Renalni a jaterni eliminace metotrexatu u pokusnych zvirat.

Methotrexate is one of the most widely used in cancer chemotherapy for variety neoplasms. It exerts its cytotoxic effect by competitively inhibiting dihydrofolat reductase, it interferes with several critical biosynthetic pathways as synthesis of DNA, RNA and proteins. MTX has been used clinically in various dose schedules. In high doses is used in the treatment of a number of pediatric and adult malignancies including acute leukemias, non Hodgkin lymphoma, osteosarcoma, head and neck carcinomas, choriocarcinoma, breast carcinoma. It is also used in low doses, for treatment of non malignant diseases such as psoriasis and rheumatoid arthritis, and for suppression of graft-versus-host disease after transplantation. Methotrexate is the only antineoplastic for which routine pharmacokinetic monitoring is currently recommended. It has been demonstrated correlation between concentrations of MTX in plasma and clinical outcome or therapeutic effect and also ship between serum concentrations and risk of toxicity has been described. For these reasons, familiarity with the pharmacokinetic properties of MTX, especially value of clearance, is essential for clinicians involved in the care of patients receiving MTX. Renal excretion of unchanged drugs is the major route of MTX elimination. Tubular secretion and reabsorption and glomerular filtration all play a part in renal MTX elimination. The renal clearance of MTX probably depends on serum concentrations. The target of this thesis is to find an appropriate model for study of renal excretion HDMTX in vivo. We also estimated a perfusion of isolated rat kidney and liver are suitable as the models of elimination MTX in vitro. In mini pigs represents MTX renal clearance the major part of MTX plasma clearance. MTX is excreted in minipigs by glomerular filtration and tubular secretion. GF correlated with pH of urine and MTX renal clearance correlated with GF. In this animal are the same mechanisms of renal excretion MTX as in man.Summary in EnglishAvailable from STL, Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Methotrexate released in vitro from bone cement inhibits human stem cell proliferation in S/G2 phase

Methotrexate (MTX) released from bone cement showed a useful local effect in animal models of bone tumours. However, local toxic reactions such as impaired wound healing were observed in areas surrounding the MTX-loaded implant. Therefore, we hypothesised that MTX released from bone cement would have harmful effects on human mesenchymal stem cells (MSC)—one of the basic components of bone marrow and tissue reparatory processes. Moreover, elution of MTX was calculated from implants prepared either with liquid or powdered MTX. During the 28-day incubation, the cement compounded with liquid MTX showed the highest elution rate of the drug. MTX released from pellets produced a significant decrease in proliferation of MSC as a consequence of a blockade of their cell cycle in the S/G2 phase. These findings indicate impairment of stem cell function in marginal areas surrounding the MTX-loaded cement and may help to explain problems with regeneration of tissues in these locations