obidoxime Chloride; Organophosphate Poisoning; Organophosphates; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Trimedoxime

The potency of newly developed monoxime bispyridinium compounds (K156, K203) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of newly developed oxime K203 is comparable with obidoxime and trimedoxime in blood and higher than the reactivating potency of trimedoxime and obidoxime in diaphragm and brain, where the difference in reactivating efficacy of obidoxime, trimedoxime and K203 is significant. On the other hand, the potency of newly developed K156 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in diaphragm and brain. It is significantly lower than the reactivating efficacy of trimedoxime and obidoxime in blood. Moreover, both newly developed oximes were found to be relatively efficacious in the reduction of lethal toxic effects in tabun-poisoned mice. Especially, the oxime K203 is able to decrease the acute toxicity of tabun nearly two times. The therapeutic efficacy of K156 and K203 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in diaphragm and brain. In contrast to obidoxime and trimedoxime, the oxime HI-6 is not effective in reactivation of tabun-inhibited acetycholinesterase and in reducing tabun lethality. While the oxime K156 does not improve the reactivating and therapeutic effectiveness of currently available obidoxime and trimedoxime, the newly developed oxime K203 is markedly more effective in reactivation of tabun-inhibited acetylcholinesterase in rats, especially in brain, and in reducing lethal toxic effects of tabun in mice and, therefore, it is suitable for the replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.

Topics: Acetylcholinesterase; Animals; Antidotes; Atropine; Cholinesterase Inhibitors; Cholinesterase Reactivators; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Injections, Intramuscular; Lethal Dose 50; Male; Mice; Molecular Structure; Obidoxime Chloride; Organophosphate Poisoning; Organophosphates; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Seizures; Species Specificity; Toxicity Tests, Acute; Trimedoxime

The potency of newly developed oximes (K074, K075) and commonly used oximes (obidoxime, trimedoxime, and HI-6) to counteract tabun or cyclosarin-induced acute toxic effects was studied in mice. The therapeutic efficacy of trimedoxime and both newly developed oximes (K074, K075) was significantly higher than the potency of obidoxime and the oxime HI-6 in the case of acute tabun poisonings. On the other hand, the oxime HI-6 was significantly more efficacious than other studied oximes when mice were intoxicated with cyclosarin. The findings support the hypothesis that the therapeutic efficacy of oximes depends on the type of nerve agent. Due to their therapeutic efficacy, both newly developed K oximes can be considered to be promising oximes for the antidotal treatment of acute tabun poisonings, while the oxime HI-6 is still the most promising oxime for the treatment of acute cyclosarin poisonings due to its high potency to counteract cyclosarin-induced acute toxic effects.

Topics: Animals; Antidotes; Atropine; Butanes; Cholinesterase Inhibitors; Cholinesterase Reactivators; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Lethal Dose 50; Male; Mice; Muscarinic Antagonists; Obidoxime Chloride; Organophosphate Poisoning; Organophosphates; Organophosphorus Compounds; Oximes; Poisoning; Pyridinium Compounds; Trimedoxime

The aim of the study was to examine antidotal potency of trimedoxime in mice poisoned with three direct dimethoxy-substituted organophosphorus inhibitors. In order to assess the protective efficacy of trimedoxime against dichlorvos, heptenophos or monocrotophos, median effective doses and efficacy half-times were calculated. Trimedoxime (24 mg/kg intravenously) was injected 5 min. before 1.3 LD50 intravenously of poisons. Activities of brain, diaphragmal and erythrocyte acetylcholinesterase, as well as of plasma carboxylesterases were determined at different time intervals (10, 40 and 60 min.) after administration of the antidotes. Protective effect of trimedoxime decreased according to the following order: monocrotophos > heptenophos > dichlorvos. Administration of the oxime produced a significant reactivation of central and peripheral acetylcholinesterase inhibited with dichlorvos and heptenophos, with the exception of erythrocyte acetylcholinesterase inhibited by heptenophos. Surprisingly, trimedoxime did not induce reactivation of monocrotophos-inhibited acetylcholinesterase in any of the tissues tested. These organophosphorus compounds produced a significant inhibition of plasma carboxylesterase activity, while administration of trimedoxime led to regeneration of the enzyme activity. The same dose of trimedoxime assured survival of experimental animals poisoned by all three organophosphorus compounds, although the biochemical findings were quite different.

Topics: Acetylcholine; Animals; Brain Chemistry; Carboxylesterase; Diaphragm; Dichlorvos; Drug Evaluation, Preclinical; Erythrocytes; Injections, Intravenous; Lethal Dose 50; Male; Mice; Monocrotophos; Organophosphate Poisoning; Organophosphorus Compounds; Oximes; Time Factors; Trimedoxime

1. The dispositions of the acetylcholinesterase reactivators: 2PAM-I, TMB4 and R665, labelled with 14C on the oxime group, have been studied in normal rats and rats poisoned by the organophosphates Soman and A4. 2. For all three compounds, radioactivity was eliminated mostly in the urine (60-90% dose in 24 h). Faecal elimination was low (5.8-17.2% in 72 h). 3. All three compounds concentrated in kidney, but only 2PAM-I and R665 concentrated in liver. TMB4 and R665 concentrated in mucopolysaccharide-containing tissues such as cartilage and intervertebral disc. Other tissues were weakly and uniformly labelled. Soman poisoning does not modify the kinetic parameters of both compounds, but A4 poisoning increases 2PAM-I tissue concentration. 4. Chromatography of urine and plasma showed only unchanged 2PAM-I, TMB4 and R665 in both healthy and poisoned animals. Despite the high concentration of 2PAM-I and R665 in liver, these oximes are not metabolized.

