Most cited article - PubMed ID 18402722
TLC analysis of intermediates arising during the preparation of oxime HI-6 dimethanesulfonate
Poisoning with organophosphorus compounds (OPCs) represents an ongoing threat to civilians and rescue personal. We have previously shown that oximes, when administered prophylactically before exposure to the OPC paraoxon, are able to protect from its toxic effects. In the present study, we have assessed to what degree experimental (K-27; K-48; K-53; K-74; K-75) or established oximes (pralidoxime, obidoxime), when given as pretreatment at an equitoxic dosage of 25% of LD01, are able to reduce mortality induced by the OPC azinphos-methyl. Their efficacy was compared with that of pyridostigmine, the only FDA-approved substance for such prophylaxis. Efficacy was quantified in rats by Cox analysis, calculating the relative risk of death (RR), with RR=1 for the reference group given only azinphos-methyl, but no prophylaxis. All tested compounds significantly (p ≤ 0.05) reduced azinphos-methyl-induced mortality. In addition, the efficacy of all tested experimental and established oximes except K-53 was significantly superior to the FDA-approved compound pyridostigmine. Best protection was observed for the oximes K-48 (RR = 0.20), K-27 (RR = 0.23), and obidoxime (RR = 0.21), which were significantly more efficacious than pralidoxime and pyridostigmine. The second-best group of prophylactic compounds consisted of K-74 (RR = 0.26), K-75 (RR = 0.35) and pralidoxime (RR = 0.37), which were significantly more efficacious than pyridostigmine. Pretreatment with K-53 (RR = 0.37) and pyridostigmine (RR = 0.52) was the least efficacious. Our present data, together with previous results on other OPCs, indicate that the experimental oximes K-27 and K-48 are very promising pretreatment compounds. When penetration into the brain is undesirable, obidoxime is the most efficacious prophylactic agent already approved for clinical use.
- Keywords
- Cox analysis, acetylcholine, azinphos-methyl, carbamates, cholinesterase, obidoxime, organophosphate, pesticide, pralidoxime, prophylaxis, rat,
- MeSH
- Survival Analysis MeSH
- Azinphosmethyl chemistry toxicity MeSH
- Cholinesterase Inhibitors pharmacology MeSH
- Inhibitory Concentration 50 MeSH
- Rats MeSH
- Molecular Weight MeSH
- Organophosphorus Compounds chemistry toxicity MeSH
- Oximes pharmacology MeSH
- Pesticides chemistry toxicity MeSH
- Rats, Wistar MeSH
- Proportional Hazards Models MeSH
- Risk MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Azinphosmethyl MeSH
- Cholinesterase Inhibitors MeSH
- Organophosphorus Compounds MeSH
- Oximes MeSH
- Pesticides MeSH
AIMS: Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators is unsatisfactory. Experimental data indicate that superior therapeutic results can be obtained when reversible cholinesterase inhibitors are administered before OPC exposure. Comparing the protective efficacy of five such cholinesterase inhibitors (physostigmine, pyridostigmine, ranitidine, tacrine, or K-27), we observed best protection for the experimental oxime K-27. The present study was undertaken in order to determine if additional administration of K-27 immediately after OPC (paraoxon) exposure can improve the outcome. METHODS: Therapeutic efficacy was assessed in rats by determining the relative risk of death (RR) by Cox survival analysis over a period of 48 h. Animals that received only pretreatment and paraoxon were compared with those that had received pretreatment and paraoxon followed by K-27 immediately after paraoxon exposure. RESULTS: Best protection from paraoxon-induced mortality was observed after pretreatment with physostigmine (RR = 0.30) and K-27 (RR = 0.34). Both substances were significantly more efficacious than tacrine (RR = 0.67), ranitidine (RR = 0.72), and pyridostigmine (RR = 0.76), which were less efficacious but still significantly reduced the RR compared to the no-treatment group (paraoxon only). Additional administration of K-27 immediately after paraoxon exposure (posttreatment) did not further reduce mortality. Statistical analysis between pretreatment before paraoxon exposure alone and pretreatment plus K-27 posttreatment did not show any significant difference for any of the pretreatment regimens. CONCLUSIONS: Best outcome is achieved if physostigmine or K-27 are administered prophylactically before exposure to sublethal paraoxon dosages. Therapeutic outcome is not further improved by additional oxime therapy immediately thereafter.
