The effect of rat strain, diet composition and feeding period on the development of a nutritional model of non-alcoholic fatty liver disease in rats.

Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver-related morbidity and mortality. The aim of this work was to establish and characterize a nutritional model of NAFLD in rats. Wistar or Sprague-Dawley male rats were fed ad libitum a standard diet (ST-1, 10 % kcal fat), a medium-fat gelled diet (MFGD, 35 % kcal fat) and a high-fat gelled diet (HFGD, 71 % kcal fat) for 3 or 6 weeks. We examined the serum biochemistry, the hepatic malondialdehyde, reduced glutathione (GSH) and cytokine concentration, the respiration of liver mitochondria, the expression of uncoupling protein-2 (UCP-2) mRNA in the liver and histopathological samples. Feeding with MFGD and HFGD in Wistar rats or HFGD in Sprague-Dawley rats induced small-droplet or mixed steatosis without focal inflammation or necrosis. Compared to the standard diet, there were no significant differences in serum biochemical parameters, except lower concentrations of triacylglycerols in HFGD and MFGD groups. Liver GSH was decreased in rats fed HFGD for 3 weeks in comparison with ST-1. Higher hepatic malondialdehyde was found in both strains of rats fed HFGD for 6 weeks and in Sprague-Dawley groups using MFGD or HFGD for 3 weeks vs. the standard diet. Expression of UCP-2 mRNA was increased in Wistar rats fed MFGD and HFGD for 6 weeks and in Sprague-Dawley rats using HFGD for 6 weeks compared to ST-1. The present study showed that male Wistar and Sprague-Dawley rats fed by HFGD developed comparable simple steatosis without signs of progression to non-alcoholic steatohepatitis under our experimental conditions.

Cardiac remodeling and MMPs on the model of chronic daunorubicin-induced cardiomyopathy in rabbits.

The matrix metalloproteinases (MMPs) play a key role during cardiac remodeling. The aim of the study was to investigate the changes in collagenous proteins and MMPs in the model of non-ischemic, anthracycline-induced chronic cardiomyopathy in rabbits using both biochemical and histological approaches. The study was carried out in three groups of Chinchilla male rabbits: 1) daunorubicin (3 mg/kg, once weekly for 10 weeks), 2) control (saline in the same schedule), 3) daunorubicin with the cardioprotectant dexrazoxane (60 mg/kg, before each daunorubicin). Morphological changes in the myocardium of daunorubicin-treated animals were characterized by focal myocardial interstitial fibrosis of different intensity. The subsequent proliferation of the fibrotic tissue was marked by an increased content of both collagen types I and III, which resulted in their typical coexpression in the majority of bundles of fibers forming either smaller or larger scars. Biochemical analysis showed a significantly increased concentration of hydroxyproline, mainly in the pepsin-insoluble fraction of collagenous proteins, in the daunorubicin-treated group (1.42+/-0.12 mg/g) as compared with the control (1.03+/-0.04 mg/g) and dexrazoxane (1.07+/-0.07 mg/g) groups. Dexrazoxane co-administration remarkably reduced the cardiotoxic effects of daunorubicin to the extent comparable with the controls in all evaluated parameters. Using zymography, it was possible to detect only a gelatinolytic band corresponding to MMP-2 (MMP-9 activity was not detectable). However, no significant changes in MMP-2 activity were determined between individual groups. Immunohistochemical analysis revealed increased MMP-2 expression in both cardiomyocytes and fibroblasts. Thus, this study has revealed specific alterations in the collagen network in chronic anthracycline cardiotoxicity in relationship to the expression and activity of major MMPs.

Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death.

