Doxorubicin is one of the most active drugs in oncology, with cardiotoxicity as a serious side effect of its application. The aim of this study was to investigate dexrazoxane and amifostine impact on the evolution of myocardial changes induced by doxorubicin. BalbC female mice were treated with doxorubicin only (10 mg/kg, single intravenous push), or with dexrazoxane (200 mg/kg, intraperitoneal [ip]) or amifostine (200 mg/kg, ip) 60 mins or 30 mins prior to treatment with doxorubicin, respectively. Blood sampling for determination of conventional serum-marker activity was performed 48 hrs later. The grade of histopathology changes was evaluated by light microscopy 1.5 and 3 months after treatments using the Billingham scoring method. Control groups consisted of nontreated mice. After doxorubicin-only treatment, the grade of heart tissue damage was found to increase in the period between 1.5 and 3 months. A similar but less intense progression was also detected in amifostine-pretreated animals, with significant difference among median Billingham scores between the two time points. The pretreatment with dexrazoxane suspended expansion of tissue lesions in time. Changes in serum enzyme activity revealed two correlations: the greater reduction in alpha-hydroxybutyrate dehydrogenase (alpha-HBDH) leakage is associated with a lower percentage of damaged tissue, and the creatine kinase to alpha-HBDH percent of difference ratio being greater than one is correlated with limited spreading of pathological lesions. Our results indicate that the development of doxorubicin-induced heart failure is based on a slow and persistent expansion of pathological process even long after the completion of the treatment. Dexrazoxane has proved to be successful and superior over amifostine against such an evolution of doxorubicin cardiomyopathy.

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Objective. The study was aimed to evaluate the effects of changing excipients, including type of Eudragit polymer, on release and absorption profiles in vitro and in vivo, of tablets containing the antiinflammatory drug, diclofenac sodium. Methods. Formulation 1 consisted of diclofenac sodium tablets containing Eudragit L30, and Formulation 2 consisted of diclofenac sodium tablets containing Eudragit L100, and both formulations contained different excipients. Tablets were assessed, in vitro, for weight, hardness, diameter, thickness, mass uniformity, disintegration and dissolution profiles and drug content. Tablets were also assessed in vivo by gavage in healthy rabbits and assessing diclofenac sodium plasma concentrations and pharmacokinetic parameters. Results. Results showed that in vitro analyses demonstrated non-equivalence while in vivo analyses demonstrated equivalence. This suggests that although different types of Eudragit and excipients modulated the in vitro dissolution and release profiles of diclofenac sodium, in vivo absorption in rabbits remained similar representing bioequivalence. Conclusion. It is needed to conduct evaluations of bioequivalence of diclofenac sodium oral preparations at both in vitro and in vivo conditions.

Background/Aims: 5-Ketoximeisosorbide-2-mononitrate (5O-IS-2-MN) was synthesized and its pharmacological and texicological characteristics were examined and compared with its parent drug, isosor-bide-5-mononitrate (IS-5-MN, CAS 16051-77-7), and its diastereoisomer 2-ketoximeisosorbide-5-mononitrate. Methods: Vasorelaxation was studied on phenylephrine-precontracted rat superior mesenteric artery rings in organ bath procedure. In some rings, the endothelium was mechanically removed. In vitro tolerance was induced by treating the precontracted rings with maximal concentrations of the parent drug and the ketoximes, and after washing out, the procedure was repeated for two times. Furthermore, rats were treated with a single oral dose (1000 mg/kg) of 5O-IS-2-MN and 2O-IS-5-MN. Results: After a phenylephrine-induced contraction, 5O-IS-2-MN (10?8?10?4 mol/l) caused a concentration-dependent relaxation of the rat superior mesenteric artery that was strongly potentiated after the removal of the vascular endothelium. In preparations with or without endothelium, 5O-IS-2-MN was a more potent relaxant than either the parent compound or its isomer. The mechanism of the relaxant effect of 5O-IS-2-MN involves the activated soluble guanylyl cyclase-cyclic GMP pathway. Hydralazine (10?5 mol/l), a strong antioxidant, ameliorated tolerance to IS-5-MN, but did not affect the absence of tolerance to either ketoxime. The minimum lethal dose in rat for 5O-IS-2-MN and 2O-IS-5-MN was greater than 1000 mg/kg. Conclusion: These results suggest that the modification of the configuration at the ester carbon of IS-5-MN contributes to more potent and tolerance-devoid activity on the rat superior mesenteric artery.