- Keywords
- carbamates, cholinesterase, cox analysis, organophosphate, oximes, paraoxon, pretreatment, prophylaxis, rat,
- MeSH
- Survival Analysis MeSH
- Cholinesterase Inhibitors administration & dosage toxicity MeSH
- Physostigmine administration & dosage chemistry MeSH
- Rats MeSH
- Organophosphates toxicity MeSH
- Oximes administration & dosage chemistry MeSH
- Paraoxon chemistry toxicity MeSH
- Post-Exposure Prophylaxis MeSH
- Rats, Wistar MeSH
- Pre-Exposure Prophylaxis MeSH
- Proportional Hazards Models MeSH
- Pyridostigmine Bromide administration & dosage chemistry MeSH
- Ranitidine chemistry pharmacology MeSH
- Cholinesterase Reactivators pharmacology MeSH
- Tacrine administration & dosage chemistry MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Cholinesterase Inhibitors MeSH
- Physostigmine MeSH
- Organophosphates MeSH
- Oximes MeSH
- Paraoxon MeSH
- Pyridostigmine Bromide MeSH
- Ranitidine MeSH
- Cholinesterase Reactivators MeSH
- Tacrine MeSH
Certain AChE reactivators, asoxime, obidoxime, K027, K048, and K075, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure the different organs. As a continuation of previously published data, in this study, Wistar rats have sacrificed 24 hrs and 7 days after single im application of 0.1LD50, 0.5LD50 and 1.0LD50 of each reactivator, and examinated tissue samples were obtained for pathohistological and semiquantitative analysis. A severity of tissue alteration, expressed as different tissue damage scores were evaluated. Morphological structure of examinated tissues treated with of 0.1LD50 of all reactivators was comparable with the control group of rats. Moderate injuries were seen in visceral tissues treated with 0.5LD50 of asoxime, obidoxime and K027. Acute damages were enlarged after treatment with 0.5LD50 and 1.0LD50 of all reactivators during the next 7 days. The most prominent changes were seen in rats treated with 1.0LD50 of K048 and K075 (P < 0.001 vs. control and asoxime-treated group). All reactivators given by a single, high, unitary dose regimen, have an adverse effect not only on the main visceral tissue, but on the whole rat as well, but the exact mechanism of cellular injury remains to be confirmed in further investigation.
- MeSH
- Biopsy MeSH
- Chemical Warfare Agents adverse effects chemistry toxicity MeSH
- Histocytochemistry MeSH
- Rats MeSH
- Lethal Dose 50 MeSH
- Molecular Structure MeSH
- Organ Specificity MeSH
- Oximes administration & dosage adverse effects chemistry toxicity MeSH
- Lung drug effects metabolism pathology MeSH
- Viscera drug effects pathology MeSH
- Dose-Response Relationship, Drug MeSH
- Stomach drug effects pathology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Chemical Warfare Agents MeSH
- Oximes MeSH
Therapeutic application of newly developed oximes is limited due to their adverse effects on different tissues. Within this article, it has been investigated which morphological changes could be observed in Wistar rats after the treatment with increasing doses of selected acetyl cholinesterase reactivators - asoxime, obidoxime, K027, K048, and K075. Subsequently, heart, diaphragm and musculus popliteus were obtained for pathohistological and semiquantitative analysis 24 hrs and 7 days after im administration of a single dose of 0.1 LD50, 0.5 LD50, and 1.0 LD50 of each oxime. Different muscle damage score was based on an estimation scale from 0 (no damage) to 5 (strong damage). In rats treated with 0.1 LD50 of each oxime, muscle fibres did not show any change. The intensive degeneration was found in all muscles after treatment with 0.5 LD50 of asoxime and obidoxime, respectively. Acute toxic muscle injury was developed within 7 days following treatment with 0.5 LD50 and 1.0 LD50 of each oxime, with the highest values in K048 and K075 group (P < 0.001 vs. control and asoxime), respectively. The early muscle alterations observed in our study seem to contribute to the pathogenesis of the oxime-induced toxic muscle injury, which probably manifests as necrosis and/or inflammation.
