Neoadjuvantní radioterapie kombinovaná s chemoterapií 5-fluorouracilem (5-FU) – chemoradioterapie (CHRT) – je považována za terapeutický standard pro lokálně pokročilý rektální karcinom (LPRK). Tato otevřená prospektivní studie získala data od 25 nemocných LPRK. Vycházela z jednotlivé dávky 1,8 Gy podávané ambulantně ve 28 frakcích, kombinované současným podáváním 5-FU v 7 denní kontinuální i.v. infuzi 200 až 1 000 mg/m2.24h-1. CHRT trvala 4–5 týdnů. Za dalších 4–6 týdnů po skončení CHRT následovala chirurgická resekce, na kterou v čase sepisování manuskriptu dosud čekali dva nemocní. Studie prokázala významnou korelaci mezi kumulativní plochou pod křivkou plazmatických koncentrací cytostatika (AUC) a reziduální chorobou. Regrese onemocnění jako odpověď na chemoradioterapii se dostavila u 19/23 nemocných (83 %), kompletní odpověď nebo remise onemocnění u 5/23 (21 %). Závažnost monitorovaných projevů toxicity – průjem, lokální bolest a perianální reakce na radioterapii – se zvyšovaly s počtem týdnů, zatímco aktivita ALT, AST a koncentrace hemoglobinu jevily ve srovnání s hodnotami předcházejícími CHRT spíše pokles. Výsledky studie svědčí pro využitelnost kinetiky 5-FU (AUC) pro kineticky řízenou chemoterapii 5-FU s cílem dosáhnout vyšší efektivity a zároveň bezpečnosti CHRT.
Neoadjuvant radiotherapy combined with chemotherapy with 5-fluorouracil (5-FU), i.e. chemoradiotherapy (ChRT), is considered a therapeutic standard for locally advanced rectal cancer (LARC). This open prospective study involved 25 patients with LARC who were administered 50.4 Gy in 28 fractions over 4 to 5 weeks in an ambulatory setting combined with concurrent 5-FU given as a 7-day continuous i.v. infusion at a dose of 200 to 1000 mg/m2.24h-1. Surgery was performed 4-6 weeks thereafter. At the time of writing this paper, two patients were still waiting for surgery. The outcome showed a significant correlation of the cumulative area under the curve of plasma concentration (cumulative AUC) with residual cancer. Cancer regression as a sign of the patient's response to ChRT was reached in 19/23 (83%) patients, while complete pathological remission was obtained in 5/23 patients (21%). Signs of toxicity, i.e. diarrhea, local pain and local reaction to radiotherapy, were increased, while ALT, AST activity and plasma hemoglobin concentration were slightly decreased with advanced cycles of ChRT compared to those prior to ChRT. These results may be useful for individual kinetically guided chemotherapy with 5-FU in order to achieve higher efficacy and safety of ChRT.
- Klíčová slova
- kineticky řízené dávkování,
- MeSH
- adenokarcinom farmakoterapie chirurgie radioterapie MeSH
- antimetabolity antitumorózní aplikace a dávkování MeSH
- časové faktory MeSH
- celková dávka radioterapie MeSH
- chemoradioterapie metody statistika a číselné údaje MeSH
- financování organizované MeSH
- fluorouracil aplikace a dávkování krev toxicita MeSH
- frakcionace dávky záření MeSH
- hemoglobiny analýza MeSH
- indukce remise MeSH
- krevní plazma chemie účinky léků MeSH
- lidé středního věku MeSH
- lidé MeSH
- metabolická clearance MeSH
- nádory rekta farmakoterapie chirurgie radioterapie MeSH
- neoadjuvantní terapie metody statistika a číselné údaje MeSH
- nežádoucí účinky léčiv MeSH
- pilotní projekty MeSH
- plocha pod křivkou MeSH
- prospektivní studie MeSH
- radioterapie metody škodlivé účinky MeSH
- rektum chirurgie MeSH
- rozvrh dávkování léků MeSH
- senioři MeSH
- statistika jako téma MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
The goal of the study was to evaluate a minipig (i.e. porcine) model as the human like model for preclinical evaluation of mechanisms involved in the renal excretion of high-dose methotrexate (HDMTX). Methotrexate is in man renaly excreted in combination of glomerular filtration and active tubular drug transport (in a proximal tubule). After intravenous MTX administration, more than 95% of the amount of delivered dose was detected in urine in the form of intact MTX. To compare glomerular filtration and other ways of renal MTX excretion, the ratio between MTX clearance and clearance of inuline (which evaluate the rate of glomerular filtration only) was calculated and analyzed. Renal clearance of MTX was higher than that of inuline (Cl/Cl = 1.50 (0.095 ml/min.kg). The results showed a significant correlation between Cl and pH of urine (r = 0.525, r = 0.7243, p < 0.001, figure 1). Similar correlations were found when comparing the results of Cl and glomerular filtration (r = 0.8589, r = 0.8939, p < 0.00001) (figure 2). Significant relationship was also evident between Cl and urine pH and GF together (simultaneously) (r = 0.8677). The renal clearance of MTX varied from 1.36 ml/min.kg (measured at pH 6.0) to 3.2 ml/min.kg (measured at pH 7.0). Finally, the results indicate a significant relationship between the renal and extrarenal clearance MTX (r = 0.7227, p < 0.0001).
- MeSH
- hodnoty glomerulární filtrace účinky léků MeSH
- inulin diagnostické užití MeSH
- koncentrace vodíkových iontů MeSH
- ledviny metabolismus MeSH
- methotrexát farmakokinetika moč MeSH
- miniaturní prasata MeSH
- moč MeSH
- prasata MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
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
- antitumorózní látky toxicita 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
- 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
