scholarly journals Optimal Choice of Acetylcholinesterase Reactivators for Antidoral Treatment of Nerve Agent Intoxication

2010 ◽  
Vol 53 (4) ◽  
pp. 207-211 ◽  
Author(s):  
Jiří Bajgar
Keyword(s):  
Nerve Agents ◽  
Nerve Agent ◽  
Optimal Choice ◽  
Simple Type ◽  
Hi 6 ◽  
Acetylcholinesterase Reactivators ◽  
Better Than

The studies dealing with mechanism of organophosphates (OP)/nerve agent action, prophylaxis and treatment of intoxications is a very hot topic at present. Though the research is very intensive, unfortunately, up to now, there is not universal or significantly better reactivator sufficiently effective against all nerve agents/OP when compared with presently available oximes (pralidoxime, methoxime, obidoxime, trimedoxime, HI-6). The use of the most effective reactivator (HI-6) using simple type of autoinjector (e.g. ComboPen) is strictly limited because of decomposition of HI-6 in solution. Thanks to better solubility it is clear that another salt of HI-6 (dimethanesulfonate, HI-6 DMS) is more convenient for the use as antidote against nerve agents in the autoinjector than HI-6 chloride (Cl). It was clearly demonstrated that reactivation potency of HI-6 DMS in comparison with HI-6 Cl in vivo was the same and bioavailability of HI-6 DMS is better than that of HI-6 Cl. Three chambered autoinjector allows administration of all three antidotes (atropine, reactivator, diazepam) simultaneously. Moreover, the content of chambers can be changed according to proposed requirements. Possible way to solve the problem of universal reactivator could be the use of two reactivators. Three chambered autoinjector is an ideal device for this purpose.

scholarly journals Evaluation of Potency of Known Oximes (Pralidoxime, Trimedoxime, HI-6, Methoxime, Obidoxime) to in vitro Reactivate Acetylcholinesterase Inhibited by Pesticides (Chlorpyrifos and Methylchlorpyrifos and Nerve Agent (Russian VX)

2007 ◽  
Vol 50 (3) ◽  
pp. 203-206 ◽  
Author(s):  
Kamil Musílek ◽  
Kamil Kuča ◽  
Daniel Jun
Keyword(s):  
Organophosphorus Pesticides ◽  
Nerve Agents ◽  
Nerve Agent ◽  
Hi 6 ◽  
Acetylcholinesterase Reactivators

Nerve agents and pesticides belong to the group of organophosphates. They are able to inhibit irreversibly the enzyme acetylcholinesterase (AChE). Acetylcholinesterase reactivators were designed for the treatment of nerve agent intoxications. Their potency to reactivate pesticide-inhibited AChE was many times evaluated. In this study, five commonly used AChE reactivators (pralidoxime, methoxime, HI-6, obidoxime, trimedoxime) for the reactivation of AChE inhibited by two pesticides (chlorpyrifos and methylchlorpyrifos) were used. Russian VX (nerve agent) as a member of nerve agents’ family was taken for comparison. Obtained results show that oximes developed against nerve agent intoxication are less effective for intoxication with organophosphorus pesticides. Especially, methylchlorpyrifos-inhibited AChE was found to be poorly reactivated by the compounds used.

scholarly journals Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning / Usporedno određivanje učinkovitosti bispiridinijevih oksima pri trovanju paraoksonom

2015 ◽  
Vol 66 (2) ◽  
pp. 129-134 ◽  
Author(s):  
Suzana Žunec ◽  
Božica Radić ◽  
Kamil Kuča ◽  
Kamil Musilek ◽  
Ana Lucić Vrdoljak
Keyword(s):  
Therapeutic Efficacy ◽  
Standard Therapy ◽  
Organophosphorus Compounds ◽  
Nerve Agents ◽  
Therapeutic Efficiency ◽  
Hi 6 ◽  
Comparative Determination

Abstract The inability of standard therapy to provide adequate protection against poisoning by organophosphorus compounds (pesticides and nerve agents) motivated us to search for new, more effective oximes. We investigated the pharmacotoxicological properties of six experimental K-oximes (K027, K033, K048, K074, K075, and K203) in vivo. The therapeutic efficacy of K-oximes (at doses of 5 or 25 % of their LD50) combined with atropine was assessed in paraoxon-poisoned mice and compared with conventionally used oximes HI-6 and TMB-4. The bisoxime K074 was the most toxic (LD50=21.4 mg kg-1) to mice, while monoxime K027 was the least toxic (LD50=672.8 mg kg-1). With the exception of K033, all of the tested K-oximes showed better therapeutic efficiency than HI-6 and TMB-4. K027 and K048 stood out by demonstrating low acute toxicities and ensuring protective indices ranging from 60.0 to 100.0 LD50 of paraoxon. Taking into account that these two oximes showed a similar therapeutic efficacy regardless of the applied doses, our results suggest that K027 and K048 could be antidotes for paraoxon intoxication.

