Assessment of subcutaneously administered insulins using in vitro release cartridge: Medium composition and albumin binding
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Biotherapeutics is the fastest growing class of drugs administered by subcutaneous injection. In vitro release testing mimicking physiological conditions at the injection site may guide formulation development and improve biopredictive capabilities. Here, an in vitro release cartridge (IVR cartridge) comprising a porous agarose matrix emulating subcutaneous tissue was explored. The objective was to assess effects of medium composition and incorporation of human serum albumin into the matrix. Drug disappearance was assessed for solution, suspension and in situ precipitating insulin products (Actrapid, Levemir, Tresiba, Mixtard 30, Insulatard, Lantus) using the flow-based cartridge. UV–Vis imaging and light microscopy visualized dissolution, precipitation and albumin binding phenomena at the injection site. Divalent cations present in the release medium resulted in slower insulin disappearance for suspension-based and in situ precipitating insulins. Albumin-binding acylated insulin analogs exhibited rapid disappearance from the cartridge; however, sustained retention was achieved by coupling albumin to the matrix. An in vitro-in vivo relation was established for the non-albumin-binding insulins. The IVR cartridge is flexible with potential in formulation development as shown by the ability to accommodate solutions, suspensions, and in situ forming formulations while tailoring of the system to probe in vivo relevant medium effects and tissue constituent interactions.Keywords:
Cartridge
Serum Albumin
Subcutaneous injection
To determine whether there was a difference between pre- and posthemodialysis serum albumin levels and, if so, whether that difference correlated with the amount of fluid removed during treatment.This descriptive study used a comparative data analysis strategy.287 paired measurements of pre- and post-hemodialysis serum albumin levels were collected from 46 patients in a midwestern hemodialysis center.Pre- and posthemodialysis serum albumin levels were obtained using the bromcresol green method.The pretreatment mean for serum albumin levels was 3.875 gm/dL (SD .4) and the posttreatment mean was 4.273 gm/dL (SD .599), significant at p < 0.0001. The amount of fluid removed during treatment was strongly correlated with the difference between pre- and posttreatment albumin levels (R = .6149; p < 0.0001). When data were sub-divided into three groups according to the amount of fluid removed during treatment, the mean differences between pre- and post hemodialysis albumin were significant at p < 0.0001.The strong correlation with fluid removed during hemodialysis suggests that fluid overload may be responsible for the significantly higher posttreatment albumin values in most patients.
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Catabolism
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The regulation of albumin synthesis and serum protein secretion was studied in regenerating rat liver by measuring incorporation of 14C-leucine. Albumin was isolated to radiochemical purity, utilizing a method which eliminates the influence of precursor pool changes on protein labeling. Changes in the size of the product pool were measured. The following results were obtained. 1. The time period between intracaval injection of 14Cleucine and the appearance of radioactive protein in the blood (secretion time) decreased from 15 min for normal animals to a minimum of 10 min at 48 hours after removal of 70% of the liver. 2. At 10 min after intracaval injection of 14C-leucine, 3.5% of total protein radioactivity was found in albumin in normal liver, whereas in regenerating liver only 1.4% of the total protein radioactivity was incorporated into albumin. 3. Albumin concentration in the serum decreased from 29.2 mg of albumin per ml of serum for normal rats to a minimum of 17.3 mg of albumin per ml of serum at 4 days after partial hepatectomy. 4. The half-life of albumin was 2.66 days for normal rats and 2.13 days for animals, 48 hours after partial hepatectomy. 5. The intravascular pool of albumin decreased from 100 mg of albumin per 100 g, body wt, in normal rats to 57.8 mg of albumin per 100 g, body wt, in partially hepatectomized animals, 48 hours after operation. The extravascular and the total body pool of albumin also decreased after partial hepatectomy to a minimum at 24 hours after the operation. In contrast to the intravascular pool, the extravascular and the total body pool increased again, reaching a plateau between 2 and 4 days after the operation. 6. During regeneration, the proportion of leucine to other amino acids in total liver protein did not change. Also, this proportion did not differ significantly from that found in serum albumin. 7. The net rate of albumin synthesis changed only slightly from 20.1 mg of albumin per day per g of liver for normal to 23.9 mg albumin per day per g of liver for regenerating liver 48 hours after partial hepatectomy. In contrast, the net rate of synthesis of total liver protein increased from 576 mg protein per day per g of liver in normal rats to 1710 mg of protein per day per g of liver in rats 48 hours after partial hepatectomy.