BACKGROUND: Dexrazoxane (DEX, ICRF-187) is the only clinically approved cardioprotectant against anthracycline cardiotoxicity. It has been traditionally postulated to undergo hydrolysis to iron-chelating agent ADR-925 and to prevent anthracycline-induced oxidative stress, progressive cardiomyocyte degeneration and subsequent non-programmed cell death. However, the additional capability of DEX to protect cardiomyocytes from apoptosis has remained unsubstantiated under clinically relevant in vivo conditions. METHODS: Chronic anthracycline cardiotoxicity was induced in rabbits by repeated daunorubicin (DAU) administrations (3 mg kg(-1) weekly for 10 weeks). Cardiomyocyte apoptosis was evaluated using TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling) assay and activities of caspases 3/7, 8, 9 and 12. Lipoperoxidation was assayed using HPLC determination of myocardial malondialdehyde and 4-hydroxynonenal immunodetection. RESULTS: Dexrazoxane (60 mg kg(-1)) co-treatment was capable of overcoming DAU-induced mortality, left ventricular dysfunction, profound structural damage of the myocardium and release of cardiac troponin T and I to circulation. Moreover, for the first time, it has been shown that DEX affords significant and nearly complete cardioprotection against anthracycline-induced apoptosis in vivo and effectively suppresses the complex apoptotic signalling triggered by DAU. In individual animals, the severity of apoptotic parameters significantly correlated with cardiac function. However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation. CONCLUSION: This study identifies inhibition of apoptosis as an important target for effective cardioprotection against chronic anthracycline cardiotoxicity and suggests that lipoperoxidation-independent mechanisms are involved in the cardioprotective action of DEX.

Early detection of anthracycline cardiotoxicity in a rabbit model: left ventricle filling pattern versus troponin T determination.

Anthracycline cardiotoxicity represents a serious risk of anticancer chemotherapy. The aim of the present pilot study was to compare the potential of both the left ventricular (LV) filling pattern evaluation and cardiac troponin T (cTnT) plasma levels determination for the early detection of daunorubicin-induced cardiotoxicity in rabbits. The echocardiographic measurements of transmitral LV inflow as well as cTnT determinations were performed weekly for 10 weeks in daunorubicin (3 mg/kg weekly) and control groups (n=5, each). Surprisingly, no significant changes in LV-filling pattern were observed through the study, most likely due to the xylazine-containing anesthesia, necessary for appropriate resolving of the E and A waves. In contrast to the echographic measurement, the dP/dt(min) index obtained invasively at the end of the study revealed a significant impairment in LV relaxation, which was further supported by observed disturbances in myocardial collagen content and calcium homeostasis. However, at the same time cTnT plasma levels were progressively rising in the daunorubicin-treated animals from the fifth week (0.024+/-0.008 microg/l) until the end of the experiment (0.186+/-0.055 microg/l). Therefore, in contrast to complicated non-invasive evaluation of diastolic function, cTnT is shown to be an early and sensitive marker of anthracycline-induced cardiotoxicity in the rabbit model.

Safety and tolerability of repeated administration of pyridoxal 2-chlorobenzoyl hydrazone in rabbits.

Recently, pyridoxal 2-chlorobenzoyl hydrazone (o-108) has been identified as an effective iron chelator [Link et al., Blood 2003; 101: 4172-79]. Since chronic treatment would be necessary in its potential indications, in the present study, the safety and tolerability of this agent after repeated administration was determined. Three doses of o-108 (25, 50, 100 mg/kg, in 10% Cremophor EL) were administered intraperitoneally, once weekly, for 10 weeks to three groups (n=5 each) of Chinchilla male rabbits. The effects on biochemical, haematological and cardiovascular parameters were examined during the experiment; histopathological examination was performed at the end of the experiment. Results were compared with control (saline 2 mL/kg, n=11) and vehicle groups (10% Cremophor EL, 2 mL/kg, n=12). No premature deaths occurred; the well-being of animals was evidenced by their body weight gain, although lower gain was observed with the highest dose (100 mg/kg). Significant elevations of cardiac troponin T plasma concentrations were observed with the highest dose of o-108, but no abnormalities were found in the cardiovascular function and only minor and inconsistent changes in haematological and biochemical parameters were observed. Histopathological examinations of selected organs revealed only weak and reversible changes through all studied groups. Thus, the data from this study suggest that o-108 remains a promising drug from the standpoint of the possibility of its repeated administration and warrants further investigation.

Study of daunorubicin cardiotoxicity prevention with pyridoxal isonicotinoyl hydrazone in rabbits.

