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Benchmark dose (BMD) approach, as an advanced statistical methodology for dose-effect analysis in toxicological research (1) was used to quantitatively characterize in vivo efficacy of two experimental bispyridinium oximes K203 and K027, following promising findings on their low acute toxicity and potential to reactivate acetylcholinesterase (AChE) inhibited by organophosphorus (OP) pesticides and nerve agents in vitro and in vivo (2). Immediately after DDVP challenge (75% LD50, s.c.), male Wistar rats were treated with oxime (0/1.25/2.5/5/25/50% LD50, i.m.). Erythrocyte and diaphragm AChE activity was determined by Ellman's method 60 min after the treatment. Benchmark analysis was done in PROAST software ver. 65.5 (RIVM, The Netherlands). Derived BMDer were K203 = 194 (153, 243) and K027 = 100 (81, 125) μmol/kg bw, BMDdiaph were K203 = 117 (56, 209) and K027 = 21 (10, 37) μmol/kg bw, indicating that oxime K027 induces the same effect size with 2 and 5.5-times lower dose compared to oxime K203 in erythrocites and diaphragm, respectively. Quantification of equieffective doses of oxime reactivators would enable more reliable definition of their therapeutic widths, which further contributes to better determination of therapeutic dosage regimens and, finally, increases the relevance of results obtained in animal models for the human population. [ABSTRACT FROM AUTHOR]

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Purpose: To examine the p38 mitogen-activated protein kinase (p38) phosphorylation and transforming growth factor beta 1 (TGF-β1) expression in rat colon enterocytes after irradiation and their contribution to pathology of intestinal radiation disease. Materials and methods: Male Wistar rats were irradiated with whole body γ-radiation of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 Gy (60Co, 1.44 Gy.min-1). Samples were taken 4 and 24 h after irradiation, immunohistochemically stained, then p38 phosphorylation and TGF-β1 expression were measured in apical and cryptal enterocytes using computer image analysis. In selected groups, morphometric parameters, mitosis and apoptosis were evaluated. Results: P38 phosphorylation integrated optical density (IOD)-based levels increased 2.4-fold ( p ≤ 0.01) and 3.6 to 22.8-fold ( p ≤ 0.001) in apical enterocytes 4 h after 0.5 Gy and 24 h after 3-10 Gy, respectively. TGF-β1 IOD-based expression increased 3.3- to 6.9-fold ( p ≤ 0.001) and 1.6- to 4.9-fold ( p ≤ 0.001) in apical cells 4 h after 0.5-2, 4, 5 Gy and 24 h after 6-10 Gy, respectively. No changes were observed in crypts. Conclusions: We found a chronological and dose-dependent order of p38 activation and TGF-β1 expression in apical enterocytes. Transient up-regulation of p38 and TGF-β1 signalling observed 4 h after low-dose irradiation may participate in molecular mechanisms creating cellular over-expression in apical compartment, while persistent patterns measured 24 h after high-dose irradiation might provide protection of remaining cells in order to maintain tissue integrity. [ABSTRACT FROM AUTHOR]

The purpose of our study was to examine the early expression of p21 and activated transcription factors ATF-2, CREB, Elk-1, p53 after soman and VX poisoning, to throw light on the pathogenetic mechanism of nerve agent-induced non-specific effects. Male Wistar rats were i.m. poisoned by soman (60 µg.kg-1 - 70% LD50) or VX (8 µg.kg-1 - 70% LD50). Samples were taken 4, 24, and 72 hours after poisoning, immunohistochemically stained and phospho-ATF-2Thr-69/71, phospho-CREBSer-133, phospho-Elk-1Ser-383, phospho-p53Ser-15, and protein p21 expressions were measured using computer Image analysis in apical and cryptal enterocytes of the colon transversum. After soman poisoning, we observed an increased phospho-CREB in cryptal enterocytes 4, 24, and 72 h after poisoning, while apical enterocytes expressed increased phospho-CREB only 72 h after intoxication. Phospho-Elk-1 significantly dropped 4 and 24 h after soman poisoning in the cryptal compartment. Activation of ATF-2 and p53 and expression of p21 were not changed 4, 24, and 72 h after soman poisoning. VX poisoning did not change any of measured parameters. Soman and VX showed a different effect on cellular signalling. Soman seems to cause additional effects, which are not related to the basic mechanism of nerve agent-induced toxicity and which temporarily suppress promitotic pathways of proliferating cells and persist in cells during the differentiation process. [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]

Copyright of Archives of Industrial Hygiene & Toxicology / Arhiv za Higijenu Rada I Toksikologiju is the property of Sciendo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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]

Newly developed oximes, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure the different organs. In this work, we focused our attention on an investigation of morphological lesions produced by increasing doses of asoxime, obidoxime, K027, K048, and K075 were selected as experimental reactivators. The whole experiment was conducted on Wistar rats. All rats were sacrificed 24 hrs and 7 days after single im application of 0.1 LD50, 0.5 LD50 and 1.0 LD50 of each reactivator. Tissue alterations were carefully quantified by semiquantitative grading scales - cardiac, diaphragm, muscular, pulmonary, gastric, hepatic and splenic damage score, respectively. Morfological structure of different tissues treated with of 0.1 LD50 of all reactivators were similar to those evaluated in the control groups. Focal and reversible degenerative and vascular changes, were established in tissue samples after treatment with 0.5 LD50 of asoxime, obidoxime and K027 (p < 0.01 vs. control group). Acute alterations were developed in tissue samples within 7 days following treatment with 0.5 LD50 and 1.0 LD50 of all reactivators. The most severe tissue alterations were found in rats treated with .0 LD50 of K048 and K075 (p < 0.001 vs. control and asoxime group, respectively). Our results showed that all AChE reactivators given by a single, high, unitary dose regimen, have adverse effect not only on the main visceral and muscular tissues, but on the whole rat as well, but the exact cause-effect relationship causing cellular injury remains to be established in further investigation. [ABSTRACT FROM AUTHOR]

Amifostine is well known cytoprotector which is efficient when administered before a wide range of antineoplastic agents. The aim of our study was to investigate amifostine effects on doxorubicin-induced toxic changes in rats. Amifostine (75 mg/kg ip) was given 30 min before each dose of doxorubicin (cumulatively 20 mg/kg ip, for 28 days). The animals’ whole-body, liver, and kidney weight, serum biochemical examination, as well as microscopic examination of bone marrow, peripheral blood, liver, and kidney, were done on day 56 of the study. Hepatic and renal alterations were carefully quantified by semiquantitative grading scales—hepatic and renal damage score, respectively. In amifostine-pretreated rats, the number of peripheral blood leukocytes was significantly higher in comparison to doxorubicin-only treated group, preferentially protecting neutrophils. In the same group of rats, hepatic and renal alterations associated with polymorphonuclear cell infiltrates were significantly less severe than those observed in animals receiving only doxorubicin. Our results showed that amifostine successfully protected rats against multiple-dose doxorubicin-induced toxicity by complex, and still not fully elucidated mechanisms of action. [ABSTRACT FROM AUTHOR]

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]