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.

• MeSH
• Survival Analysis MeSH
• Azinphosmethyl chemistry   toxicity   MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Inhibitory Concentration 50 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
• Animals MeSH
• Publication type
• Journal Article 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.

• 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

Organophosphates, useful agents as pesticides, also represent a serious danger due to their high acute toxicity. There is indication that oximes, when administered before organophosphate exposure, can protect from these toxic effects. We have tested at equitoxic dosage (25% of LD01 ) the prophylactic efficacy of five experimental (K-48, K-53, K-74, K-75, K-203) and two established oximes (pralidoxime and obidoxime) to protect from mortality induced by the organophosphate paraoxon. Mortalities were quantified by Cox analysis and compared with those observed after pretreatment with a strong acetylcholinesterase inhibitor (10-methylacridine) and after the FDA-approved pretreatment compound pyridostigmine. All nine tested substances statistically significantly reduced paraoxon-induced mortality. Best protection was conferred by the experimental oxime K-48, reducing the relative risk of death (RR) to 0.10, which was statistically significantly superior to pyridostigmine (RR = 0.31). The other oximes reduced the RR to 0.13 (obidoxime), 0.20 (K-203), 0.21 (K-74), 0.24 (K-75) and 0.26 (pralidoxime), which were significantly more efficacious than 10-methylacridine (RR = 0.65). These data support the hypothesis that protective efficacy is not primarily due to cholinesterase inhibition and indicate that the tested experimental oximes may be considered promising alternatives to the established pretreatment compound pyridostigmine.

• MeSH
• Survival Analysis MeSH
• Lethal Dose 50 MeSH
• Obidoxime Chloride administration & dosage   pharmacology   MeSH
• Protective Agents administration & dosage   pharmacology   MeSH
• Paraoxon chemistry   toxicity   MeSH
• Rats, Wistar MeSH
• Pralidoxime Compounds administration & dosage   pharmacology   MeSH
• Proportional Hazards Models MeSH
• Cholinesterase Reactivators administration & dosage   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Organophosphates (OPs) irreversibly inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The reactivation of these inhibited enzymes is paramount for their normal function. Present study evaluates reactivation potency of two newly developed oximes, K456 and K733, against paraoxon (POX)-inhibited human-RBC-AChE and human-plasma-BChE in comparison to reported reactivator, pralidoxime (2-PAM). In vitro studies showed higher intrinsic toxicities of both oximes than 2-PAM for AChE. No substantial reactivation of hBChE was noted by tested concentration. Contrary to 2-PAM, the in silico study predicted lower binding free energies for both oximes. However, the detailed interaction study revealed inability of oximes to interact with catalytic anionic site of AChE and hBChE in contrast to 2-PAM. Both in vitro and in silico studies conclude that K456 and K733 are unlikely to be used as reactivators of paraoxon-inhibited AChE or BChE.

• MeSH
• Acetylcholinesterase chemistry   MeSH
• Butyrylcholinesterase chemistry   MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Erythrocytes enzymology   MeSH
• Humans MeSH
• Oximes pharmacology   MeSH
• Paraoxon antagonists & inhibitors   pharmacology   MeSH
• Pyridinium Compounds pharmacology   MeSH
• Cholinesterase Reactivators pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Pralidoxime (2-PAM) is a monopyridinium aldoxime-type compound of acetylcholinesterase reactivators. 2-PAM was introduced about five decades ago for the treatment of organophosphorus poisoning in order to reactivate inhibited acetylcholinesterase. The application of organophosphorus compounds is varied, including warfare agents, insecticides and pesticides in agriculture, the chemical industry, etc. The exposure is not limited to certain groups of humans: rather everyone can be affected, including pregnant women, and consequently fetuses as well. The present study was aimed to determine the 2-PAM concentration in the plasma of pregnant mice, assuming a different physiological condition than non-pregnant ones. Blood-placenta penetration of 2-PAM was also investigated. 2-PAM was intraperitoneally injected into mice on gestational day 18 and mother blood was collected following 5, 15, 30 and 90 minutes. Four fetuses along with their placentas were collected at every time point. HPLC-UV method was employed to determine the 2-PAM concentrations. The result showed higher levels of 2-PAM at 15 minutes (tmax) in the plasma of pregnant mice compared to non-pregnant ones. Moreover, 2-PAM copiously reached the placenta, which is a store house of nutrients for the fetus. A higher concentration of 2-PAM was found in the brain of fetuses in comparison to that of the mothers’. Our study concludes that 2-PAM crosses the placenta barrier and reaches the brain of the fetus in a more ample quantity than that in the mother’s brain. The results provide an insight into a special condition of pregnancy when antidotal application of the acetylcholinesterase reactivator 2-PAM in organophosphorus poisoning results in 2-PAM exposure in the fetus.

