Biochemical effects of low level exposure to soman vapour.

The aim of this study was to demonstrate changes in acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities, tyrosine aminotransferase activity (TAT) and plasma corticosterone level, neuroexcitability and behavior following 24 hours and 4 weeks of soman sublethal inhalation exposure at low level. AChE activity in erythrocytes and BuChE activity in plasma was decreased (dependent on the concentration of soman) 24 h and 4 weeks after the exposure. Similar decrease in AChE activity in different brain parts was observed. One of stressogenic parameters (TAT) was changed after 24 h exposure only. 4 weeks after the exposure, these parameters (corticosterone and TAT) were in the range of normal values. Behaviour of experimental animals was changed 24 h after the exposure persisting 4 weeks after the exposure as well as neuroexcitability.

[Early postdenervation depolarization: effect of NO, acetylcholine and glutamates on chloride transporter and a general view of nerve functions]. / Casná postdenervacní depolarizace: vliv NO, acetylcholinu a glutamátu na chloridový transportér a obecnejsí pohled na nervové funkce.

The survey of the original papers by Vyskocil and his co-workers draws attention to their contribution not only to the classic theory of neuromuscular transmission, but it discusses them especially in relation to some general principles of nervous functions. The mechanisms of synaptic plasticity, co-localization of various types of receptors in a single synapse, as well as practical therapeutic implications could serve as examples. The regulatory functions connected with NO synthase and calcineurin are then discussed in a broader context.

The long-term influence of low-level sarin exposure on behavioral and neurophysiological functions in rats.

1. Long term effects of low doses of highly toxic organophosphorus agent sarin on behavioral and neurophysiological functions were studied in rats exposed to sarin by inhalation. The toxic effects of sarin were monitored using a functional observational battery (FOB), an automatic measurement of motor activity and a test of excitability of central nervous system at 3, 6 and 12 months following sarin exposure. 2. The results indicate that sarin at symptomatic as well as asymptomatic doses (level 2 and 3) is able to induce some neurotoxic effects (a decrease in activity and mobility, an alteration of gait, an increase in stereotyped behavior) including an increase in the excitability of central nervous system (an increase in convulsive activity following the administration of pentamethylenetetrazole) in rats at 3 months following inhalation exposure. Some sings of increased excitability were also observed in sarin-exposed rats following 6 or 12 months (an increase in exploratory activity, body temperature and a hindlimb grip strength at 6 months following exposure to sarin at asymptomatic doses, an increase in tail-pinch response at 12 months following exposure to sarin at symptomatic doses). 3. Therefore, nerve agents such as sarin seem to be harmful not only at high, clinically symptomatic doses but also at low, clinically asymptomatic doses because of long term manifestation of alteration of neurophysiological functions in sarin-exposed rats without disruption of cholinergic nervous system.

[Clinical and economic significance of iron replacement in anemia treated with recombinant human erythropoietin in patients on hemodialysis]. / Klinický a ekonomický význam dusledné náhrady zeleza pri lécbe anémie rekombinantním humánním erytropoetinem u hemodialyzovaných nemocných.

BACKGROUND: Anaemia is a common phenomenon encountered in patients on hemodialysis. Although treatment with rHuEPO therapy is effective, it may fail even at high doses. As rHuEPO efficacy depends on the bioavailability of iron, we monitored the effect of consistent iron supplementation on hematocrit levels and rHuEPO dosage. METHODS AND RESULTS: 24 patients of our outpatient dialysis centre were included in this study. The mean age was 59 years. The age group over 60 included 14 patients. The mean duration of dialysis treatment was 23.8 months. The patients were followed for 6 months according to the NKF-DOQI (National Kidney Foundation Dialysis Outcomes Quality Initiative) recommendations for the treatment of anaemia. Following values were examined monthly: hematocrit, transferin saturation (TSAT) and ferritin. Iron and rHuEPO dosage was adjusted accordingly. Genetic tests for haemochromatosis were conducted in 4 patients with the highest value of TSAT and ferritin. TSAT increased from a mean of 15.9% to 35.9% (p < 0.001). In 23 patients (96%) TSAT levels were within the recommended range after the treatment. Hematocrit increased from 27.7% to 35.7% (p < 0.001). The recommended value of 33% was achieved in 18 patients (75%). The weekly dose of eHuEPO fell from 3958 IU (International Unit) to 2042 IU (p < 0.001), i.e. 1857 IU of rHuEPO were saved per week, per patient. The average dose of iron administered was 157 mg per week. The average level of ferritin rose from 457 micrograms/k to 1387 micrograms/l (p < 0.001). All results were comparable, even in the group of the senior's selected cases. Genetic testing for haemochromatosis showed mutation H63D in heterozygous state of HFE gene in 2 of 4 patients with the highest value of TSAT and ferritin. Sufficient iron supplementation leads to a significant rise in hematocrit and a concomitant decrease of required rHuEPO doses. TSAT, and not ferritin, is a good marker of iron bioavailability. CONDITIONS: The financial savings due to decreased rHuEPO requirements are 20 times higher than the costs related to iron supplementation, calculated in relation to prices valid for the Czech Republic in 1999. Cause and effect of increased level of ferritin should be carefully studied.

