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Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Ferric Carboxymaltose in Chinese Patients with Iron-deficiency Anemia.
Ding, Y, Zhu, X, Li, X, Zhang, H, Wu, M, Liu, J, Palmen, M, Roubert, B, Li, C
Clinical therapeutics. 2020;(2):276-285
Abstract
PURPOSE Iron deficiency (ID) is one of the most commonly known nutritional deficiencies and is considered the primary cause of anemia (iron-deficiency anemia). Ferric carboxymaltose (FCM), an intravenous iron preparation, has been widely used for >10 years for iron-deficiency anemia treatment worldwide because of its many advantages. METHODS This single-center, open-label, single dose escalation study in Chinese subjects was designed to assess the pharmacokinetic/pharmacodynamic parameters and safety of FCM in this population. The first 12 subjects received a 500-mg dose; after assessing safety data from the first 6 subjects in this cohort, another 12 subjects were assigned to the 1000-mg dose cohort. FINDINGS After an infusion of FCM over 15 min, a rapid dose-dependent increase in total serum iron levels was observed with a median Tmax of 30 min following the start of the infusion for both cohorts. The Cmax and AUC for the 1000-mg dose were ~1.8-fold (p = 0.2929) and 2.3-fold (p = 0.0318) those associated with the 500-mg dose, respectively. Mean terminal t1/2 values were 12.3 and 10.5 h for the 2 cohorts. The renal elimination of FCM was negligible (<0.1%). Increase in mean serum iron levels and ferritin concentrations showed dose dependency. Iron-binding capacity was transiently well utilized after dosing, as indicated by transferrin saturation >88% with 500-mg FCM and >90% with 1000-mg FCM. Hemoglobin levels did not show significant changes during the 7-day observation period, whereas mean reticulocyte counts significantly increased in both cohorts, suggesting activation of the hematopoietic system. FCM was well tolerated in these Chinese subjects. No new or unexpected treatment-emergent adverse events were attributable to FCM. IMPLICATIONS The pharmacokinetic/pharmacodynamic and safety profiles in Chinese subjects seemed comparable to those in white and Japanese populations. ChinaDrugTrials.org.cn identifier: CTR20160863.
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Physiological characteristics of Magnetospirillum gryphiswaldense MSR-1 that control cell growth under high-iron and low-oxygen conditions.
Wang, Q, Wang, X, Zhang, W, Li, X, Zhou, Y, Li, D, Wang, Y, Tian, J, Jiang, W, Zhang, Z, et al
Scientific reports. 2017;(1):2800
Abstract
Magnetosome formation by Magnetospirillum gryphiswaldense MSR-1 is dependent on iron and oxygen levels. We used transcriptome to evaluate transcriptional profiles of magnetic and non-magnetic MSR-1 cells cultured under high-iron and low-iron conditions. A total of 80 differentially expressed genes (DEGs) were identified, including 53 upregulated and 27 downregulated under high-iron condition. These DEGs belonged to the functional categories of biological regulation, oxidation-reduction process, and ion binding and transport, and were involved in sulfur metabolism and cysteine/methionine metabolism. Comparison with our previous results from transcriptome data under oxygen-controlled conditions indicated that transcription of mam or mms was not regulated by oxygen or iron signals. 17 common DEGs in iron- and oxygen-transcriptomes were involved in energy production, iron transport, and iron metabolism. Some unknown-function DEGs participate in iron transport and metabolism, and some are potential biomarkers for identification of Magnetospirillum strains. IrrA and IrrB regulate iron transport in response to low-oxygen and high-iron signals, respectively. Six transcription factors were predicted to regulate DEGs. Fur and Crp particularly co-regulate DEGs in response to changes in iron or oxygen levels, in a proposed joint regulatory network of DEGs. Our findings provide new insights into biomineralization processes under high- vs. low-iron conditions in magnetotactic bacteria.
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Mechanistic insights into metal ion activation and operator recognition by the ferric uptake regulator.