• MeSH
• Antidotes pharmacology   metabolism   therapeutic use   MeSH
• Maternal-Fetal Exchange MeSH
• Models, Animal MeSH
• Brain growth & development   drug effects   MeSH
• Mice MeSH
• Organophosphorus Compounds adverse effects   MeSH
• Pralidoxime Compounds * pharmacology   metabolism   therapeutic use   MeSH
• Cholinesterase Reactivators pharmacokinetics   metabolism   therapeutic use   MeSH
• Pregnancy MeSH
• Fetal Development drug effects   MeSH
• Check Tag
• Mice MeSH
• Pregnancy MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

Pre-treatment with reversible acetylcholinesterase (AChE) inhibitors before organophosphorous compound (OPC) exposure can reduce OPC-induced mortality. However, pyridostigmine, the only substance employed for such prophylaxis, is merely efficacious against a limited number of OPCs. In search of more efficacious and broad-range alternatives, we have compared in vivo the ability of five reversible AChE inhibitors (pyridostigmine, physostigmine, ranitidine, tacrine and K-27) to reduce mortality induced by the OPC azinphos-methyl. Protection was quantified using Cox analysis by determining the relative risk (RR) of death in rats that were administered these AChE inhibitors in equitoxic dosage (25% of LD01) 30 min before azinphos-methyl exposure. Azinphos-methyl-induced mortality was significantly reduced by all five tested compounds as compared with the reference group that was only exposed to azinphos-methyl without prior pre-treatment (RR = 1). The most efficacious prophylactic agents were K-27 (RR = 0.15) and physostigmine (RR = 0.21), being significantly more efficacious than ranitidine (RR = 0.62) and pyridostigmine (RR = 0.37). Pre-treatment with tacrine (RR = 0.29) was significantly more efficacious than pre-treatment with ranitidine, but the difference between tacrine and pyridostigmine was not significant. Our results indicate that prophylactic administration of the oxime K-27 may be a promising alternative in cases of imminent OPC exposure. Copyright © 2014 John Wiley & Sons, Ltd.

• MeSH
• Azinphosmethyl * toxicity   MeSH
• Cholinesterase Inhibitors * pharmacology   MeSH
• Physostigmine pharmacology   MeSH
• Rats MeSH
• Oximes pharmacokinetics   MeSH
• Rats, Wistar MeSH
• Proportional Hazards Models MeSH
• Pyridinium Compounds pharmacology   MeSH
• Pyridostigmine Bromide pharmacology   MeSH
• Ranitidine pharmacology   MeSH
• Tacrine pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH

Organophosphorus compounds (OPCs) are a wide group of compounds both structurally and functionally. Each OPC has a unique toxicological profile. The exposure to this type of poison is not limited only to certain occupationally exposed people but also to children, women, pregnant women; all have chances to be exposed to this poison. During the recent past years it has been reported in many poison epidemiological studies and case reports that exposure of OPCs during pregnancy caused malformed fetuses, neural tube defect (NTD) and shortening of pregnancy. The literature for animal models reveals inconclusive evidence. The generalized view is that they are neither teratogenic nor embryotoxic. But it is not true. There is a lack of systematic study and scarcity of reports on the topic. The present study was undertaken to investigate the teratogenicity induced by organophosphorus compounds in different animal models by literature review. Literature was searched by Toxicology Data NetWork (TOXNET), Developmental and Reproductive Toxicology Database (DART), Toxicology Literature Online (TOXLINE), Hazardous Substances Data Bank (HSDB), Pubmed Central, Entrez-Pubmed, Science Direct, Directory Of Open Access Journal (DOAJ), Google Scholar and International Program on Chemical Safety (IPCS-INCHEM), Embase. The terms for literature search were teratogenicity, organophosphorus compounds; fetal toxicity, organophosphorus compounds; organophosphorus poisoning and pregnancy; organophosphorus poisoning and growth restriction; organophosphorus poisoning and IUGR; organophosphorus poisoning and reproduction; organophosphates and reproduction; pregnancy and organophosphates. The outcome of the study concludes that the work on teratogenicity induced by organophosphorus compounds was completely neglected, inconclusive, and only carried out on less than half of the OPCs available in the market. A more comprehensive and systemic study on the subject is clearly needed and its importance should not be ignored because more positive cases are being reported on the teratogenicity and embryotoxicity of OPCs.

• MeSH
• Maternal-Fetal Exchange MeSH
• Maternal Exposure MeSH
• Models, Animal MeSH
• Organophosphorus Compounds classification   toxicity   MeSH
• Pesticides toxicity   MeSH
• Pregnancy MeSH
• Teratogens toxicity   MeSH
• Fetal Development drug effects   MeSH
• Animals MeSH
• Check Tag
• Pregnancy MeSH
• Animals MeSH
• Publication type
• Review MeSH