Glycation involves the non-enzymatic addition of reducing sugars and/or their reactive degradation products to amine groups on proteins. This process is promoted by the presence of elevated blood glucose concentrations in diabetes and occurs with various proteins that include human serum albumin (HSA). This review examines work that has been conducted in the study and analysis of glycated HSA. The general structure and properties of HSA are discussed, along with the reactions that can lead to modification of this protein during glycation. The use of glycated HSA as a short-to-intermediate term marker for glycemic control in diabetes is examined, and approaches that have been utilized for measuring glycated HSA are summarized. Structural studies of glycated HSA are reviewed, as acquired for both in vivo and in vitro glycated HSA, along with data that have been obtained on the rate and thermodynamics of HSA glycation. In addition, this review considers various studies that have investigated the effects of glycation on the binding of HSA with drugs, fatty acids and other solutes and the potential clinical significance of these effects.
The primary endogenous ligands of human serum albumin (HSA) are non-esterified fatty acids, with 0.1–2 moles of fatty acids normally being bound to HSA. In type II diabetes, fatty acid levels in serum are often elevated, and the presence of high glucose results in an increase in the non-enzymatic glycation of HSA. High-performance affinity chromatography (HPAC) was used to examine the combined effects of glycation and the presence of long chain fatty acids on the binding of HSA with R-warfarin and L-tryptophan (i.e., probes for Sudlow sites I and II, the major sites for drugs on this protein). Zonal elution competition studies were used to examine the interactions of myristic acid, palmitic acid and stearic acid with these probes on HSA. It was found that all these fatty acids had direct competition with R-warfarin at Sudlow site I of normal HSA and glycated HSA, with the glycated HSA typically having stronger binding for the fatty acids at this site. At Sudlow site II, direct competition was observed for all the fatty acids with L-tryptophan when using normal HSA, while glycated HSA gave no competition or positive allosteric interactions between these fatty acids and L-tryptophan. These data indicated that glycation can alter the interactions of drugs and fatty acids at specific binding sites on HSA. The results of this study should lead to a better understanding of how these interactions may change during diabetes and demonstrate how HPAC can be used to examine drug/solute-protein interactions in complex systems.
Background Although oral iron therapy is often the initial approach for the treatment of iron deficiency anemia (IDA) many patients fail to respond and tolerate. Approved parenteral iron treatment options have inconvenient dosing schedules, safety warnings and require an infusion center. Since the availability of parenteral Ferumoxytol (FER) more and more patients have been treated with this drug in the community setting. Methods Efficacy and safety data of FER treatment in general IDA population at Saint Francis Cancer Treatment Center, a community based hematology/oncology clinic in Grand Island Nebraska, were analyzed. Patients received one dose, one course (i.e. 2x 510 mg iv 1 week apart) or more than one course of FER. For patients with persistent or recurrent IDA (defined as hemoglobin (Hgb) <11.0 g/dL and transferrin saturation (TSAT) <20%, second or more courses of FER were given. All patients were evaluated for efficacy, safety, number of doses of FER treatment, underlying causes of iron deficiency, presence or absence of Chronic Kidney Disease (CKD), and presence or absence of prior iron therapy. Changes in mean Hgb, MCV, RDW, and TSAT from baseline to week five and comparisons between the groups of patients treated with one or more doses of FER, between the groups of patients with or without CKD, and between the groups of patients with or without prior iron treatment were analyzed. Fisher`s exact test and Wilcoxon 2-way test were used for statistical calculations. Results A total of 140 patients with IDA treated with FER were identified. Sixty patients had one course and eight patients had more than one course, while seventy-two patients had only one dose of FER. CKD was present in 46 (33%) patients and prior iron therapy was given to 93 (66 %) patients. Underlying causes of IDA were gastrointestinal in 73(52%) patients, genitourinary in 17(12%), gynecological in 14(10%) and were unclear in 36(26%) patients. Overall, 63(45%) patients had more than 2 g/dL increase in Hgb. Mean changes in Hgb, MCV, RDW, and TSAT from baseline to week five were 1.76 g/dL, 5.42 fL, 2.74%, and 10%, respectively. FER treatment increased Hgb (p=0.02) and TSAT (p=0.01) significantly only in CKD patients with prior iron treatment. There were no significant improvements in other settings and other anemia parameters, (Table 1). Adverse events were mild and transient and included nausea, myalgia, headache, dizziness. Conclusion FER was well tolerated and safe but showed only modest activity in general IDA patients in the community setting. Improvements in IDA parameters did not reach statistical significance between the groups of patients given one versus more doses of the drug and between the groups of patients without CKD with or without prior iron treatment. FER treatment seemed to be effective in raising Hgb and TSAT only in CKD patients with prior iron treatment. Prospective controlled studies of this drug in various IDA settings, dose and frequency are needed to better evaluate and define the optimal use. Table. Efficacy Results Overall CKD with Prior Iron CKD without Prior Iron P-Value Non- CKD with Prior Iron Non- CKD without Prior Iron P-value Pts. who received one dose Pts. who received one or more courses P-value # of patients 140 36 10 56 38 72 68 Increase Hgb >2 g/dL(%) 45% 44% 10% 0.065 55% 39% 1.00 43% 44% 0.96 Mean change Hgb g/dL 1.76 1.7 0.78 0.020* 2.06 1.64 0.104 1.67 1.87 0.72 Mean change MCV 5.42 8.6 5.94 0.891 3.18 5.58 0.567 6.21 4.6 0.89 Mean change RDW% 2.74 1.98 2.08 0.076 3.51 2.47 0.262 2.71 2.77 0.50 Mean change TSAT% 10% 10% 3% 0.011* 11% 11% 0.653 6% 13% 0.09 Disclosures Off Label Use: Ferumoxytol is labeled for iron deficiency anemia of chronic kidney disease. The purpose of this abstract is to provide efficacy and safety data of ferumoxytol in anemia of iron deficiency patients with or without chronic kidney disease. .
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