Disappearance of radioactivity from perfusate of isolated rat liver after administration of different doses of tritiated DH-ergotoxine.

In ergot alkaloids a disproportion between the size of the peroral dose and the achieved area under the curve concentrations was described. This process can be explained by nonlinearity in the absorption, distribution or elimination of alkaloids. The aim of the present paper is to find whether elimination of tritiated DH-ergotoxine (3HDHE) in the liver is a linear, dose-independent process. Therefore on the model of the isolated rat liver disappearance of radioactivity in perfusate after the administration of two doses of 3HDHE, viz. 60 ng g-1 of the liver and 3030 ng g-1 of the liver, was investigated. The disappearance curves of radioactivity expressed as the percentage of the administered dose did not significantly differ between both groups. No significant changes between the groups were found either in the size of pharmacokinetic parameters, or in the portion of the administered radioactivity excreted in bile. Therefore the present authors think that disappearance of radioactivity in perfusate of the isolated liver after administration of 3HDHE is a linear process following first-order kinetics.

Kinetics of 3H-thymidine label in rat liver regenerating after partial hepatectomy and after damage with carbon tetrachloride or silica.

Rat liver DNA was labelled with [methyl-3H] thymidine after partial hepatectomy, carbon tetrachloride poisoning, or an intravenous injection of silica dust. Changes in DNA labelling were studied for 4 weeks after the single pulse. Total radioactivity incorporated into liver DNA after partial hepatectomy and after carbon tetrachloride administration remained on the same level when compared with that found after 1 h. DNA activity in liver of untreated rats and of rats treated with silica decreased by about 50% within the first 2 weeks and then remained on this level for the rest of the studied period. These differences may reflect the fact that hepatocytes that have a long life span are preferentially labelled in partially hepatectomized and CCl4-treated rats, while liver macrophages with a short half-life take up a large part of the label in intact rats and in rats treated with silica.

Contribution to some radiobiological aspects of the investigation of radiosensitizers of hypoxic cells. Part IV: Radiosensitizing effect of metronidazole evaluated on the level of postirradiation changes of bone marrow cellularity in rats protected by induced hypoxia of lower body half.

Radiosensitizing effect of metronidazole (Entizol, Polfa, Poland) was tested on an experimental model of ischaemized bone marrow. The changes of bone marrow cellularity were recorded after whole body irradiation of rats protected with abdomen compression during irradiation. With an increasing dose of irradiation proportional and significant decrease of nuclear elements in bone marrow occurred the third day after irradiation. Metronidazole administered to unprotected rats (without compression) did not show any effect. The abdomen compression led to a pronounced radioprotection but metronidazole administration reduced this effect significantly. Ischaemization of the lower half of rat body produced on the level of bone marrow cellularity the protection corresponding to DRF (dose reduction factor) = 1.96 the third day after irradiation. DRF value decreased to 1.52 by metronidazole application which corresponds to ER (enhancement ratio) = 1.29.

Contribution to some radiobiological aspects of the investigation of chemical radiosensitizers of hypoxic cells. Part V: Metronidazole--dependence of its radiosensitizing effect on the dose, time interval of administration and hypoxia degree of the bone marrow evaluated according to the changes of its cellularity in rats.

In the experiments on female rats of Wistar strain the effect of metronidazole (Entizol - Polfa) was studied administrated in aqueous solution with a gastric pipette into the stomach. Dependence was analyzed on the dose of metronidazole, on the time interval of administration before irradiation and on the degree of hypoxia of bone marrow during irradiation induced in the lower part of the body and graded by the abdomen compression with an inflatable rubber cuff with overpressure 4, 6.7, 13.3 and 20 kPa. The effect of whole body irradiation (60Co source) was evaluated according to the changes of bone marrow cellularity (BMC) the third day after irradiation. The sensitizing effect of metronidazole increases rapidly up to dose of 30 mg/kg with rising dose of the drug, then at higher doses only slowly. With prolonging interval of the application of 600 mg/kg body weight the sensibilization increases and reaches the peak after 1-2 hours, then it gradually decreases till the complete disappearance after 10-15 hours. In both cases irradiation was carried out at abdomen compression corresponding to 20 kPa of overpressure in the rubber cuff. The induced hypoxia of bone marrow demonstrated a significant, protective effect, corresponding to the degree of abdomen compression which was reduced by metronidazole administration in the dose of 600 mg/kg. The reduction represents one half to one third of the protective value and is proportional to the degree of induced bone marrow hypoxia during irradiation.