Risk of cardiotoxicity is the most serious drawback of the clinical usefulness of anthracycline antineoplastic antibiotics, which however, remain among the most powerful and widely employed anticancer drugs. In this study we have used daunorubicin-induced cardiomyopathy in rabbits as a model to investigate possible cardioprotective effects of pyridoxal isonicotinoyl hydrazone (PIH)-a principal representative of a novel group of aroylhydrazone iron chelators. Three groups of animals were used: a control group (n=11; i.v. saline), daunorubicin-treated animals (n=11; 3mg/kg, i.v.), and animals pretreated with PIH (n=9, 25 mg/kg, i.p.) 60 min before daunorubicin administration. All substances were administered once weekly for 10 weeks. Repeated administration of daunorubicin caused premature death in four animals and induced conspicuous histopathological changes in the myocardium, progressive and significant impairment of systolic heart function (a decrease in left ventricular dP/dt(max), ejection fraction, an increase in the pre-ejection period/left ventricular ejection time index), and a gradual increase in cardiac troponin T plasma concentrations. On the contrary, all the PIH-treated animals have survived all daunorubicin applications. Furthermore, in this group, the daunorubicin-induced cardiac changes were in most functional, biochemical as well as morphological parameters less pronounced than in the group receiving daunorubicin alone. Hence, PIH and other aroylhydrazones merit further investigation as potentially protective agents against anthracycline-induced cardiotoxicity.

Protein profiling in daunorubicin-induced cardiomyopathy.

The aim of this paper was to study the protein remodelling of the left ventricle following repeated administration of either daunorubicin (DNR) or DNR in combination with the cardioprotective agent dexrazoxane (DXZ). The experiment was carried out on three groups of Chinchilla male rabbits: 1. DNR (3 mg/kg i.v.), 2. DNR (3 mg/kg i.v.) + DXZ (60 mg/kg i.p.), and 3. the control group (saline 1 ml/kg i.v. in the same schedule). The drugs were given once weekly, max. 10 administrations. Protein fractions were isolated by stepwise extraction from the samples of the left ventricle. In the DNR-group, the concentrations of both, metabolic and contractile proteins were significantly reduced, while the amount of collagen was significantly higher in comparison with the control group. In the group treated with DNR and DXZ, the concentrations of individual protein fractions (except metabolic proteins) were comparable to those of the control group, which confirms a significant cardioprotective effect of DXZ. The changes of protein profiling corresponded to functional examination of both cardiac parameters (EF, dP/dt(max), PEP: LVET index) and histological examination. These data should be used in further studies dealing with evaluation of cardiotoxic and, possibly, cardioprotective effects of new drugs.

Evaluation of cardiac effects of the new antineoplastic drug --dimethoxybenfluron--in the rabbit.

Cardiotoxicity ranks among the most serious adverse effects of some cytostatics. The cardiac effects of repeated i.v. administration of a new antineoplastic agent, dimethoxybenfluron (once a week, 10 administrations), were investigated in rabbits with respect to cardiac function and the release of cardiac troponin T (cTnT). Different doses of dimethoxybenfluron were administered to two groups of animals (12 mg/kg; n = 7 and 24 mg/kg; n = 6) and compared with either a control group (saline 1 ml/kg; n = 6) or a group with experimentally induced cardiomyopathy (daunorubicin 50 mg/m2; n = 13). In daunorubicin-induced cardiomyopathy, cTnT levels in animals with premature deaths were significantly higher (0.31 +/-0.11 microg/l) in comparison with the surviving animals (0.04 +/- 0.03 microg/l). However, cardiac TnT levels after the administration of dimethoxybenfluron in both doses were within the physiological range (lower than 0.1 microg/l) during the whole experiment as it was in the control group. The lack of cardiotoxicity of this new antineoplastic drug was supported by the absence of alterations in PEP:LVET ratio, left ventricle dP/dtmax or histological heart examination as well as by the fact that no premature death of animals occurred following repeated administration of dimethoxybenfluron. It is possible to conclude that no signs of cardiotoxicity were observed following repeated i.v. administration of dimethoxybenfluron.

[Plasma levels of troponin T in rabbits after administration of new antineoplastic agents (Oracin and Dimefluron) and daunorubicin]. / Plazmatické hladiny troponinu T u králíku po podání nových antineoplastických látek (Oracinu a Dimefluronu) s daunorubicinem.

