Magnetic nanoparticle-incorporated liposomes (magnetic liposomes) are considered a promising site-specific drug delivery carrier vehicle. With regard to their surface charge, magnetic anionic liposomes (Mag-AL) demonstrate little toxicity in comparison with magnetic cationic liposomes (Mag-CL), whereas their cellular association and uptake efficiency are low. In the current study, we constructed complexes of Mag-AL and atelocollagen (ATCOL), which is a biocompatible and minimally immunogenic biomaterial, to improve the cellular uptake properties of Mag-AL in vitro and in vivo. The cellular association and/or uptake of Mag-AL in RAW264 cells, a murine macrophage-like cell line, under a magnetic field was significantly increased when Mag-AL was complexed with ATCOL, and the highest cellular association was observed with complexes constructed using 5 µg/mL of ATCOL. The complexes showed liposome concentration-dependent and time-dependent cellular association under a magnetic field, and their cellular uptake efficiency was comparable with that of Mag-CL. In addition, Mag-CL showed significant cytotoxicity in a liposome concentration-dependent manner, whereas Mag-AL/ATCOL complexes produced no cytotoxic effect against RAW264 cells. Furthermore, the efficient cellular association of Mag-AL/ATCOL complexes in RAW264 cells was observed even in the presence of serum, and their liver accumulation was significantly increased at a magnetic field-exposed region after intravenous injection in rats. These results indicate that Mag-AL/ATCOL complexes could be a safe and efficient magnetic responsive drug carrier.
Leptin is an adipose-derived hormone that primarily regulates energy balance in response to nutrition. Human placental cells produce leptin, whereas murine placental cells produce soluble leptin receptors (Ob-R). However, the roles of these proteins during pregnancy have not been elucidated completely. As an essential metal, zinc (Zn) is central to insulin biosynthesis and energy metabolism. In the present study, the effects of Zn deficiency and supplementation on maternal plasma leptin and soluble Ob-R regulation in pregnant mice placentas were examined using enzyme-linked immunosorbent assay, reverse transcriptionpolymerase chain reaction, and Western blotting. Nutritional Zn deficiency significantly reduced plasma insulin concentrations and fetal and placental weights in pregnant mice. Plasma leptin concentrations in pregnant mice also increased 20-to 40-fold compared with those in non-pregnant mice. Although dietary Zn deficiency and supplementation did not affect plasma leptin concentrations in non-pregnant mice, Zndeficient pregnant mice had significantly reduced plasma leptin concentrations and adipose leptin mRNA expression. In contrast, Zn-supplemented pregnant mice had increased plasma leptin concentrations without increased adipose leptin mRNA expression. Placental soluble Ob-R mRNA expression also decreased in Zndeficient mice and tended to increase in Zn-supplemented mice. These results indicate that Zn influences plasma leptin concentrations by modulating mRNA expression of soluble Ob-R in the placenta, and leptin in visceral fat during pregnancy. These data suggest that both adipose and placenta-derived leptin system are involved in the regulation of energy metabolism during fetal growth. Key words leptin; leptin receptor; dietary zinc; pregnancy; placentaLeptin is a 16-kDa protein hormone encoded by lep and is mainly produced in adipose tissues. Initial studies indicated that it regulates body weight by suppressing appetite and stimulating energy consumption via the hypothalamic leptin receptor (Ob-R).1,2) In addition to its known role in energy metabolism, pleiotropic effects of leptin have been identified, involving modulation of thermogenesis, homeostasis, hematopoiesis, angiogenesis, neuroendocrine, and immune functions. Moreover, leptin regulates ovarian function, oocyte maturation, and implantation.3,4) Recently, significantly elevated plasma leptin concentrations were found in pregnant women, with considerable leptin secretion from the placenta in comparison with that observed in non-pregnant women. 5)In the second and third trimesters, plasma leptin concentrations further increased in comparison with that observed in the first trimester and returned to normal after expulsion of placenta, suggesting that the placenta is the major source of leptin during pregnancy. 5) Leptin is not produced in mouse placentas, although plasma leptin concentrations are also elevated during pregnancy, and high placental production of soluble Ob-R has been demonstrated in mice. It was reported that secretions ...