Nanoscavenger provides long-term prophylactic protection against nerve agents in rodents

2019 ◽  
Vol 11 (473) ◽  
pp. eaau7091 ◽  
Author(s):  
Peng Zhang ◽  
Erik J. Liu ◽  
Caroline Tsao ◽  
Shane A. Kasten ◽  
Michael V. Boeri ◽  
...  
Keyword(s):  
Organophosphorus Compounds ◽  
Pharmacokinetic Profile ◽  
Nerve Agents ◽  
Nerve Agent ◽  
Prophylactic Administration ◽  
Guinea Pig Model ◽  
Effective Drugs ◽  
Scavenging Efficiency

Nerve agents are a class of organophosphorus compounds (OPs) that blocks communication between nerves and organs. Because of their acute neurotoxicity, it is extremely difficult to rescue the victims after exposure. Numerous efforts have been devoted to search for an effective prophylactic nerve agent bioscavenger to prevent the deleterious effects of these compounds. However, low scavenging efficiency, unfavorable pharmacokinetics, and immunological problems have hampered the development of effective drugs. Here, we report the development and testing of a nanoparticle-based nerve agent bioscavenger (nanoscavenger) that showed long-term protection against OP intoxication in rodents. The nanoscavenger, which catalytically breaks down toxic OP compounds, showed a good pharmacokinetic profile and negligible immune response in a rat model of OP intoxication. In vivo administration of the nanoscavenger before or after OP exposure in animal models demonstrated protective and therapeutic efficacy. In a guinea pig model, a single prophylactic administration of the nanoscavenger effectively prevented lethality after multiple sarin exposures over a 1-week period. Our results suggest that the prophylactic administration of the nanoscavenger might be effective in preventing the toxic effects of OP exposure in humans.

scholarly journals Detection of Chemical Weapon Nerve Agents in Bone by Liquid Chromatography–Mass Spectrometry

2020 ◽  
Vol 44 (4) ◽  
pp. 391-401 ◽  
Author(s):  
Katie M Rubin ◽  
Bruce A Goldberger ◽  
Timothy J Garrett
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Chemical Properties ◽  
Nerve Agents ◽  
Nerve Agent ◽  
Quantitative Detection ◽  
Chemical Weapon ◽  
Liquid Chromatography Mass Spectrometry ◽  
Chromatography Mass Spectrometry

Abstract A recently proposed model for the incorporation of xenobiotics of forensic interest into the human skeleton suggests nerve agent metabolites may incorporate into bone at relatively elevated concentrations based on their unique chemical properties. To test the hypothesis that nerve agent metabolites interact with bone, methods for the extraction, isolation and semi-quantitative detection of nerve agent metabolites (MPA, EMPA, IMPA, iBuMPA, CMPA and PMPA, corresponding to the nerve agents VX, Russian VX, sarin, cyclosarin and soman, respectively) from osseous tissue were developed using liquid chromatography–mass spectrometry with both quadrupole time-of-flight and triple quadrupole (QqQ) instruments. The optimized methods were validated on the QqQ instrument. Despite high ion suppression, the achieved limits of detection (5–20 pg/g for four analytes; 350 pg/g for the fifth analyte) were lower than many of those published for the same analytes in other biomatrices, including serum and urine. These methods were tested on the skeletal remains of minipigs exposed to the chemical weapon VX in vivo. The VX metabolite was detected in multiple minipig bone samples; to the authors’ knowledge, this is the first time in vivo nerve agent exposure has been detected from bone. Further, detected concentrations and diaphyseal-to-epiphyseal area count ratios reflect animal exposure history. Although the results are limited, they are promising, indicating that nerve agent metabolites may interact with bone as a pharmacokinetic compartment and can be extracted from bone postmortem. Additional studies, assessing the effects of different agents, exposure pathways and taphonomic variables, are needed; however, these results suggest the method may be used with human bone to detect use of chemical weapons from postmortem biomatrices even well after a suspected attack. More general implications for both nerve agent toxicology and skeletal toxicology are also discussed.

