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albumin human [keywords]
- Open Flow Microperfusion: Pharmacokinetics of human insulin and insulin detemir in the interstitial fluid of subcutaneous adipose tissue. [JOURNAL ARTICLE]
- Diabetes Obes Metab 2014 Sep 19.
To compare the time profile of insulin detemir and human insulin concentrations in the interstitial fluid (ISF) of subcutaneous adipose tissue during constant intravenous infusion and to investigate the relationship between the pharmacokinetics of both insulin molecules in plasma and the ISF of subcutaneous adipose tissue.During a 6 h hyperinsulinemic euglycemic clamp (plasma glucose level: 8 mmol/l) human insulin (21 and 42 pmol/min/kg) or insulin detemir (209 and 417 pmol/min/kg) were infused intravenously in 8 rats per dose level. Open flow microperfusion (OFM) was used to continuously assess interstitial insulin concentrations in subcutaneous adipose tissue.At the low infusion rate insulin detemir appeared significantly later in the interstitial fluid compared to plasma (p < 0.05) and also exhibited a delayed interstitial appearance relative to human insulin (p < 0.005).By using OFM we were able to monitor albumin bound insulin detemir directly in the interstitial fluid of subcutaneous tissue and confirm its delayed transendothelial passage to a peripheral site of action.
- An Overview of the Effects of anti-IgE Therapies. [Journal Article]
- Med Sci Monit 2014.:1691-9.
Abstract Omalizumab, a humanized mAb that binds to the CH3 domain near the binding site for the high-affinity type-I IgE Fc receptors of human IgE, can neutralize free IgE and inhibit the IgE allergic pathway without sensitizing mast cells and basophils. We found that omalizumab in patients with severe persistent asthma (SPA) was an effective therapy for asthma and the following co-morbid conditions: chronic urticaria (CU), bee venom allergy, latex allergy, atopic dermatitis, food allergy and Samter's syndrome. Information on the use of omalizumab in treatment of asthma and other allergic diseases has improved our understanding that treatment acts on many levels, including regulating levels of inflammatory proteins, including cytokines (copper-containing alpha- 2-glycoprotein, total antioxidant capacity, MDA, NO, H2O2, CXCL8, IL-10, TGF-β, GMCSF, IL-17, IL-1β), MPV, Hs-CRP, eosinophil cationic peptide, vitamin-D (25(OH)D), homocysteine (Hcy), OX-2, d- dimer, albumin, and sApo-2L. The decrease in Hcy concentrations and increase in 25(OH)D also support the existence of a vascular endothelial protection mechanism. Mediators and cells classically involved in pro-coagulant and anticoagulant pathways together play a role in SPA and CU pathophysiology and omalizumab effect. The mechanism of action of omalizumab in the treatment of asthma is believed to be multifactorial, and includes effects mediated through altered production of redox metabolites, extrinsic coagulation pathway, oxidative markers-related mi RNA, TRAIL-related mi RNA, and regulation of production of known inflammatory proteins.
- Analysis of the structure and dynamics of human serum albumin. [Journal Article]
- J Mol Model 2014 Oct; 20(10):2450.
Human serum albumin (HSA) is a biologically relevant protein that binds a variety of drugs and other small molecules. No less than 50 structures are deposited in the RCSB Protein Data Bank (PDB). Based on these structures, we first performed a clustering analysis. Despite the diversity of ligands, only two well defined conformations are detected, with a deviation of 0.46 nm between the average structures of the two clusters, while deviations within each cluster are smaller than 0.08 nm. Those two conformations are representative of the apoprotein and the HSA-myristate complex already identified in previous literature. Considering the structures within each cluster as a representative sample of the dynamical states of the corresponding conformation, we scrutinize the structural and dynamical differences between both conformations. Analysis of the fluctuations within each cluster set reveals that domain II is the most rigid one and better matches both structures. Then, taking this domain as reference, we show that the structural difference between both conformations can be expressed in terms of twist and hinge motions of domains I and III, respectively. We also characterize the dynamical difference between conformations by computing correlations and principal components for each set of dynamical states. The two conformations display different collective motions. The results are compared with those obtained from the trajectories of short molecular dynamics simulations, giving consistent outcomes. Let us remark that, beyond the relevance of the results for the structural and dynamical characterization of HAS conformations, the present methodology could be extended to other proteins in the PDB archive.