- MeSH
- Diaphragm drug effects injuries MeSH
- Muscle, Skeletal drug effects injuries MeSH
- Rats MeSH
- Myositis chemically induced MeSH
- Necrosis MeSH
- Oximes toxicity MeSH
- Rats, Wistar MeSH
- Pyridinium Compounds toxicity MeSH
- Heart drug effects MeSH
- Muscles drug effects pathology MeSH
- Toxicity Tests, Acute MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Browser
- 1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane MeSH Browser
- K075 compound MeSH Browser
- Oximes MeSH
- Pyridinium Compounds MeSH
Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8), and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6) are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called “oximes”) depends on their chemical structure and also the type of organophosphorus inhibitor. Three novel oximes (K131, K142, K153) with an oxime group in position four of the pyridinium ring were designed and then tested for their potency to reactivate human (Homo sapiens sapiens) AChE (HssACHE) and BChE (HssBChE) inhibited by the pesticide paraoxon (diethyl 4-nitrophenyl phosphate). According to the obtained results, none of the prepared oximes were able to satisfactorily reactivate paraoxon-inhibited cholinesterases. On the contrary, extraordinary activity of obidoxime in the case of paraoxon-inhibited HssAChE reactivation was confirmed. Additional docking studies pointed to possible explanations for these results.
- Keywords
- acetylcholinesterase, antidote, butyrylcholinesterase, organophosphate, oxime, paraoxon,
- MeSH
- Acetylcholinesterase chemistry MeSH
- Antidotes chemical synthesis pharmacology MeSH
- Butyrylcholinesterase chemistry MeSH
- Cholinesterase Inhibitors chemistry MeSH
- Enzyme Assays MeSH
- Erythrocytes drug effects enzymology MeSH
- Insecticides antagonists & inhibitors chemistry toxicity MeSH
- Protein Interaction Domains and Motifs MeSH
- Humans MeSH
- Obidoxime Chloride chemistry pharmacology MeSH
- Oximes chemical synthesis pharmacology MeSH
- Paraoxon antagonists & inhibitors chemistry toxicity MeSH
- Cholinesterase Reactivators chemical synthesis pharmacology MeSH
- Protein Structure, Secondary MeSH
- Molecular Docking Simulation MeSH
- Thermodynamics MeSH
- Protein Binding MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Antidotes MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Insecticides MeSH
- Obidoxime Chloride MeSH
- Oximes MeSH
- Paraoxon MeSH
- Cholinesterase Reactivators MeSH
BACKGROUND: Based on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes. METHODS: To determine if this reactivating efficacy would extend to humans, studies were conducted in vitro using human brain homogenate as the source of AChE. The efficacy of K203 was compared with commercially available oximes; pralidoxime, obidoxime and asoxime (HI-6). RESULTS: Reactivation studies showed that K203 was the most effective reactivator with a second order kinetic constant (kr) of 2142 min- 1. M- 1, which was 51 times higher than that obtained for obidoxime (kr = 42 min- 1. M- 1). Both pralidoxime and asoxime (HI-6) failed to significantly reactivate tabun-inhibited human AChE. DISCUSSION: According to these results and previous studies, using K203, it appears that oxime K203 is the most effective reactivator of tabun-inhibited cholinesterase in several species including humans and should be considered as a possible medical countermeasure to tabun exposure.
- Keywords
- Antidotes, Chemical warfare agents, Oxime, Poisoning, Reactivator, Treatment,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Antidotes metabolism MeSH
- Cholinesterase Inhibitors metabolism MeSH
- Rats MeSH
- Humans MeSH
- Brain enzymology MeSH
- Organophosphates metabolism MeSH
- Oximes metabolism MeSH
- Pyridinium Compounds metabolism MeSH
- Cholinesterase Reactivators metabolism MeSH
- Molecular Docking Simulation MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene MeSH Browser
- Acetylcholinesterase MeSH
- Antidotes MeSH
- Cholinesterase Inhibitors MeSH
- Organophosphates MeSH
- Oximes MeSH
- Pyridinium Compounds MeSH
- Cholinesterase Reactivators MeSH
- tabun MeSH Browser
Four novel bisquaternary aldoxime cholinesterase reactivators differing in their chemical structure were prepared. Afterwards, their biological activity was evaluated for their ability to reactivate acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BuChE; EC 3.1.1.8) inhibited by paraoxon. Their reactivation activity was compared with standard reactivators--pralidoxime, obidoxime and HI-6--which are clinically used at present. As it resulted, none of the prepared compounds surpassed obidoxime, which is considered to be the most potent compound if used for reactivation of AChE inhibited by paraoxon. In case of BuChE reactivation, two compounds (K053 and K068) achieved similar results as obidoxime.
- MeSH
- Acetylcholinesterase drug effects metabolism MeSH
- Butyrylcholinesterase drug effects metabolism MeSH
- Enzyme Reactivators pharmacology MeSH
- Magnetic Resonance Spectroscopy MeSH
- Oximes chemistry MeSH
- Paraoxon pharmacology MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Butyrylcholinesterase MeSH
- Enzyme Reactivators MeSH
- Oximes MeSH
- Paraoxon MeSH