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K048 is a member of K-oximes, a new oxime class that has recently been confirmed effective against poisoning by the nerve agent tabun and several pesticides. The toxicity profile of the K048 oxime has not been fully characterized and its optimal therapeutic dose has not yet been established. Earlier studies report excellent results with K048 in reactivating tabun-phosphorylated AChE and in the therapy of tabun-poisoned mice. It possesses a low acute toxicity and exerts an acceptable toxicity profile on isolated human peripheral blood lymphocytes in vitro. Intraperitoneal administration of K048 in rats resulted in an LD50 of 238.3 mg/kg. In this in vivo study, we investigated cholinesterase ( ChE) activity and oxidative stress marker levels (lipid peroxidation and superoxide dismutase activity) in the plasma of exposed rats after administering the compound at 25% of its LD50. Lymphocyte viability was evaluated using an acridine orange/ethidium bromide in situ fluorescent assay. The levels of primary DNA damage in rat white blood cells were measured using the alkaline comet assay. The compound applied at 25% of its LD50 did not significantly affect ChE activity and lipid peroxidation and did not cause significant changes in the SOD activity in plasma. The cytotoxicity profile of K048 in the tested dose was also acceptable, and it did not possess significant DNA-damaging potential. The obtained results are promising for further evaluations of the K048 oxime, which should include tests on a broader concentration range and longer incubation times. [ABSTRACT FROM AUTHOR]

Some compounds, although not primarily designed as supportive drugs in chemotherapy, are promising candidates for clinical use. The ability of HI-6 oxime to relieve the side effects of irinotecan was recently determined in vitro. In this animal study, we investigated the efficacy of HI-6 in vivo, when given as a pre-treatment and concomitantly with irinotecan. We evaluated the cholinesterase (ChE)/acetylcholinesterase (AChE) activity, the levels of oxidative stress markers, DNA damage and the radical scavenging capacity of HI-6. Both HI-6 and irinotecan inhibited ChE/AChE activity but showed different levels of ChE inhibition in plasma and AChE inhibition in the liver and brain tissue. We also observed a weak antioxidant capacity of HI-6, undiscovered until now, and found an acceptable genotoxicity profile in three types of somatic cells in rats. The in vivo erythrocyte micronucleus assay showed that HI-6 did not significantly change either the frequency of micronuclei or the ratio of polychromatic and normorchromatic erythrocytes. Taken together, our results provide a good argument in favour of HI-6 as a promising molecule for further studies and eventual use in humans. [ABSTRACT FROM AUTHOR]

The bimolecular rate constants (ka) of inhibition were determined for cholinesterase in rat blood in vivo and three nerve agents in vitro. They were in the range of 105-106 M·min-1 with the highest value for VX (ka = 8.92 x 106), the next highest for soman (ka = 3.22 x 106) and the lowest for sarin (ka = 0.39 x 106), respectively. The inhibition rate is the same in vitro and in vivo; when the real inhibition in vivo and in vitro is compared, it is possible to assess the concentration of the nerve agent present in the blood stream. When administered intramuscularly it is about 70% of the dose administered. [ABSTRACT FROM AUTHOR]

We studied the influence of four methods of euthanasia (decapitation, exsanguination via cardiocentesis following ether anaesthesia, Nembutal anaesthesia, or immersion in a CO2 atmosphere) on the activity of acetylcholinesterase (AChE) and butyryicholinesterase (BChE) in the brain and in the blood of mature female rats. A significant decrease was observed in the activity of AChE in the whole blood in the group treated with Nembutal. There were no significant changes in the activity of BChE with any method of euthanasia. Euthanasia in a CO2 atmosphere was the best technique with respect to the results indicating lack of affect on the activity of AChE and BChE in the periphery and the brain, as well as from the point of view of the welfare of the animals. [ABSTRACT FROM AUTHOR]

This article is focused on an optimization of acetylcholinesterase immobilization on screen printed platinum electrodes. An acetylcholinesterase layer cross linked by glutaraldehyde and another non cross linked were compared according to several parameters including background current, current before and current after inhibition by paraoxon. The percentage of inhibition was also calculated. The results obtained confirmed the importance of glutaraldehyde cross linking in the design of the acetylcholinesterase based biosensor. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase (AChE) is a widely spread enzyme playing a very important role in nerve signal transmission. As AChE controls key processes, its inhibition leads to the very fast death of an organism, including humans. However, when this feature is to be used for killing of unwanted organisms (i.e. mosquitoes), one is faced with the question - how much do AChEs differ between species and what are the differences? Here, a theoretical point of view was utilized to identify the structural basis for such differences. The various primary and tertiary alignments show that AChEs are very evolutionary conserved enzymes and this fact could lead to difficulties, for example, in the search for inhibitors specific for a particular species. [ABSTRACT FROM AUTHOR]

The article presents a study which examined how equine butyrylchlolinesterase (Eq BuChE) protects rats against inhalation exposure to sublethal sarin concentrations. Cholinesterase and brain acetylcholinesterase (AChE) activities were determined. Results showed decreases in plasma Eq BuChE activity and red blood cells and brain AChE activities in rats after sarin inhalation exposure.

