- Pharmacodynamics of the hydrolysis-activation of the cardioprotective agent (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane
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The hydrolysis of the cardioprotective agent ICRF-187 [(+)-1,2-bis(3,5- dioxopiperazinyl-1yl)propane] to its presumed active form under conditions of physiologic pH and temperature were followed by HPLC chromatography. Successful chromatography of all of the hydrolysis products required the use of EDTA in the aqueous eluant to prevent metals in the HPLC flow system from binding to the strongly metal ion-binding product ADR-925. The kinetics of the hydrolysis was followed to ~200 h. The ring closest to the methyl group on ICRF-187 was observed to open at about twice the rate of the other ring. This product accumulates in the reaction mixture not only because it is produced more quickly but also because it decays more slowly. ICRF-187 is lost from the reaction mixture with a half-life of 9.3 h, whereas the final hydrolysis product ADR-925 is produced with a half-life of 23.0 h. Rate constants for ring opening to one-ring and two-ring opened hydrolysis products were obtained with a reaction scheme that assumed parallel and consecutive first-order reactions for these steps.
- Hasinoff
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- Pharmacokinetics of the cardioprotective drug dexrazoxane and its active metabolite adr-925 with focus on cardiomyocytes and the hearts
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Dexrazoxane (DEX), the only cardioprotectant approved against anthracycline cardiotoxicity, has been traditionally deemed to be a prodrug of the iron-chelating metabolite ADR-925. However, pharmacokinetic profile of both agents, particularly with respect to the cells and tissues essential for its action (cardiomyocytes/myocardium), remains poorly understood. The aim of this study is to characterize the conversion and disposition of DEX to ADR-925 in vitro (primary cardiomyocytes) and in vivo (rabbits) under conditions where DEX is clearly cardioprotective against anthracycline cardiotoxicity. Our results show that DEX is hydrolyzed to ADR-925 in cell media independently of the presence of cardiomyocytes or their lysate. Furthermore, ADR-925 directly penetrates into the cells with contribution of active transport, and detectable concentrations occur earlier than after DEX incubation. In rabbits, ADR-925 was detected rapidly in plasma after DEX administration to form sustained concentrations thereafter. ADR-925 was not markedly retained in the myocardium, and its relative exposure was 5.7-fold lower than for DEX. Unlike liver tissue, myocardium homogenates did not accelerate the conversion of DEX to ADR-925 in vitro, suggesting that myocardial concentrations in vivomay originate fromits distribution from the central compartment. The pharmacokinetic parameters for both DEX and ADR-925 were determined by both noncompartmental analyses and population pharmacokinetics (including joint parent-metabolite model). Importantly, all determined parameters were closer to human than to rodent data. The present results open venues for the direct assessment of the cardioprotective effects of ADR-925 in vitro and in vivo to establish whether DEX is a drug or prodrug.
- Jirkovsky, Eduard,Jirkovská, Anna,Bures, Jan,Chládek, Jaroslav,Lencová, Olga,Stariat, Ján,Pokorná, Zuzana,Karabanovich, Galina,Roh, Jaroslav,Brázdová, Petra,Simunek, Tomás,Kovaríková, Petra,Sterba, Martin
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- Prevention and treatment of cardiac conditions
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The present invention provides a method of treating conditions associated with iron and calcium overload comprising administering an effective amount of dexrazoxane or a non-dexrazoxane compound of formula (IA), (IB), or (IC) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
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(2008/12/08)
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