- Molecular recognition pattern of cytotoxic alkaloid vinblastine with multiple targets. [JOURNAL ARTICLE]
- J Mol Graph Model 2014 Sep 16.:1-9.
Vinblastine (VLB), a cytotoxic alkaloid is used extensively against various cancer types and the crystal structure of its tubulin complex is already known. Multitarget affinity of vinblastine has been investigated and the nature of binding with biological receptors namely, duplex DNA and Human serum albumin (HSA) has been compared to the binding characteristics of its known complex with natural high affinity receptor tubulin using molecular docking and QM-MM calculations. VLB is found to interact with DNA as well as HSA protein, though, with weaker affinity as compared to tubulin. Analysis of various docked complexes revealed that the H-bonds and cation-pi bonds do not have significant contribution to the binding interactions and despite its large size, VLB remains in relaxed conformation and fits in the hydrophobic regions on the receptors.
- Ga-68-labeled neolactosylated human serum albumin (LSA) for PET imaging of hepatic asialoglycoprotein receptor. [JOURNAL ARTICLE]
- Nucl Med Biol 2014 Aug 13.
The purpose of this study was the development of (68)Ga-labeled neolactosylated human serum albumin (LSA) for imaging asialoglycoprotein receptors in the liver by using positron emission tomography (PET), which would enable functional imaging with higher resolution than single-photon emission computed tomography (SPECT).LSA was synthesized by conjugating α-lactose to human serum albumin (HSA) by reductive amination. LSA was conjugated with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-NOTA) and the resultant NOTA-LSA was labeled with (68)Ga at room temperature. The labeling efficiency of NOTA-LSA was evaluated as a function of pH and time. The stability of (68)Ga-NOTA-LSA in phosphate buffered saline (PBS) and human serum at 37°C was determined. Biodistribution and PET studies of (68)Ga-NOTA-LSA were performed in mice following tail vein injection of radiotracer.The numbers of lactose and NOTA units per HSA were determined to be 31.7 and 4.6, respectively. When the reaction was done at room temperature, the labeling efficiency of NOTA-LSA was higher than 99% at pH4.8 and 96% at pH6. More than 95% of the detected radioactivity was associated with the intact molecule for at least the 4h following synthesis when incubated in PBS or human serum at 37°C. Biodistribution and animal PET studies showed specific retention of (68)Ga-NOTA-LSA in liver following intravenous administration.(68)Ga-NOTA-LSA was successfully developed for imaging asialoglycoprotein receptors in the liver with a simple labeling method, high labeling efficiency, and high stability.
- The PRIMARA study: a prospective, descriptive, observational study to review cinacalcet use in patients with primary hyperparathyroidism in clinical practice. [JOURNAL ARTICLE]
- Eur J Endocrinol 2014 Sep 20.
