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.
- MeSH
- biologické markery krev MeSH
- daunomycin aplikace a dávkování toxicita MeSH
- ethanolaminy aplikace a dávkování toxicita MeSH
- fluoreny aplikace a dávkování toxicita MeSH
- isochinoliny aplikace a dávkování toxicita MeSH
- kardiomyopatie chemicky indukované diagnóza MeSH
- králíci MeSH
- protinádorová antibiotika aplikace a dávkování toxicita MeSH
- protokoly protinádorové kombinované chemoterapie toxicita MeSH
- troponin T krev MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- kardiomyopatie etiologie MeSH
- králíci MeSH
- protinádorové látky škodlivé účinky MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- MeSH
- fluoreny toxicita MeSH
- králíci MeSH
- nemoci srdce diagnóza chemicky indukované krev MeSH
- protinádorové látky toxicita MeSH
- troponin T krev MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : il., tab., grafy ; 32 cm
Study of cardiotoxicity and potential cardioprotective effects of new cytostatic drugs (benzo/c/fluorens, Oracin) using approaches of quantal-chemistry, cardiovascular pharmacology, toxicology, biochemistry and morphology in animals in vivo and in vitro.
Studium kardiotoxicity a potenciálních kardioprotektivních účinků nových cytostatik (benzo/c/fluoreny, Oracin) metodami kvantový chemickými, biochemickými, kardiovaskulárně farmakologickými, toxikologickými a morfiologickými u zvířat in vivo a in vitro.
- MeSH
- daunomycin MeSH
- fluoreny analogy a deriváty chemická syntéza MeSH
- hodnocení léčiv MeSH
- protinádorové látky škodlivé účinky MeSH
- srdce účinky léků MeSH
- Konspekt
- Farmacie. Farmakologie
- NLK Obory
- farmacie a farmakologie
- farmacie a farmakologie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
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.
- MeSH
- daunomycin toxicita MeSH
- ethanolaminy toxicita MeSH
- fluoreny toxicita MeSH
- funkce levé komory srdeční účinky léků MeSH
- hemodynamika účinky léků MeSH
- isochinoliny toxicita MeSH
- králíci MeSH
- krevní tlak účinky léků MeSH
- myokard metabolismus patologie MeSH
- protinádorové látky toxicita MeSH
- srdce účinky léků MeSH
- srdeční frekvence účinky léků MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- daunomycin toxicita MeSH
- fluoreny chemie toxicita MeSH
- isochinoliny chemie toxicita MeSH
- králíci MeSH
- myokard metabolismus patologie MeSH
- protinádorové látky toxicita MeSH
- srdce účinky léků MeSH
- troponin analýza biosyntéza MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