Recently, cardiac troponin T (cTnT) has been shown to be a sensitive marker of anthracycline-induced cardiomyopathy. In our study, the cardiotoxicity of repeated i.v. administration (once a week, 10 administrations) of daunorubicin combined with new antineoplastic drugs (with mild side-effects) were followed in two groups of rabbits: 1) Dimefluron (3,9-dimethoxybenfluron hydrochloride-12 mg/kg) + daunorubicin (3 mg/kg), 2) Oracin (6-[2-(2-hydroxyethyl)aminoethyl]-5,11-dioxo-5,6-dihydro-11H- indeno[1,2c]isoquinoline hydrochloride--10 mg/kg) + daunorubicin (3 mg/kg) and compared with the control group (saline--1 ml/kg) and the group with experimentally induced cardiomyopathy (daunorubicin--3 mg/kg). The concentration of cTnT in heparinized plasma samples was measured using commercial kit (Roche). In the control group, plasma levels of cTnT were always within the physiological range (i.e. lower than 0.1 microgram/l) during the experiment. During the development of daunorubicin-induced cardiomyopathy, after the eighth administration of drug, cTnT was significantly higher (0.31 +/- 0.11 microgram/l) in animals with premature deaths compared with the rest of the group (0.04 +/- 0.03 microgram/l). The animals with pathological values of cTnT were at higher risk of premature deaths (P = 0.0006). The combination of daunorubicin either with Oracin or with Dimefluron caused neither significant changes of cTnT levels nor significant deterioration of other followed-up parameters (especially, functional and toxicological parameters). Similarly to the daunorubicin group, the animals with pathological levels of cTnT after the eighth administration of antineoplastic drugs were at higher risk of premature death (P = 0.025). Our results show that the plasma concentration of cardiac troponin T could be a suitable predictive marker of cardiotoxicity of antineoplastic drugs.

New therapeutic approaches for the treatment of Huntington's disease.

The use of transplantation (TR) of fetal neural tissue as a therapeutic method started much later in patients suffering from Huntington's disease (HD) than in those with Parkinson's disease. The clinical trial, following a wide range of animal experiments (neurotoxic models and newly also transgenic mice), includes about 30 HD patients until now. Because of limited use of the human fetal tissue by ethical and technical concerns, there is necessity to search for the alternative sources for neural grafting. The first attempt with xenotransplantation (in 12 HD patients) and with TR of encapsulated genetically modified cells (in 6 HD patients) was performed, but no appreciable improvement of status in any of those patients was noted. Since no effective pharmacological treatment of HD is available, the TR of fetal neural tissue is now the only therapeutic approach which provides a reduction of symptoms in most of grafted patients. The possibilities are enormous offered by neural stem cells, optionally by embryonic stem cells, which could be expanded in cultures, cloned or genetically modified and then grafted into the patient's brain. On the other hand, the neural progenitor and stem cells, normally present within the subependymal layer of the lateral brain ventricles also in adulthood, might be induced to become an endogenous source of glia and neurons participating in the brain's repair.

[Effects of new antineoplastic agents (dimethoxybenflurone and Oracin) on the cardiovascular system and other parameters in the rabbit in vivo]. / Ucinky nových antineoplastických látek (dimethoxybenfluronu a Oracinu) na kardiovaskulární systém a dalsí parametry u králíku in vivo.