Objective: Medical management of primary hyperparathyroidism (PHPT) is important in patients for whom surgery is inappropriate. We aimed to describe clinical profiles of adults with PHPT receiving cinacalcet. Design: Descriptive, prospective, observational study in hospital and specialist care centres. Methods: For patients with PHPT aged 23-92 years starting cinacalcet for the first time, information was collected on dosing pattern, biochemistry and adverse drug reactions (ADRs). Initial cinacalcet dosage and subsequent dose changes were at the investigator's discretion. Results: Of 303 evaluable patients with pHTP, 134 (44%) had symptoms at diagnosis (mostly bone pain  or renal stones ). Mean albumin-corrected serum calcium (ACSC) at baseline was 11.4 mg/dL (2.9 mmol/L). Reasons for prescribing cinacalcet included: surgery deemed inappropriate (35%), patient declined surgery (28%), and surgery failed or contraindicated (22%). Mean cinacalcet dose was 43.9 (SD, 15.8) mg/day at treatment start and 51.3 (31.8) mg/day at Month 12; 219 (72%) completed 12 months' treatment. The main reason for cinacalcet discontinuation was parathyroidectomy (40; 13%). At 3, 6 and 12 months from the start of treatment, 63%, 69% and 71% of patients, respectively, had an ACSC of ≤10.3 mg/dL versus 9.9% at baseline. Reductions from baseline in ACSC of ≥1 mg/dL were seen in 56%, 63% and 60% of patients, respectively. ADRs were reported in 81 patients (27%), most commonly nausea. 7.6% of patients discontinued cinacalcet due to ADRs. Conclusions: Calcium reductions of ≥1 mg/dL were observed in 60% of patients 12 months after initiating cinacalcet, without notable safety concerns.
- GSK2374697, a novel albumin binding domain antibody (AlbudAb™) extends systemic exposure of exendin-4: first study in humans, PK/PD and safety. [JOURNAL ARTICLE]
- Clin Pharmacol Ther 2014 Sep 19.
GSK2374697 is a genetically engineered fusion protein of a human domain antibody to exendin-4. This molecule binds with high affinity to human serum albumin creating a long duration GLP-1 receptor agonist. This study is the first evaluation of the AlbudAb™ drug delivery platform in humans. The aim of this randomized clinical study was to determine the pharmacokinetics, pharmacodynamics, safety and tolerability of GSK2374697. The pharmacokinetic profile was prolonged with estimated half-lives ranging from 6-10 days. Postprandial glucose and insulin were reduced and gastric emptying delayed in healthy subjects confirming anticipated GLP-1 receptor agonist pharmacology. The safety and tolerability were as expected for a potent GLP-1 agonist. Gradual titration of doses greatly improved tolerability. Rapid tolerance to nausea was observed. Study results support further investigation in type 2 diabetes and for weight loss.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 19 September 2014. doi:10.1038/clpt.2014.187.
- The Structural Basis of Action of Vanadyl (VO(2+)) Chelates in Cells. [JOURNAL ARTICLE]
- Coord Chem Rev 2014 Nov 1.:1-22.
Much emphasis has been given to vanadium compounds as potential therapeutic reagents for the treatment of diabetes mellitus. Thus far, no vanadium compound has proven efficacious for long-term treatment of this disease in humans. Therefore, in review of the research literature, our goal has been to identify properties of vanadium compounds that are likely to favor physiological and biochemical compatibility for further development as therapeutic reagents. We have, therefore, limited our review to those vanadium compounds that have been used in both in vivo experiments with small, laboratory animals and in in vitro studies with primary or cultured cell systems and for which pharmacokinetic and pharmacodynamics results have been reported, including vanadium tissue content, vanadium and ligand lifetime in the bloodstream, structure in solution, and interaction with serum transport proteins. Only vanadyl (VO(2+)) chelates fulfill these requirements despite the large variety of vanadium compounds of different oxidation states, ligand structure, and coordination geometry synthesized as potential therapeutic agents. Extensive review of research results obtained with use of organic VO(2+)-chelates shows that the vanadyl chelate bis(acetylacetonato)oxidovanadium(IV) [hereafter abbreviated as VO(acac)2], exhibits the greatest capacity to enhance insulin receptor kinase activity in cells compared to other organic VO(2+)-chelates, is associated with a dose-dependent capacity to lower plasma glucose in diabetic laboratory animals, and