Topics: Acetylcholinesterase; Animals; Carbon Radioisotopes; Cholinesterase Reactivators; Male; Organophosphate Poisoning; Oximes; Poisoning; Pralidoxime Compounds; Rats; Rats, Inbred Strains; Tissue Distribution; Trimedoxime

Fetal bovine serum acetylcholinesterase (FBS-AChE, EC 3.1.1.7) was titrated, both in vitro and in vivo, with a highly toxic anti-ChE organophosphate, 7-(methylethoxyphosphinyloxy)-1-methyl-quinolinium iodie (MEPQ). Approximately 1:1 stoichiometry was obtained for the sequestration of MEPQ by FBS-AChE in mice. A quantitative, linear correlation was demonstrated between blood-AChE levels and the protection afforded by exogenously administered AChE in mice when challenged with anti-ChE MEPQ. The results presented in this report demonstrate that such prophylactic measures are indeed sufficient to protect animals against poisoning by as high as an 8 x LD50 dose of organophosphate without the administration of any supportive drug. Despite the relatively large toxic dose, most of the mice that survived the challenge did not show any classical clinical signs of severe anti-ChE poisoning. MEPQ may be considered a suitable model compound for studying the quantitative aspects of the scavenger prophylactic approach described here.

Topics: Acetylcholinesterase; Animals; Cholinesterase Inhibitors; Drug Stability; Lethal Dose 50; Male; Mice; Mice, Inbred ICR; Organophosphate Poisoning; Quinolinium Compounds; Serum Albumin, Bovine; Trimedoxime

W84 (hexamethylene-bis-[dimethyl-(3-phthalimidopropyl)-ammonium bromide]) protects overadditively against an organophosphate-intoxication when applied in combination with atropine. Further experimental evidence led to the hypothesis that W84 exerted an allosteric effect on muscarinic acetylcholine receptors. In order to investigate the action of W84 on the receptor level, binding studies with 3H-N-methylscopolamine were performed in homogenized and intact guinea-pig myocardium. For sake of comparison three bispyridinium oximes were included, i.e. Uno3 (trimethylene-bis-[4-hydroxyiminomethyl-pyridinium] dibromide mono-2,6-dichlorobenzylether), obidoxime, and TMB4. In cardiac membrane suspensions, all compounds inhibited 3H-NMS-binding after 2 hrs of incubation concentration-dependently by reducing its affinity, whereas leaving the number of binding sites unaltered. However, with increasing concentrations W84 suppressed 3H-NMS-binding less than expected for a competitive antagonist. Kinetic studies revealed that W84 did not only slow the association of 3H-NMS, but additionally retarded its dissociation over the entire range of concentrations that inhibited 3H-NMS-binding. At lmM, W84 augmented the half life time of the 3H-NMS-receptor complexes from a control value of 4 min to more than 120 min. The stabilization of the radioligand-receptor complexes is indicative of an allosteric effect of W84. Obidoxime, TMB4 and Uno3 at low concentrations acted like competitive inhibitors of 3H-NMS-binding. From 10(-5)M onwards, Uno3 retarded 3H-NMS-dissociation concentration-dependently. It is concluded that the effect of bisquaternary compounds on 3H-NMS-association and -dissociation is mediated via binding to two separate sites, i.e. the muscarinic receptor site and an allosteric effector site, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Allosteric Regulation; Animals; Antidotes; Binding, Competitive; Female; Guinea Pigs; Heart; In Vitro Techniques; Isoindoles; Male; Myocardium; N-Methylscopolamine; Obidoxime Chloride; Organophosphate Poisoning; Parasympatholytics; Phthalimides; Receptors, Muscarinic; Scopolamine Derivatives; Trimedoxime

Topics: Aminoacridines; Animals; Benactyzine; Cholinesterase Inhibitors; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Medulla Oblongata; Organophosphate Poisoning; Organothiophosphates; Organothiophosphorus Compounds; Pons; Rats; Rats, Inbred Strains; Tacrine; Trimedoxime

An aqueous solution of trimedoxime bromide, atropine, and benactyzine hydrochloride was formulated to have maximum stability as an antidote in organophosphorus poisoning. The stability of the mixture in glass and plastic cartridges was determined. Glass cartridges were more desirable than plastic; there was less vapor loss, color formation, and anomalous reaction. Trimedoxime was stable, losing 1.4% of its potency after 1 year at 25 degrees and atropine was more stable than trimedoxime. Considerable degradation of benactyzine occurred; 20% of its potency was lost after 1 year at 25 degrees. Equations for predicting the shelf life of each ingredient at selected temperatures are presented.

Topics: Antidotes; Atropine; Benactyzine; Drug Packaging; Drug Stability; Glass; Kinetics; Organophosphate Poisoning; Plastics; Trimedoxime

The antidotal action of atropine with trimedoxime, obidoxime or methoxime against isopropyl methylphosphonofluoridate intoxication in mice was studied. The best antidotal effect was demonstrated for the combination of atropine and methoxime (tested as therapeutic index or D50 index). The effect of atropine (constant dose) and methoxime (different doses) on acetylcholinesterase (AChE) activity in four parts of the mouse brain following isopropyl methylphosphonofluoridate intoxication was described. The therapeutic effect could be improved by increasing dose of methoxime. AChE activity in the pontomedullar area was increased on increasing the dose of methoxime (p less than 0.005). A correlation between residual AChE activity in the pontomedullar part of the mouse brain and mortality was demonstrated.

Topics: Acetylcholinesterase; Animals; Antidotes; Atropine; Brain; Dose-Response Relationship, Drug; Drug Synergism; Male; Mice; Obidoxime Chloride; Organophosphate Poisoning; Oximes; Sarin; Trimedoxime