Toxic effects of sarin in rats at three months following single or repeated low-level inhalation exposure.

Male albino Wistar rats were once or repeatedly exposed to three various low concentrations of sarin for 60 min. in the inhalation chamber. The clinical status of control as well as sarin-poisoned rats was tested 3 months after exposure to sarin using biochemical, haematological, neurophysiological, behavioural and immunotoxicological methods. While biochemical and haematological parameters, including the activities of cholinesterases in erythrocytes, plasma and various organs (brain, diaphragm), did not differ from the control values regardless of the sarin concentration used, few signs of sarin-induced neurotoxicity and immunotoxicity in sarin-poisoned rats were demonstrated. This was especially true when the single exposure of rats to non-convulsive symptomatic concentration and repeated exposure of rats to clinically asymptomatic concentration of sarin was used. In rats repeatedly poisoned with clinically asymptomatic concentrations of sarin, the alteration of the gait characterized by ataxia, the increase in the stereotyped behaviour, the increase in the excitability of the central nervous system following the administration of the convulsive drug pentamethylenetetrazol were observed. In rats poisoned with non-convulsive symptomatic concentration of sarin, the subtle supression of spontaneous, as well as lipopolysaccharides-stimulated, proliferation of spleen lymphocytes and the bactericidal activity of peritoneal macrophages was primarily observed besides the signs of neurotoxicity. Our findings confirm that both non-convulsive symptomatic and clinically asymptomatic concentrations of sarin can only cause very few, subtle long-term signs of neurotoxicity and immunotoxicity in sarin-poisoned rats when the rats were exposed to asymptomatic sarin concentrations repeatedly.

Influencing of spatial memory in rats by DSP-4 and mescaline.

Behavioural effects of two experimental neurotoxins, mescaline and DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine), on retention of spatial orientation were studied in the T-maze. The stereotaxic administration of both neurotoxins into the selected brain structures was chosen to reveal this effect. The intensity and time course of the neurotoxic effect were dependent on the brain area administered. Nevertheless, the lengthening of the latencies in reaching the goal was generally more marked after mescaline in comparison with DSP-4.

Effect of 7-methoxytacrine and L-carnitine on the activity of choline acetyltransferase.

Changes of choline acetyltransferase (ChAT) activity in the hippocampus and the basal ganglia were studied in rats treated i.p. with L-carnitine (CRT) and 7-methoxytacrine (7-MEOTA) (i.m.) separately or 3-days treated with L-carnitine and then with one administration of 7-MEOTA. Both compounds increased ChAT activity when administered separately. 3-day treatment of CRT followed by administration of 7-MEOTA normalized ChAT activity.

Atropine-induced convulsions in the septohippocampal system. I. Effects of cannula position and sex.

Effects of local administration of atropine into the medial septal nucleus (MSN) and dorsal septal nucleus (DSN) were tested in laboratory rats. Atropine administration led to the development of a spike/wave activity in the hippocampus as well as amygdala within 10 minutes. The frequency of spikes ranged in the absolute values from 20 to 25 spikes per minute in the case of atropine administration to MSN, while in the case of DSN it reached only about 16 spikes per minute. Spike/wave activity outlasted in the EEG record within 2 hours. The average incidence of spikes was somewhat lower in females than in males. A possible relation of the atropine-induced spike/wave activity to another kinds of limbic convulsions is discussed.

Effect of alprazolam and ketamine on seizures induced by two different convulsants.

Effect of two anticonvulsants with different mechanism of action, i.e. alprazolam and ketamine, was tested in two types of seizure activity. The first one was induced by N-(3,5-dimethoxy-4-propoxyphenylethyl)-aziridine, the second one by pentylenetetrazol. While alprazolam alleviated both the minimal as well as major paroxysms, ketamine suppressed only major seizures. These effects are discussed in terms of the both N-methyl-D-aspartate and GABA receptors involvement.

