The Liver and Kidneys mediate clearance of cardiac troponin in the rat

Cardiac-specific troponins (cTn), troponin T (cTnT) and troponin I (cTnI) are diagnostic biomarkers when myocardial infarction is suspected. Despite its clinical importance it is still not known how cTn is cleared once it is released from damaged cardiac cells. The aim of this study was to examine the clearance of cTn in the rat. A cTn preparation from pig heart was labeled with fluorescent dye or fluorine 18 (18 F). The accumulation of the fluorescence signal using organ extracts, or the 18 F signal using positron emission tomography (PET) was examined after a tail vein injection. The endocytosis of fluorescently labeled cTn was studied using a mouse hepatoma cell line. Close to 99% of the cTnT and cTnI measured with clinical immunoassays were cleared from the circulation two hours after a tail vein injection. The fluorescence signal from the fluorescently labeled cTn preparation and the radioactivity from the 18F-labeled cTn preparation mainly accumulated in the liver and kidneys. The fluorescently labeled cTn preparation was efficiently endocytosed by mouse hepatoma cells. In conclusion, we find that the liver and the kidneys are responsible for the clearance of cTn from plasma in the rat.

Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability Toward Adverse Events

Background: Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model. Results: The incidence rates of any grade and grade ≥ 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival (p < 0.001 and p < 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs. Conclusion: Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs.

Novel Chemical Method for Decreasing of Toxicity of Highly Cytotoxic Amidoximes by Introduction of Benzo[4,5]imidazo[2,1-b]thiazolyl Fragment

Aims and Objectives: The aim of the research is to obtain and to investigate the cytotoxicity of a novel class of non-toxic oximes – derivatives of N-(benzo[4,5]imidazo[2,1-b]thiazol-3-ylmethoxy)-ω- (hetarylsulfanyl)-alkanamidines. Materials and Methods: To assess the possible toxicity of the compounds, acute oral LD50 was calculated. The calculations were based on tested compounds IC50 values in relation to 3T3 (mouse fibroblast cell line) using NRU assay. Monolayer tumor cell lines HT-1080 (human fibrosarcoma, ATCC® CCL-121™), MH-22A (mouse hepatoma, ECACC code, 96121721) and NIH/3T3 (mouse Swiss Albino embryo fibroblasts, ATCC® CRL-1658™), were cultured in standard medium (Dulbecco`s modified Eagle`s medium) supplemented with 10% fetal bovine serum (“Sigma”). Results: E-Stereoselective synthesis of novel N-(benzo[4,5]imidazo[2,1-b]thiazol-3-ylmethoxy)-ω- (hetarylsulfanyl)alkanamidines as potential cytotoxic agents was carried out in three steps from corresponding thiones. N-(Benzo[4,5]imidazo[2,1-b]thiazol-3-ylmethoxy)-5-(benzothiazol-2-ylsulfanyl)-pentanamidine exhibits high activity in vitro on the monolayer tumour cell lines: MG-22A (mouse hepatoma) and HT-1080 (human fibrosarcoma). Besides this, the above compound exhibits low toxicity on the 3T3 cell line and low estimated acute oral LD50 (LD50 2759 mg/kg). Conclusion: In conclusion, such dramatic decreasing of expected acute toxicity and high cytotoxicity by the introduction of benzo[4,5]imidazo[2,1-b]thiazolyl fragment into N-hydroxy-ω-(hetarylsulfanyl)alkanamidines were demonstrated for the first time (see, for example, toxicity and cytotoxicity of compound 8b and corresponding unsubstituted oxime).