Anthracycline derivatives belong among the most effective antineoplastic drugs but their therapeutic use is limited by their side effects--a dose-related cardiotoxicity. The influence of repeated i.v. administration (once weekly, max. 10 weeks) of new antineoplastic agents--dimethoxybenfluron (DMB) (3,9-dimethoxybenfluron hydrochloride, C23H24O4NCl, M.w. 413.9, Institute of Experimental Biopharmaceutics, Czech Academy of Sciences, Hradec Králové, Czech Republic; 12 or 24 mg base/kg) and Oracin (6-[2-(2-hydroxyethyl)aminoethyl]-5,11-dioxo-5,6-dihydro-11H- indeno[1,2c]isoquinoline hydrochloride), C20H19N2O3Cl, M.w. 370.84, Research Institute for Pharmacy and Biochemistry, Prague, Czech Republic; 5 or 10 mg/kg) on cardiovascular, biochemical, haematological and histological parameters were studied in rabbits in vivo. Data obtained in these groups were compared with the group with experimentally induced cardiomyopathy (daunorubicin 50 mg/m2 i.v.) and with the control group (saline 1 ml/kg). Only mild and mostly no significant changes of the cardiovascular parameters (DMB 12 group: PEP:LVET ratio--0.408-0.502, LV dP/dtmax.--1337.0 kPa/s; DMB 24 group: PEP:LVET ratio--0.407-0.433, LV dP/dtmax.--1438.2 kPa/s), biochemical parameters (decrease in natrium, ALP and increase in glucose, GPX and GSH levels) and haematological parameters (increase in erythrocytes and decrease in leukocytes after the larger dose of the drug) were found in the dimethoxybenfluron groups. Repeated administration of the lower dose of Oracin induced only mild and mostly no significant changes of parameters (PEP:LVET ratio--0.393-0.475, LV dP/dtmax.--1092.4 kPa/s) in comparison with the control group. Though significant in some intervals, only a mild oscillation of the PEP:LVET ratio (0.368-0.446), decrease in LV dP/dtmax. (991.2 kPa/s) and--in comparison with control group--significantly higher blood pressure and lower heart rate were found after the higher dose of Oracin. In the most of haematological and biochemical parameters (with the exception of chlorides, protein and albumin levels) no significant changes were present. Histological examination of the heart revealed normal structure of the myocardium including minute changes of myocardium following administration of antineoplastic agents in all groups. Administration of new antineoplastic agents induced mostly mild changes of the followed-up parameters (PEP:LVET ratio, LV dP/dtmax., heart rate, levels of cardiac troponin T, survival of animals, haematological and biochemical parameters); the values of parameters were mostly significantly different from those in rabbits with daunorubicin-induced cardiomyopathy. On the basis of our results it is possible to conclude that the administration of dimethoxybenflurone and Oracin did not induce signs of cardiotoxicity in rabbits in vivo. This observation is considered to be important from the viewpoint of possible further clinical use of these new antineoplastic agents.

Cardiac troponin T as a marker of myocardial damage caused by antineoplastic drugs in rabbits.

Anthracycline derivatives are among the most effective antineoplastic drugs but their therapeutic use is limited by their adverse effects. The cardiac side-effects of antineoplastic drugs were investigated in rabbits in vivo from the viewpoint of release of cardiac troponin T (cTnT) measured by Elecsys Troponin T STAT immunoassay (Boehringer Mannheim, Germany). No increase in cTnT was found following administration of a single dose of daunorubicin (3 mg/kg i.v., n = 4). During development of daunorubicin-induced cardiomyopathy (daunorubicin 3 mg/kg i.v., once a week; maximum nine administrations, n = 7), the levels of cTnT were within the physiological range (i.e. cTnT <0.1 microg/l) at the beginning of the experiment and before and after the 5th administration, but the pathological values of cTnT after the 8th administration in 43% animals (0.22+/-0.08 microg/l) correlated with their premature death. In the control group, the levels of cTnT were always lower than 0.1 microg/l during the experiment. Following administration of a new antineoplastic drug - Oracin [6-[2-(2-hydroxyethyl) aminoethyl]-5,11-dioxo-5,6-dihydro-11H-indeno [1,2-c]-isoquinoline hydrochloride, 10 mg/kg i.v., once weekly, ten administrations, n = 7], there was no increase in cTnT levels. These findings correlated with the PEP: LVET index, histological examination and no animal succumbing to premature death. It is possible to conclude that cTnT is a useful marker for the prediction of experimentally induced anthracycline cardiomyopathy and for the evaluation of cardiotoxic (and, possibly, cardioprotective) effects of new drugs in rabbits.

IGF-I in experimental daunorubicin-induced cardiomyopathy in rabbits.

