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1.
The treatment of paroxysmal nocturnal hemoglobinuria (PNH) was revolutionized by the introduction of the anti-C5 agent eculizumab, which resulted in sustained control of intravascular hemolysis, leading to transfusion avoidance and hemoglobin stabilization in at least half of all patients. Nevertheless, extravascular hemolysis mediated by C3 has emerged as inescapable phenomenon in PNH patients on anti-C5 treatment, frequently limiting its hematological benefit. More than 10 years ago we postulated that therapeutic interception of the complement cascade at the level of C3 should improve the clinical response in PNH. Compstatin is a 13-residue disulfide-bridged peptide binding to both human C3 and C3b, eventually disabling the formation of C3 convertases and thereby preventing complement activation via all three of its activating pathways. Several generations of compstatin analogs have been tested in vitro, and their clinical evaluation has begun in PNH and other complement-mediated diseases. Pegcetacoplan, a pegylated form of the compstatin analog POT-4, has been investigated in two phase I/II and one phase III study in PNH patients. In the phase III study, PNH patients with residual anemia already on eculizumab were randomized to receive either pegcetacoplan or eculizumab in a head-to-head comparison. At week 16, pegcetacoplan was superior to eculizumab in terms of hemoglobin change from baseline (the primary endpoint), as well as in other secondary endpoints tracking intravascular and extravascular hemolysis. Pegcetacoplan showed a good safety profile, even though breakthrough hemolysis emerged as a possible risk requiring additional attention. Here we review all the available data regarding this innovative treatment that has recently been approved for the treatment of PNH.  相似文献   
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目的:利用溶血指数探讨标本溶血对常规生化检验项目的影响。方法:参考美国临床实验室标准化委员会(CLSI)制定的评价方案EP7-A2文件标准程序,在西门子全自动生化分析仪ADVIA 2400上对40份标本的27 项生化常规检测项目及溶血指数进行检测。利用机械破坏法对这40 份标本的血球进行不同程度的破坏,得到溶血程度分别为+、++、+++、++++标本各10份,再对这40份人工溶血标本进行27项生化项目及溶血指数检测,计算各项目溶血前后的结果偏倚,并与CLIA’88能力比对的最大允许误差比较。以每份测试血清的△H为X 轴、其对应的检测项目干扰值为Y 轴绘制干扰曲线。结果:不同溶血程度对DBil、TBil、PA、TP、TG、UA、Alb、ALP、ALT、BUN、ChE、TC、Cr、GGT、HDL、LDL、Ca、P、Mg、Na+和Cl-这21个生化项目无明显干扰;溶血程度为+时,Glu存在明显负干扰,AST、K+和LDH存在明显正干扰;CK在溶血程度为++ 时出现明显正干扰;Fe在溶血程度为+++时出现明显正干扰。结论:溶血程度为+时,对西门子ADVIA 2400测定AST、K+、Glu和LDH存在明显干扰;若无法重新采集血标本,需根据相应的溶血指数将检测结果校正后报告。  相似文献   
3.
Chromogenic anti‐Xa assays for unfractionated heparin monitoring (heparin activity) are susceptible to interference from hemolysis and icterus. The purpose of this study was to better understand the effect of hemolysis and icterus on anti‐Xa heparin activity and to predict the magnitude of the error. Increasing levels of hemoglobin and unconjugated bilirubin were added to pooled normal plasma or buffer containing known levels of heparin. Increased plasma hemoglobin or bilirubin produced falsely increased residual factor Xa activity as measured by the absorbance change (OD/min) in the Stago heparin activity assay. This increased absorbance change slope resulted in falsely lower estimates of heparin activity. The falsely lower heparin activity measurement occurred even when heparin was not present, indicating it was not due to heparin neutralization. In a sample containing 0.62 ± 0.06 U/mL heparin and 228 mg/dL hemoglobin, the measured heparin activity was 0.41 ± 0.03 U/mL, underestimating heparin activity by 0.21 ± 0.07 U/mL. Interference occurred if plasma hemoglobin was above 70 mg/dL or bilirubin was above 16 mg/dL, which happened in 16%–26% of samples from pediatric patients on extracorporeal life support (ECLS). In conclusion, hemolysis and icterus were common in ECLS patients, leading to underestimates of unfractionated heparin activity and potentially higher doses of heparin than intended. The magnitude of the heparin activity measurement error could be predicted based on plasma hemoglobin and bilirubin levels until these levels exceeded the technical limits of the assay, ~230 mg/dL hemoglobin and 55 mg/dL bilirubin.  相似文献   
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王锋  张超  郑栓 《中草药》2021,52(24):7473-7483