scholarly journals An In Vitro Nerve Agent Brain Poisoning Transwell Model for Convenient and Accurate Antidote and Nanomedicine Evaluation

2021 ◽  
Author(s):  
Yao Li ◽  
Jingyi Huang ◽  
Huanchun Xing ◽  
Zinan Zhang ◽  
Xin Sui ◽  
...  
Keyword(s):  
Large Scale ◽  
Lower Pool ◽  
Nerve Agent ◽  
Effective Dosage ◽  
Optimal Dosage ◽  
Sprague Dawley ◽  
Hi 6 ◽  
Upper Pool

Abstract Background: Nerve agents (NAs) can irreversibly inhibit acetylcholinesterase (AChE). An effective NA antidote should permeate the blood–brain barrier (BBB) to reactivate the inhibited AChE in brain. There is an urgent requirement for the large-scale evaluation and screening of antidotes. Existing methods for evaluating reactivators in vitro can only examine the reactivation effect of drugs and not brain-target properties. The current Transwell BBB model can only evaluate the drug penetration performance for crossing the barrier, but not the pharmacodynamics. Methods: Highly purified rat brain microvascular endothelial cells (RBMECs) from 2-week-old Sprague Dawley rats were inoculated into the upper chamber of Transwell plates to establish a BBB model. Three key parameters of AChE reactivation were determined by the Ellman method: the minimum detection limit of AChE, the effective dosage of NAs (70% enzyme inhibition rate), and the optimal dosage of reactivators. AChE and NAs were added to the lower pool of Transwell plates to simulate central poisoning, and antidotes of reactivators were added to the upper pool to simulate drug administration. The AChE activity of samples, collected from the lower pool, was measured. A liposomal nanomedicine loaded with the reactivator asoxime chloride (HI-6) was prepared using the extraction method and tested by the model.Results: The obtained RBMECs exhibited a typical monolayer “paving stone” morphology, and tight junctions were expressed among the RBMECs. The concentrations of AChE, sarin, and the reactivator were 0.07 mg/mL, 10–6 v/v, and 0.03 mg/mL, respectively. The reaction rate of the reactivators obtained from the model was significantly lower than that obtained from the non-model group. Furthermore, a nanomedicine loaded with HI-6 was synthesized. The final results and rules obtained from the model were in accordance with those evaluated in vivo. Conclusion: The therapeutic effect of antidotes can be rapidly and accurately evaluated using this model. In addition to small-molecule drugs, nanomedicines can also be evaluated by this method. A liposomal nanomedicine with a high reactivation rate against the nerve agent sarin was discovered.

scholarly journals A Comparison of the Potency of the Oxime HLö-7 and Currently Used Oximes (HI-6, Pralidoxime, Obidoxime) to Reactivate Nerve Agent-Inhibited Rat Brain Acetylcholinesterase by in vitro Methods

2005 ◽  
Vol 48 (2) ◽  
pp. 81-86 ◽  
Author(s):  
Kamil Kuča ◽  
Jiří Cabal ◽  
Jiří Kassa ◽  
Daniel Jun ◽  
Martina Hrabinová
Keyword(s):  
Rat Brain ◽  
Nerve Agents ◽  
Nerve Agent ◽  
The Other ◽  
In Vitro Evaluation ◽  
In Vitro Methods ◽  
Hi 6 ◽  
Hlö 7 ◽  
Brain Acetylcholinesterase

1. The efficacy of the oxime HLö-7 and currently used oximes (pralidoxime, obidoxime, HI-6) to reactivate acetylcholinesterase inhibited by various nerve agents (sarin, tabun, cyclosarin, VX) was tested by in vitro methods. 2. Both H oximes (HLö-7, HI-6) were found to be more efficacious reactivators of sarin and VX-inhibited acetylcholinesterase than pralidoxime and obidoxime. On the other hand, their potency to reactivate tabun-inhibited acetylcholinesterase is very low and does not reach the reactivating efficacy of obidoxime. In the case of cyclosarin, the oxime HI-6 was only found to be able to sufficiently reactivate cyclosarin-inhibited acetylcholinesterase in vitro. 3. Thus, the oxime HLö-7 does not seem to be more efficacious reactivator of nerve agent-inhibited acetylcholinesterase than HI-6 according to in vitro evaluation of their reactivation potency and, therefore, it is not more suitable to be introduced for antidotal treatment of nerve agent-exposed people than HI-6.