1. The occurrence of IGF-I was investigated in rabbits with experimentally daunorubicin-induced cardiomyopathy. IGF-I was measured in the heart, serum, liver and skeletal muscle. 2. A significant increase in the IGF-I was found in the left heart ventricle in daunorubicin cardiomyopathy (152.9 +/- 10.0 ng/g vs 95.1 +/- 4.2 ng/g in the control group). This site of increased IGF-I activity corresponded well with the maximum of morphological changes (dispersed cytolysis of cardiomyocytes mostly without developed subsequent interstitial myofibrosis). 3. The highest levels of IGF-I were present in right and left cardiac atrium (but without significant differences between the groups). Furthermore, in skeletal muscle, the levels of IGF-I in the daunorubicin group (839.0 +/- 142.1 ng/g) were significantly higher in comparison with the control group (482.5 +/- 83.1 ng/g). 4. The level of IGF-I in the left ventricle in the daunorubicin group (but not in the control group) was significantly higher than that in the liver. There were no correlations observed between the levels of IGF-I in the heart and in the serum. 5. The increase in IGF-I concentrations in the left heart ventricle after the administration of daunorubicin may thus reflect possible autocrine/paracrine role of IGF-I in cardiomyopathy.

Cholinesterases in dexrazoxane-treated daunorubicin cardiomyopathy in rabbits.

Changes in cholinesterases activities in daunorubicin cardiomyopathy and in dexrazoxane (DRZX)-treated daunorubicin cardiomyopathy were investigated in rabbits. Acetyl- and butyrylcholinesterase (AChE and BuChE) were determined using Ellman's method. In the serum, a significant decrease of BuChE was observed in the daunorubicin group (9.05 at the beginning and 7.15 microcat/l at the end of the experiment). After DRZX, no significant changes were found and a significant increase in BuChE was observed in the control group (10.26-12.38 microcat/l). AChE activity in the left and right cardiac ventricles was not significantly different between the groups while in the septum there was a significantly lower AChE activity found in the daunorubicin group only. BuChE activity was significantly decreased in the left (15.64 ncat/g) and right (19.27 ncat/g) heart ventricles, in the septum and in the liver in the daunorubicin group. A significant decrease in serum total protein and albumin was demonstrated only in the daunorubicin group. Our results support the hypothesis about the influence of daunorubicin on protein (and enzyme) synthesis in the liver and heart. A protective effect of DRZX on cholinesterases activity was observed. The changes in cholinesterase activities may thus reflect their possible role in cardiomyopathy.

Myocardial elements content and cardiac function after repeated i.v. administration of DMPS in rabbits.

1. A dithiol chelating agent--2,3-dimercapto-1-propanesulphonate (DMPS)--may be administered in acute or chronic intoxication with certain heavy metals (e.g. cadmium, cobalt, lead) that may cause cardiotoxicity. 2. DMPS can act as a depleter of physiologically important elements (e.g. potassium, magnesium, calcium) in various tissues including cardiac one. The possibility of subsequent alteration in cardiac function cannot be excluded. 3. Changes in the myocardial concentration of the above mentioned elements at the end of the experiment and cardiac function were studied during repeated i.v. administration of DMPS as single doses of 50 mg/kg/ week for 10 weeks in rabbits. Biochemical, haematological and histological examinations were also performed. 4. Most of the measured parameters were not affected by the repeated administration of DMPS. A significant decrease in magnesium and a near significant decrease in calcium in cardiac muscle was not accompanied by functional or morphological changes. It is still suggested, however, that care should be taken in using DMPS for treating patients with cardiotoxicity as a result of poisoning with heavy metals.

Effects of repeated administration of dithiol chelating agent--sodium 2,3-dimercapto-1-propanesulphonate (DMPS)--on biochemical and haematological parameters in rabbits.

The effects of weekly intravenously administered a dithiol chelating agent-sodium 2,3-dimercaptopropane-sulphonate (DMPS)-in a single dose of 50 mg/kg/week for 10 weeks on biochemical and haematological parameters were studied in rabbits. DMPS was well tolerated, an increase in body weight was similar in the DMPS-treated and control animals. DMPS caused significant decrease in plasma calcium and vitamin E concentrations at the end of the experiment. No significant differences in haematological parameters between the DMPS and control groups were observed. A significant decrease in magnesium content in myocardial tissue was observed in the DMPS-treated rabbits. The above-mentioned biochemical changes should be taken into account in studies of possible chelating and radical scavenging effects of DMPS in various pathological conditions.