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Non-oncotic albumin functions such as transport, antioxidant and immunomodulatory capacities may be associated with the beneficial effects of albumin therapy in liver disease patients. For acute-on-chronic liver failure (ACLF) patients, characterized mainly by severe systemic inflammation and organ failure, plasma exchange with human serum albumin (PE-A5%) may be an effective treatment. In fact, the effects of PE-A5% on short-term survival in patients with ACLF are currently under investigation (APACHE phase 3 trial, NCT03702920). To characterize albumin levels with intact structure (effective albumin) in patients with ACLF compared with healthy controls (HC) and to assess the effect of PE-A5% treatment on eAlb levels in patients with ACLF. Plasma samples from 10 patients included in the Pilot-APACHE trial (NCT01201720) were assessed. This was a prospective, open-label, non-controlled study in which ACLF patients were treated with six PE-A5% for 10 days. At baseline, results were compared with HC (n=10). Albumin post-translational modifications (PTMs) were determined by mass spectrometry (LC_ESI_qTOF-MS). Native albumin (%) (the primary structure preserved form without PTMs) and effective albumin levels (mg/mL) (calculated as (total albumin x native albumin)/100)) were evaluated. Results were expressed as median (IQR). At baseline, ACLF patients showed a significantly lower proportion of native albumin, 19.4% (10.0-28.5), compared with HC, 51.3% (49.0-52.6), P<0.0001. Similarly, effective albumin levels, 6.8 mg/mL (3.5-8.9), were lower than HC, 19.8 mg/mL (18.9-20.7), P<0.0001. This reduction in native albumin was associated with higher cysteinylated and glycated isoforms. After six PE-A5%, native albumin (27.6% (17.1-35.3), p=0.036) and effective albumin (10.4 mg/mL (6.4-13.8); p=0.0067) were significantly increased. Remarkably, this effect was observed right after each PE-A5% session. ACLF patients presented albumin structural abnormalities that led to decreased effective albumin levels. PE-A5% not only improved non-oncotic albumin functions1 but increased structurally preserved albumin in these patients. 1J Hepatol 2018;68(Suppl1):S105-S364
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Albumin infusion is one of the therapeutic options in hypoalbuminemia patients. Serum albumin can be used to determine the albumininfusion therapy, prognosis and monitoring of liver cirrhosis. The time difference in measurement of serum albumin by bromcresol green(BCG) and bromcresol purple (BCP) methods can give different results. Serum albumin examination was done in 20 sera taken fromcirrhosis patients. Serum albumin was then evaluated before treatment, one (1) hour and 24 hours after the patient received an infusionof albumin and examined by bromcresol green (BCG) and bromcresol purple (BCP) methods. The serum albumin level by BCG methodincreased with a coefficient of 0.12 (p-value=0.022) with BCG method before (1.94±0.32 mg/dL) and after one (1) hour (2.06±0.32mg/dL) receiving intravenous albumin. The coefficient of albumin levels before and after 24 hours (2.12±0.38 mg/dL) was 0.18 (pvalue=0.07), whereas the increased levels of serum albumin after one (1) hour and after 24 hours of intravenous albumin, were notsignificant (p-value=0.467). The BCP method showed that serum albumin before, after one (1) hour and after 24 hours receivingintravenous albumin were 1.68±0.36 mg/dL, 1.87±0.36 mg/dL and 2.12±0.63 mg/dL respectively. The albumin levels showed asignificant increase before and after one (1) hour infusion of albumin (p-value=0.00), both levels shown before and after 24 hours(p-value=0.001), as well as one (1) hour and 24 hours after receiving intravenous albumin (p-value=0.04). The results of this studyshowed that increased serum albumin by BCG method could be detected after 1 (one) hour, whereas by BCP method could only be detectedafter 24 hours receiving intravenous albumin.
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Studies have been made on the molecular weight and amino acid composition of albumin from the blood serum and liver, as well as on its content in liver extracts and in the blood serum of male rabbits at the age of 1, 30, 180, and 720 days. During postnatal life, quantitative changes in the amino acid composition of the proteins investigated take place, which are more significant in liver albumin than in serum albumin. Albumin content of the blood serum and liver extracts decreases at later ontogenetic stages (in 180- and 720-day animals), which is presumably associated with the decrease in synthesis of this protein by the liver. The molecular weight of the albumin remains constant in all age groups being typical for serum albumin of vertebrates.
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Hypoalbuminemia
Serum Albumin
Liver disease
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The interaction of long-chain fatty acids with cells is important for their uptake and metabolism, as well as their involvement in signalling processes. The majority of long-chain fatty acids circulating in plasma exist as complexes with serum albumin. Thus an understanding of the involvement of serum albumin in these processes is vitally important. The effect of serum albumin on the uptake of long-chain fatty acids was studied in 3T3-L1 adipocytes. Serum albumin had a stimulatory effect on oleate uptake at all ratios of oleate: serum albumin tested. Furthermore, the rate of oleate uptake was saturable with increasing concentrations of serum albumin when the oleate: serum albumin ratio, and therefore the concentration of uncomplexed oleate, remained constant. This was not due to uptake being limited by dissociation of oleate from serum albumin, because oleate did not appear to be limiting. Furthermore, at very high ratios of oleate: serum albumin, when the concentration of uncomplexed oleate was predicted to be large relative to the amount of oleate taken up by cells, the rate of oleate uptake was still dependent on the albumin concentration. Serum albumin, covalently labelled with the photoreactive fatty acid 11-m-diazirinophenoxy[11-3H]undecanoate, bound to cells in a manner exhibiting both saturable (Kd 66.7 microM) and non-saturable processes. These results indicate that the stimulatory effect of serum albumin on the rate of oleate uptake is due to a direct interaction of serum albumin with the cells and point to an involvement of albumin binding sites in the cell surface in the cellular uptake of long-chain fatty acids.
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