Deng, Z, Wang, Q, Liu, Z, Zhang, M, Machado, AC, Chiu, TP, Feng, C, Zhang, Q, Yu, L, Qi, L, et al
Nature communications. 2015;:7642
Abstract
Ferric uptake regulator (Fur) plays a key role in the iron homeostasis of prokaryotes, such as bacterial pathogens, but the molecular mechanisms and structural basis of Fur-DNA binding remain incompletely understood. Here, we report high-resolution structures of Magnetospirillum gryphiswaldense MSR-1 Fur in four different states: apo-Fur, holo-Fur, the Fur-feoAB1 operator complex and the Fur-Pseudomonas aeruginosa Fur box complex. Apo-Fur is a transition metal ion-independent dimer whose binding induces profound conformational changes and confers DNA-binding ability. Structural characterization, mutagenesis, biochemistry and in vivo data reveal that Fur recognizes DNA by using a combination of base readout through direct contacts in the major groove and shape readout through recognition of the minor-groove electrostatic potential by lysine. The resulting conformational plasticity enables Fur binding to diverse substrates. Our results provide insights into metal ion activation and substrate recognition by Fur that suggest pathways to engineer magnetotactic bacteria and antipathogenic drugs.
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Weight loss, inflammatory markers, and improvements of iron status in overweight and obese children.
Gong, L, Yuan, F, Teng, J, Li, X, Zheng, S, Lin, L, Deng, H, Ma, G, Sun, C, Li, Y
The Journal of pediatrics. 2014;(4):795-800.e2
Abstract
OBJECTIVE To assess the effect of a weight-loss program on improving iron status in overweight and obese school-aged children. STUDY DESIGN The data were analyzed in overweight and obese children (7-11 years of age; 114 girls and 212 boys) with body mass index-for-age z-scores (BAZ) >1 from a weight-loss program. Schools were randomly divided into 2 groups: intervention and control. Children in the intervention group underwent a 1-year, nutrition-based comprehensive intervention weight-loss program. Anthropometric, dietary intake, and physical activity data were collected at baseline and follow-up (1 year). Iron status and inflammatory markers were assessed within a month. RESULTS In the intervention group, BAZ decreased more than that in the control group (-0.4 ± 0.7 vs -0.1 ± 0.6, P < .0001); and iron profiles and inflammation status were improved at follow-up. In multivariable linear regression models, a greater decrease of BAZ and inflammation factors predicted a better improvement of iron status. After adjustment of ΔBAZ, ΔC-reactive protein was significantly associated with Δserum ferritin (β: 1.89; 95% CI, 0.70-3.09; P = .002) and Δsoluble transferrin receptor (β: 0.88; 95% CI, 0.16-0.59; P = .017); Δinterleukin-6 was significantly associated with Δserum ferritin (β: 1.22; 95% CI, 0.64-1.79; P < .0001). CONCLUSIONS Iron status and inflammation were improved by weight reduction. The improvement in inflammatory markers during weight reduction was independently associated with improvements of iron status.
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Iron chelation and neuroprotection in neurodegenerative diseases.
Li, X, Jankovic, J, Le, W
Journal of neural transmission (Vienna, Austria : 1996). 2011;(3):473-7
Abstract
Iron is an essential element for multiple functions of the brain. Maintenance of iron homeostasis involves regulation of iron influx, iron efflux and iron storage. Mismanagement of brain iron has been implicated in neuronal injury and death in several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (PD) and Amyotrophic lateral sclerosis (ALS). Multiple iron chelators have been shown neuroprotective and neurorestorative in these diseases, suggesting that iron chelation might be a promising therapeutics. In this paper, we briefly review the new findings of biological function of several molecules that regulate iron homeostasis in the brain, the possible role of iron mismanagement in the pathogenesis of PD, AD and ALS, and then discuss the putative mechanisms for current available iron chelators as potential therapeutics for neurodegenerative diseases.