The effects of subchronical exposure to SO2 on biochemical and hematological parameters in guinea pigs.

The effects of subchronical exposure to SO2 (400ppm, 3 hours daily, 28 days) on biochemical and hematological parameters were investigated in guinea pigs. Mostly no significant changes in the values of biochemical parameters and no significant changes in hematological parameters were found. The levels of investigated ions (K+, Na+, Cl-, Ca++, Mg++ and phosphates), proteins (albumines, globulines, total proteins), enzymes (LD, ALT, AST, CK) and other biochemical parameters (urea, creatinine, bilirubin) were not significantly different between groups, with the exception of a significantly higher ALP concentration in the exposed group as compared with controls (2.17 mukat and 1.85 mukat, respectively. It can be concluded that a subchronical exposure to sulphur dioxide mostly did not induce any definite changes in biochemical and hematological parameters in guinea pigs.

Changes in cholinesterase activities after daunorubicin administration to rabbits.

1. Acetyl- and butyrylcholinesterase (AChE, BuChE) activities were studied in rabbits with experimentally induced daunorubicin cardiomyopathy. 2. A significant decrease of the plasma BuChE in the daunorubicin group was observed. 3. In the daunorubicin group, AChE activity in the heart was significantly decreased only in the interventricular septum. 4. BuChE activity was significantly decreased in the cardiac septum and ventricles and in the liver following daunorubicin treatment. 5. Changes in cholinesterase activities are probably caused by an effect of daunorubicin oon protein synthesis during the development of certain types of cardiomyopathy.

Lack of cardiotoxicity of a new antineoplastic agent, a synthetic derivative of indenoisochinoline: comparison with daunorubicin in rabbits.

The effect of repeated i.v. administration (once weekly, 12 administrations) of a new antineoplastic agent, Oracin (6-[2-(2-hydroxyethyl)aminoethyl]-5, 11-dioxo-5,6-dihydro-11 H-indeno [1,2-c]-isochinoline hydrochloride, 10 mg/kg) and daunorubicin (3 mg/kg) were investigated in rabbits in vivo. The criterion of occurrence of cardiotoxicity was compared with a control group of animals. Noninvasive polygraphic records were used to evaluate the function of the heart. The morphological changes of the heart were evaluated after the death of animals. There were no significant changes found in the ratio of the pre-ejection period/left ventricular ejection time (PEP: LVET ratio) after administration of Oracin (values between 0.3080 and 0.3310) or in the control group (values between 0.3425 and 0.3885). The administration of daunorubicin induced a significant, progressive increase in the PEP: LVET ratio (0.3775-0.9473), which was significantly different both from the Oracin-treated and the control group of animals. Histological examination of the hearts from the control group revealed normal structure of the myocardium including minute changes (dispersed cardiomyocytes with intensively eosinophilic cytoplasm, and several single cells with degenerated myofibrils) similar to the normal changes in muscle tissue. A very similar scenario was found in the Oracin group with the exception of one case where a slightly higher number of degenerated and necrotic cells was occurring. Administration of daunorubicin resulted in severe dispersed damage of the myocardium (myocytolysis with subsequent interstitial fibrosis), the changes being markedly different from those of the Oracin treatment and the control group. On the basis of our results it is possible to conclude that the administration of Oracin (10 mg/kg i.v.) did not induce signs of cardiotoxicity in rabbits in vivo.

Cerebrospinal fluid dissemination of fetal neural isografts in brain of adult rats.

Our previous studies tend to document the temporary invasiveness of intraparenchymal fetal isografts. The present study exploits a model situation in which contacted host brain surface remains undamaged. We analyzed the behavior of transplant fragments that accidentally disseminated in cerebrospinal fluid pathways. The transplant seeding occurred in 7 cases out of 85 cases of healthy solid isografts taken from various parts of fetal brain. Fragments were found either as free (floating or simply lying close to the surface) or attached. Some attached fragments invasively penetrated the brain parenchyma. This speaks in favor of invasive properties of fetal neural transplants.