Background Hyponatremia and syndrome of inappropriate antidiuretic hormone (SIADH) is a potentially fatal adverse effect of antidepressants (ADs) and antipsychotics (APs), although its frequency and onset time have not been well documented. Objective To analyze the frequency and onset time of AD- or AP-induced hyponatremia/SIADH. Methods We used plural data-mining techniques to search the US Food and Drug Administration Adverse Event Reporting System (FAERS) database for reports on hyponatremia/SIADH induced by psychotropic drugs from January 2004 to June 2020. For each item, we assessed the reporting odds ratio, 95% CI, median onset time, and Weibull distribution parameters. Results We identified 36 422 reports related to hyponatremia/SIADH. Signals were detected for all psychotropic drugs that we analyzed, except for clozapine. The median onset time of total AD-induced hyponatremia/SIADH was shorter than that of AP. For all ADs and APs except clozapine, hazards were considered to be the early failure type. In contrast, the hazard of clozapine was considered to be the random failure type. The limitations of this study included several reporting biases and the presence of confounding variables, particularly age. Conclusion and Relevance Most ADs and APs were found to be associated with a risk for hyponatremia/SIADH. In addition, sufficient attention should be paid to signs of hyponatremia/SIADH in the early phase when most ADs and APs are administered. These data are potentially useful for determining AD- or AP-induced hyponatremia/SIADH in the early stage and for preventing its further aggravation into a serious condition.
Purpose: Currently, CDK4/6i combined with endocrine therapy (ET) has become the standard of care as first- or second-line treatment for estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, at present, there are no guidelines for the selection of appropriate treatments after disease progression on prior CDK4/6i treatment combined with ET. Therefore, this retrospective study aimed to verify the efficacy and evaluate predictive factors of clinical outcomes in the patients with ER+/HER2- MBC during subsequent-abemaciclib treatment after disease progression on prior-palbociclib combined with ET. Methods: In total, 81 patients with ER+/HER2- MBC were treated with palbociclib and ET at our medical center between December 2017 and November 2020. Among them, 25 patients who received subsequent-abemaciclib after disease progression on prior-palbociclib were included. All patients provided informed consent for the indicated treatment. Clinicopathological variables were compared using Fisher’s exact test. The Mann–Whitney U test was used to compare categorical variables. PFS and time to chemotherapy (TTC) were estimated using Kaplan–Meier analysis with 95%CIs. Results: The median age was 69 years, and four women were premenopausal. Stage IV disease occurred in 28.0% (7/25) and visceral metastases were observed in 68.0% (17/25) of the patients. The treatment line of prior-palbociclib was the first-line in 3 (12.0%), second-line in 11 (44.0%), and third- and late-line in 11 patients (44.0%). The median PFS of prior-palbociclib plus ET was 6.3 months (95%CI=5.814–6.786). Subsequent-abemaciclib combined with fulvestrant after disease progression on prior-palbociclib was administered in 64.0% (16/25) of the patients. Median numbers of previous ET and chemotherapy of subsequent-abemaciclib were 2 and 0, respectively. Subsequent-abemaciclib after disease progression on prior-palbociclib resulted in an ORR and clinical benefit rate (CBR) of 16.0% (4/25) and 44.0% (11/25), respectively (Table 1). Kaplan–Meier curve analysis showed that the median PFS was 5.3 months (95%CI=3.082–7.518). Univariate analysis revealed that the best overall response (BOR) ≥PR and progression-free interval (PFI) ≥6 months in prior-palbociclib contributed to better clinical outcomes. Moreover, in multivariate analysis, BOR to prior-palbociclib was the only independent predictive factor for PFS (HR=0.190; 95%CI=0.050–0.722; p=0.015) (Table 2). With regard to grade ≥3 TRAEs in the subsequent-abemaciclib, neutropenia and diarrhea were observed in 16.0% (4/25); appetite loss and fatigue in 12.0% (3/25); leukopenia and anemia in 8.0% (2/25); and thrombocytopenia and liver dysfunction in 4.0% (1/25) of patients. Twelve patients (48.0%) required dose reduction due to TRAEs grade ≥3 in subsequent-abemaciclib. Of them, 10 patients required one dose-level reduction and 2 needed two dose-level reductions. Three patients (12.0%) required dose discontinuation: two had uncontrollable appetite loss and nausea and one had pneumonia. Of the 25 patients, 12 were not administered any prior chemotherapy and the median TTC in those treated with subsequent-abemaciclib was 33.9 months (95%CI=11.334–56.136). Next-line treatment after disease progression on subsequent-abemaciclib in the patients who were not administered prior chemotherapy was performed in 2 (8.0%) who were treated with ET and in 12 (48.0%) who were treated with chemotherapy (1 taxane-based, 7 eribulin, and 4 oral 5-fluorouracil). The median PFS in patients treated with chemotherapy after disease progression on subsequent-abemaciclib treatment was 6.2 months (95%CI=3.484–8.916). Table 1. Best overall response rate in patients with ER+/HER- MBC who were treated with subsequent-abemaciclib after disease progression on prior-palbociclib Table 2. Univariate and multivariate analyses of the progression-free survival in patients with ER+/HER2- MBC treated with subsequent-abemaciclib after progression on prior-palbociclib Citation Format: Hirohito Seki, Taketo Nakai, Ken Shimizu. Efficacy of subsequent-abemaciclib treatment after disease progression on palbociclib combined with endocrine therapy in patients with ER-positive HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-49.
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