exhibits a sufficiently long lifetime in the blood stream to allow correlation of its dose-dependent action with blood vanadium content. The properties underlying this behavior appear to be its high stability and capacity to remain intact upon binding to serum albumin. We relate the capacity to remain intact upon binding to serum albumin to the requirement to undergo transcytosis through the vascular endothelium to gain access to target tissues in the extravascular space. Serum albumin, as the most abundant transport protein in the blood stream, serves commonly as the carrier protein for small molecules, and transcytosis of albumin through capillary endothelium is regulated by a Src protein tyrosine kinase system. In this respect it is of interest to note that inorganic VO(2+) has the capacity to enhance insulin receptor kinase activity of intact 3T3-L1 adipocytes in the presence of albumin, albeit weak; however, in the presence of transferrin no activation is observed. In addition to facilitating glucose uptake, the capacity of VO(2+)- chelates for insulin-like, antilipolytic action in primary adipocytes has also been reviewed. We conclude that measurement of inhibition of release of only free fatty acids from adipocytes stimulated by epinephrine is not a sufficient basis to ascribe the observations to purely insulin-mimetic, antilipolytic action. Adipocytes are known to contain both phosphodiesterase-3 and phosphodiesterase-4 (PDE3 and PDE4) isozymes, of which insulin antagonizes lipolysis only through PDE3B. It is not known whether the other isozyme in adipocytes is influenced directly by VO(2+)- chelates. In efforts to promote improved development of VO(2+)- chelates for therapeutic purposes, we propose synergism of a reagent with insulin as a criterion for evaluating physiological and biochemical specificity of action. We highlight two organic compounds that exhibit synergism with insulin in cellular assays. Interestingly, the only VO(2+)- chelate for which this property has been demonstrated, thus far, is VO(acac)2.
- Haemoglobin wrapped covalently by human serum albumin mutants containing Mn(iii) protoporphyrin IX: an O2 complex stable in H2O2 solution. [JOURNAL ARTICLE]
- Chem Commun (Camb) 2014 Sep 19.
We describe the synthesis of a haemoglobin (Hb) wrapped covalently by recombinant human serum albumin mutants [HSA(Y161H)] containing Mn(iii) protoporphyrin IX (MnPP), the Hb-[HSA(Y161H)-MnPP]3 cluster, highlighting the formation of its O2-complex stable even in H2O2 solution.
- Carnosine treatment in combination with ACE inhibition in diabetic rats. [JOURNAL ARTICLE]
- Regul Pept 2014 Sep 16.
In humans, we reported an association of a certain allele of carnosinase gene with reduced carnosinase activity and absence of nephropathy in diabetic patients. CN1 degrades histidine dipeptides such as carnosine and anserine. Further, we and others showed that treatment with carnosine improves renal function and wound healing in diabetic mice and rats. We now investigated the effects of carnosine treatment alone and in combination with ACE inhibition, a clinically established nephroprotective drug in diabetic nephropathy. Male Sprague-Dawley rats were injected i.v. with streptozotocin (STZ) to induce diabetes. After 4weeks, rats were unilaterally nephrectomized and randomized for 24weeks of treatment with carnosine, lisinopril or both. Renal CN1 protein concentrations were increased under diabetic conditions which correlated with decreased anserine levels. Carnosine treatment normalized CN1 abundance and reduced glucosuria, blood concentrations of glycosylated hemoglobin (HbA1c), carboxyl-methyl lysine (CML), N-acetylglucosamine (GlcNac; all p<0.05 vs. non-treated STZ rats), reduced cataract formation (p<0.05) and urinary albumin excretion (p<0.05), preserved podocyte number (p<0.05) and normalized the increased renal tissue CN1 protein concentration. Treatment with lisinopril had no effect on HbA1C, glucosuria, cataract formation and CN1 concentration, but reduced albumin excretion rate more effectively than carnosine treatment (p<0.05). Treatment with both carnosine and lisinopril combined the effects of single treatment, albeit without additive effect on podocyte number or albuminuria. Increased CN1 amount resulted in decreased anserine levels in the kidney. Both carnosine and lisinopril exert distinct beneficial effects in a standard model of diabetic nephropathy. Both drugs administered together combine the respective effects of single treatment, albeit without exerting additive nephroprotection.