Enhancing effect of L-carnitine on some abnormal signs induced by pentylenetetrazol.

L-carnitine (CRT) is known to enhance penetration of some drugs of chemical groups across biological barriers. The aim of the study is to contribute to the problem of influencing the blood-brain-barrier (BBB) under CRT administration. In the case of validity of this presumption, CRT would be able to increase some effects of the central analeptic drug pentylenetetrazol (PTZ). Two different experimental schedules were chosen in respect of PTZ administration. The first one was an administration of a high convulsive dose of 100 mg/kg PTZ, the second one was a repeated administration of low (i.e., subconvulsive) doses of PTZ. CRT increased the total score of abnormal signs induced by a convulsive dose of PTZ. Moreover, CRT was able to accelerate the development of kindling induced by repeated administration of low doses of PTZ.

Convulsive properties of N-(3,5-dimethoxy-4-propoxyphenyl-ethyl) aziridine and their influencing by diazepam and triazolam.

Convulsive activity of N-(3,5-dimethoxy-4-propoxy-phenyl-ethyl)-aziridine (FAZ-4), a newly synthetized aziridine compound was studied in rats. There is a lack of tonic component of major paroxysm in comparison with the classical convulsive agent pentylenetetrazol. This effect of FAZ-4 is probably due to the forebrain mechanism without the midbrain involvement. Both anticonvulsants tested suppressed seizures in a different manner, however triazolam exerted stronger anticonvulsive activity than the same dose of diazepam did.

[Review of present knowledge on the pathogenesis and pathophysiology of Amanita phalloides poisoning]. / Prehled soucasných poznatku o patogenezi a patofyziologii otravy muchomurkou zelenou (Amanita phalloides).

The mushroom poisoning of phalloid type is caused by amatoxins, mainly by alpha-amanitine. It is a cytotoxin which acts through an indirect mechanism. It binds irreversibly the nucleolar enzyme, RNA-polymerase II in cells with intensive proteosynthesis (enterocytes in the digestive tract, hepatocytes in the liver and epithelial cells of proximal renal tubules). A tight binding of the toxin with the enzyme blocks the transcription from DNA to m-RNA and thus makes the proteosynthesis impossible. This results in the cell necrosis. Pathophysiology of the phalloid type poisoning is rather complicated, as the disorders of primarily affected organs (gastrointestinal tract, liver and kidney) produce a derangement of other remote organs and systems. After a relatively long period of latency (average 8-10 hours) the symptoms of the initial phase of the symptomatologic course of intoxication--excessive vomiting and diarrhea (during one or two days)--are observed, leading to dehydration which culminates in the hypovolemic shock. A short subsequent phase of an apparent improvement (in the 3rd day) is followed, beginning with the fourth day, by an acute failure of the liver and kidney. The cause of the failure of both the organs is the same--the toxic noxa. Therefore it is not possible to classify the coexistence of acute hepatal and renal failure as a so-called hepatorenal syndrome. The true hepatorenal syndrome is namely a potentially reversible prerenal failure accompanying a variety of serious liver diseases, namely in their terminal phase. The phalloid nephropathy, however, has two constituents.(ABSTRACT TRUNCATED AT 250 WORDS)

Methods for testing of compounds with non-lethal effect.

The effect of some toxic chemicals differing in their mechanism of action was studied by means of the method of the spontaneous motoric activity. Qualitative and quantitative changes in behaviour following administration of sublethal doses of these compounds were found. Depending on the doses administered, exploratory activity (both horizontal and vertical) following soman administration was decreased. Very low doses of VX decreased motoric activity of animals in dependence in time of its action. Anticholinergic substance QB significantly increased the frequency of motor activity. Noradrenergic neurotoxin DSP 4 decreased both horizontal and vertical activities depending on time of its exposition. The increase followed by decrease of spontaneous motor activity was observed following administration of yperite.

Molecular forms of hippocampal acetylcholinesterase and their changes following septal lesions in the rat.

Changes of acetylcholinesterase activity and its molecular forms, extracted by Triton X-100 and separated by polyacrylamide gel electrophoresis, were studied in the rat hippocampus following septal lesions. Detection of acetylcholinesterase was made densitometrically. While the total activity of acetylcholinesterase was decreased, its molecular forms exhibited a different pattern of changes: the heavy forms were decreased, while the light ones were increased. The results support the view that different acetylcholinesterase molecular forms serve different regulatory mechanisms.