Factor-VIII Inhibitor in Less Severely Affected Haemophilic Patients

1975 ◽  
Author(s):  
E. G. D. Tuddenham ◽  
A. L. Bloom ◽  
J. C. Giddings ◽  
C. A. Barrett
Keyword(s):  
Factor Viii ◽  
Factor Viii Inhibitor ◽  
Factor Viii Level ◽  
Replacement Treatment ◽  
Viii Level ◽  
Viii Inhibitor ◽  
In Vivo Recovery ◽  
Better Than

The occurrence of factor VIII inhibitor in five mild or moderately affected liaemophilic patients is described. In four patients the inhibitor inactivated endogenous factor VIII an dtemporarily converted them to severely affected haemophiliacs with factor VIII level of 0%. In the fifth patient, a brother of one of the others, the inhibitor although more potent did not inactivate the patient’s own factor VIII and did not completely inactivate normal factor VIII in vitro. This patient responded to treatment with factor-VIII concentrate but the in-vivo recovery was reduced. The patient’s plasma was tested against a panel of normal donors but it inactivated factor VIII in each to a similar extent and no evidence for normal factor-VIII groups was obtained. In the other patients the response to replacement treatment was also better than that usually seen in severely affected haemophilic patients with inhibitor. In the two related patients the inhibitors have so far persisted but in the unrelated patients the inhibitors eventually disappeared and did not always recur with subsequent therapy. The incidence of factor- VIII inhibitor in less severe haemophiliacs (factor VIII > 3% ) in this centre is 6% suggesting that the complication is more frequent in this type of patient than hitherto recognised.

scholarly journals In vitro and in vivo Evaluation of Ibuprofen Nanosuspensions for Enhanced Oral Bioavailability

2021 ◽  
Author(s):  
Mohsen Hedaya ◽  
Farzana Bandarkar ◽  
Aly Nada
Keyword(s):  
Particle Size ◽  
Tween 80 ◽  
Aqueous Solubility ◽  
In Vitro Dissolution ◽  
In Vivo Evaluation ◽  
Poorly Soluble ◽  
Extent Of Absorption ◽  
Better Than

Introduction: The objectives were to prepare, characterize and in vivo evaluate different ibuprofen (IBU) nanosuspensions prepared by ultra-homogenization, after oral administration to rabbits. Methods: The nanosuspensions produced by ultra-homogenization were tested and compared with a marketed IBU suspension for particle size, in vitro dissolution and in vivo absorption. Five groups of rabbits received orally 25 mg/kg of IBU nanosuspension, nanoparticles, unhomogenized suspension, marketed product and untreated suspension. A sixth group received 5 mg/kg IBU intravenously. Serial blood samples were obtained after IBU administration. Results: The formulated nanosuspensions showed significant decrease in particle size. Polyvinyl Pyrrolidone K30 (PP) was found to improve IBU aqueous solubility much better than the other tested polymers. Addition of Tween 80 (TW), in equal amount as PP (IBU: PP:TW, 1:2:2 w/w) resulted in much smaller particle size and better dissolution rate. The Cmax achieved were 14.8±1.64, 11.1±1.37, 9.01±0.761, 7.03±1.38 and 3.23±1.03 μg/ml and the tmax were 36±8.2, 39±8.2, 100±17.3, 112±15 and 105±17 min for the nanosuspension, nanoparticle, unhomogenized suspension, marketed IBU suspension and untreated IBU suspension in water, respectively. Bioavailability of the different formulations relative to the marketed suspension were the highest for nanosuspension> unhomogenized suspension> nanoparticles> untreated IBU suspension. Conclusion: IBU/PP/TW nanosuspensions showed enhanced in vitro dissolution as well as faster rate and higher extent of absorption as indicated from the higher Cmax, shorter tmax and larger AUC. The in vivo data supported the in vitro results. Nanosuspensions prepared by ultra-high-pressure-homogenization technique can be used as a good formulation strategy to enhance the rate and extent of absorption of poorly soluble drugs.

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