目的 成功制备雷公藤甲素(3-丙羧基)三苯基溴化膦(TPP)-聚乙二醇-b-聚己内脂(PEG-PCL)脂质体(Tr@TPP/Lip),评价其靶向性及促肝肿瘤细胞凋亡效果。方法 采用正交试验优选Tr@TPP/Lip的制备工艺,再研究该载药系统的粒径、Zeta电位、载药量、包封率和多分散系数及透射电镜微观形态,评价Tr@TPP/Lip的稳定性、溶血性、释放情况;采用荧光试验,研究脂质体与肝肿瘤细胞的融合情况、线粒体靶向性和肝脏靶向性;在等剂量给药条件下,评价Tr@TPP/Lip促肝癌细胞凋亡效果。结果 正交试验优选的Tr@TPP/Lip粒径为(113.5±17.6)nm,Zeta电位(12.6±0.7)mV,包封率为(71.3±3.2)%,载药量为(3.9±1.1)%,多分散系数为0.12±0.04;透射电子显微镜图片显示Tr@TPP/Lip呈规则圆球形,该脂质体稳定性良好,具有较小的溶血率和良好的缓释药物性能;荧光试验结果显示,TPP阳离子能促进脂质体与肿瘤细胞的融合,并靶向线粒体,还能提高药物在肝肿瘤部位的靶向和滞留效果;细胞药效结果显示,Tr@TPP/Lip具有良好的促肝肿瘤细胞凋亡效果,能明显降低线粒体膜Zeta电位、增加细胞内活性氧水平和Caspase-3的释放,显著增加促凋亡蛋白Bcl-2、减少抗凋亡Bax蛋白的表达,这些细胞凋亡试验结果均明显优于雷公藤甲素普通脂质体和雷公藤甲素。结论 Tr@TPP/Lip具有较好的线粒体靶向功能,能增强药物促肝肿瘤细胞凋亡效果。  相似文献   
6.
Solubilization of new chemical entities for toxicity assessment must use excipients that do not negatively impact drug pharmacokinetics and toxicology. In this study, we investigated the tolerability of a model freebase compound, GDC-0152, solubilized by pH adjustment with succinic acid and complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) to enable intravenous use. Solubility, critical micelle concentration, and association constant with HP-β-CD were determined. Blood compatibility and potential for hemolysis were assessed in vitro. Local tolerability was assessed after intravenous and subcutaneous injections in rats. A pharmacokinetic study was conducted in rats after intravenous bolus administration.GDC-0152 exhibited pH-dependent solubility that was influenced by self-association. The presence of succinic acid increased solubility in a concentration-dependent manner. HP-β-CD alone also increased solubility, but the extent of solubility enhancement was significantly lower than succinic acid alone. Inclusion of HP-β-CD in the solution of GDC-0152 improved blood compatibility, reduced hemolytic potential by ~20-fold in vitro, and increased the maximum tolerated dose to 80 mg/kg.  相似文献   
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The growing usage of nanoscale zerovalent iron particles (nZVI) in the remediation of soil, ground/surface water has elicited large‐scale environmental release triggering human exposure. The size of nanomaterials is a key regulator of toxicity. However, the effect of a variable size of nZVI on genotoxicity is unexplored in human cells. To the best of our knowledge, in this study, the cytotoxic, genotoxic and hemolytic potential of nZVI‐1 (15 nm) and nZVI‐2 (50 nm) at concentrations of 5, 10 and 20 μg/mL was evaluated for the first time in human lymphocytes and erythrocytes treated for 3 hours. In erythrocytes, spherocytosis and echinocytosis occurred upon exposure to nZVI‐1 and nZVI‐2, respectively, leading to hemolysis. Lymphocytes treated with 20 μg/mL nZVI‐2 and 10 μg/mL nZVI‐1, incurred maximum DNA damage, although nZVI‐2 induced higher cyto‐genotoxicity than nZVI‐1. This can be attributed to higher Fe ion dissolution and time/concentration‐dependent colloidal destabilization (lower zeta potential) of nZVI‐2. Although nZVI‐1 showed higher uptake, its lower genotoxicity can be due to lesser Fe content, Fe ion dissolution and superior colloidal stability (higher zeta potential) compared with nZVI‐2. Substantial accumulation of Ca2+, superoxide anions, hydroxyl radicals and H2O2 leading to mitochondrial impairment and altered antioxidant enzyme activity was noted at the same concentrations. Pre‐treatment with N‐acetyl‐cysteine modulated these parameters indicating the indirect action of reactive oxygen species in nZVI‐induced DNA damage. The morphology of diffused nuclei implied the possible onset of apoptotic cell death. These results validate the synergistic role of size, ion dissolution, colloidal stability and reactive oxygen species on cyto‐genotoxicity of nZVI and unlock further prospects in its environmental nano‐safety evaluation.  相似文献   
10.
A1c is used extensively in diagnosing diabetes and evaluating glycemic control. This value can be unreliable with certain comorbidities such as hemoglobinopathies. A false high or low A1c can lead to over- or undertreatment of diabetes with adverse outcomes. This article describes a patient situation in which A1c was inaccurate in estimating mean serum glucose. Providers unknowingly based treatment plans on a false low A1c value. Comorbidities that can lead to false high or low A1c results are discussed with recommendations for using the A1c value to plan patient care decisions for people with diabetes.  相似文献   
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