Hormonal and organ weight changes in rats exposed to simultaneous chronic effects of CO and NO2.

UNLABELLED: Activity of the pituitary-adrenocortical, sympathico-adrenomedullary and thyroid gland systems was examined in groups of male adult rats, average weight 180 g, exposed for 2 months to a mixture of 7 mg.m-3 NO2 and 32 mg.m-3 CO in air and in groups of matched controls inhaling fresh air. Corticosterone (B) concentrations in the serum of rats were determined by the competitive protein-binding method, noradrenaline (NA) in the hypothalamus and catecholamines (CA) in suprarenals by fluorometry, thyroxine (T4) and triiodothyronine (T3) in the thyroid gland by the RIA technique. Measurements of organ weight were related to overall body weight. The data emerging from this study were evaluated using the Student t-test. CONCLUSIONS: one-month exposure led to a decrease in hypothalamic NA and an increase in rat spleen weight; increase in CA concentration in the adrenals was initially insignificant, by the end of a 2-month exposure it reached the level of statistical significance; serum concentrations of B, T3 and T4 remained unaffected and so was the weight of the body, liver, lungs, suprarenals and the hypothalamus of exposed rats; at the concentrations used, NO2 and CO acted as synergists producing a mild stressogenic reaction affecting the activity of the sympathico-adrenomedullary system of exposed rats.

The renal excretion and retention of macromolecules: The chemical structure effect.

Five derivatives of polyaspartamide were used as macromolecular models to study the effect of chemical structure of macromolecules on their renal excretion and retention. The parent polymer was formed solely by N(2-hydroxyethyl)aspartamide units (I) and in its derivatives about 20% of 2-hydroxyethyl groups were randomly replaced by either n-butyl- (II), 2(4-hydroxyphenyl)ethyl- (III, N- dimethylamino propyl- (IV) or the aspartamide unit was modified to free aspartic acid carboxyl (V). The rate of clearance from the serum, the deposition in the kidney tissue in comparison with the deposition in reticuloendothelial system organs-liver and spleen, as well as tissue and cellular localisation of deposits were studied on rabbits and mice taking advantage of fluorescence labelling. The clearance of macromolecular models from the serum compartment by the glomerular filtration is mainly molecular weight controlled, while the retention of macromolecules possessing the same molecular weight by the kidney tubular epithelium is strongly affected chemical modification. About thirty and hundred times higher retentions due to reabsorption in proximal tubule were found with macromolecular models II and III respectively.

Effect of realimentation and triiodothyronine on DNA synthesis in intact and partially resected rat liver.

Whereas DNA synthesis in the liver of rats with permanent access to food fell markedly between the 72nd and 96th hour after partial hepatectomy, the decrease in the same post-operative interval in rats realimented after 3 days' starvation was less pronounced. The difference between the values in the control and the experimental group 96 hours after partial hepatectomy was statistically significant for p less than 0.01). In rats given glucose after the operation, 24 hours' realimentation caused a nonsignificant increase in DNA synthesis. The difference between the values 96 h after partial hepatectomy in this group and in the group fed the whole time on the standard diet was statistically significant for p less than 0.001. The administration of triiodothyronine (200 microgram/kg i.g.) to the above groups of rats at the outset of realimentation did not affect the development of changes in liver DNA synthesis. It likewise had no effect on the outcome of the realimentation of rats with an intact, unresected liver fed 3 days on plain glucose. In the intact control rats fed the whole time on the standard laboratory diet, triiodothyronine produced a distinct increase in liver DNA synthesis (p less than 0.01).