The article presents an in vitro study of three potential acetylcholinesterase (AChE) reactivators taken from a monoquaternary reactivator pralidoxime. The compounds used in the study include pyridinium-2-aldoxime-4- carbamoyl-N-methyl iodide, pyridinium-2-aldoxime-4-ethoxycarbonyl-N-methyl iodide, and pyridinium-2-aldoxime-5-ethoxycarbonyl-N-methyl iodide. Results showed that none of the tested oximes was able to reactivate cyclosarin-inhibited AChE.

In this work in vitro evaluation of the reactivation potency of the newly synthesized reactivators for acetylcholinesterase (AChE; EC 3.1.1.7) is described. Using this method, reactivation potency of 21 potential reactivators of AChE inhibited by the nerve agent sarin has been evaluated. We have confirmed the fact that currently the most promising AChE reactivator, HI-6, is the most effective reactivator of sarin-inhibited AChE. There are only three AChE reactivators—HI-6, TO033 and TO047—able to satisfactorily reactivate sarin-inhibited AChE at the concentration 10 -5 M, which is nontoxic for human use. On the other hand, there are 14 AChE reactivators, that are able to reactivate sarin-inhibited AChE at the concentration 10 -3 M. However, this concentration of reactivator is probably toxic for human use. [ABSTRACT FROM AUTHOR]

A comparison of one mono- and seven bisquaternary acetylcholinesterase (AChE) reactivators of acetylcholinesterase inhibited by VX agent was performed. As a source of the acetylcholinesterase, a rat brain homogenate was taken. There were significant differences in reactivation potency of all tested oximes. The oxime TO205 seems to be the most efficacious followed by TO046, HI-6, HS-6, K027, obidoxime, MMC and 2-PAM. In addition, the results of this study showed that the reactivation potency of the tested reactivators depends on many factors - such as the number of pyridinium rings, the number of oxime groups and their position, as well as the length and the shape of linkage bridge between two pyridinium rings. [ABSTRACT FROM AUTHOR]

Nerve Agents are toxic organophosphorus compounds which inhibit cholinesterases, pivotal enzyme in Parasympathetic Neurotransmission. As they are Schedule 1 compounds in accordance to Chemical Weapons Convention, strict controls are applied and some research groups may have their work hampered due to requirements for synthesis and manipulation. Nerve Agents' surrogates have emerged as affordable substitutes for more realistic approach for development of antidotes and biochemical and toxicity studies, as they are structurally related to Nerve Agents and considered as CWC Schedule 2 compounds, yielding similar enzyme adducts. As Laboratório de Análises Químicas - LAQ (ISO 17025) at IDQBRN have been participated in OPCW Proficiency Tests, striven to obtain the "OPCW Designated Laboratory" status, we have synthesized different dialkyl alkylphosphonates for verification purposes. Therefore, we have proposed synthesis of surrogates for our research on Medicinal Chemistry using them as starting materials. They have proven to be very useful compounds in our research and our syntheses have delivered good yields and purity of final compounds. [ABSTRACT FROM AUTHOR]

Abstract: A series of planar Ni(II) dithiolenes derived of maleonitriledithiol (mnt), benzene-1,2-dithiol (bdt) and toluene-3,4-dithiol (tdt) with bidentate P,P-ligands (dppe=1,2-bis(diphenylphosphino)ethane, dppp=1,3-bis(diphenylphosphino)propane, dppb=1,4-bis(diphenylphosphino)butane, dpppn=1,5-bis(diphenylphosphino)pentane) of the [Ni(P,P)(dithiol)] type have been synthesized. The compounds have been characterized by elemental analysis, IR and electronic spectroscopies, magnetochemical, conductivity measurements and thermal analysis. Single crystal X-ray analysis of [Ni(dpppn)(mnt)] confirmed a planar geometry of NiP2S2 chromophore. Possible practical applications such as use of these compounds for vulcanization accelerators and their anticholinesterase activity were evaluated. [Copyright &y& Elsevier]

The highly toxic nature of tabun has been known for many years, but there are still serious limitations to antidotal therapy. In this study, we used rats as an experimental model to evaluate the efficiency of bispyridinium para-oxime K203 as therapy against tabun poisoning as well as to examine if induction of oxidative stress is linked to organophosphate toxicity. K203 showed high potency in counteracting tabun poisoning. Either alone or in combination with atropine, this oxime significantly increased cholinesterase activity at 0.5 and 1 h compared to untreated rats poisoned with tabun. Simultaneous measurements of markers of oxidative stress (lipid peroxidation and superoxide dismutase) showed that tabun poisoning, but also therapy (oxime alone or oxime plus atropine) applied immediately after tabun poisoning, could generate free radical species that may cause oxidative stress in rats. [ABSTRACT FROM AUTHOR]