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PubMed1988

Extravasation of plasma proteins in brain trauma.

The cellular distribution of extravasated plasma proteins in cortical contusions was studied with an immunoperoxidase method using polyclonal antibodies against human plasma albumin, alpha 1-acid glycoprotein, alpha 2-macroglobulin, alpha 1-antitrypsin, transferrin, hemopexin, haptoglobin, fibrinogen, fibronectin and immunoglobulin G. The material consisted of 24 human autopsy brains with a primary diagnosis of cerebral contusion due to blunt trauma. The time interval between injury and death ranged between minutes and 7 years. Immediately after the trauma, a complete breakdown of the blood-brain barrier (BBB) occurred with hemorrhage and extravasation of all types of plasma proteins. This was followed by spreading of edema fluid within the extracellular space in and around the wound. Uptake of extravasated protein by glial cells began on the 3rd day followed by proliferation of reactive astrocytes whose ample cytoplasm appeared to serve as a reservior for the extravasated plasma proteins. Within the reactive astrocytes, plasma proteins and S-100 protein had a similar and diffuse distribution in the immunostained sections. The plasma proteins once incorporated into the glial cells remained unchanged for several years with little sign of degradation. It is suggested that the extravasated plasma proteins subsequent to uptake and processing by the glial cells, may serve some important physiological function in wound healing.

Adolescent↗
PubMedDate not supplied

Disposition of ethopropazine enantiomers in the rat: tissue distribution and plasma protein binding.

PURPOSE: To determine the in vitro plasma protein binding, and the in vivo brain, heart and plasma concentrations of ethopropazine (ET) enantiomers in the rat after iv doses. METHODS: For in vivo assessment of ET enantiomer concentrations, rats with implanted jugular vein cannulae were injected with 10 mg/kg of (+/-)-ET HCl. At selected times after dosing, rats were sacrificed and heart, brain, and plasma were collected. Equilibrium dialysis was used to determine the unbound fraction of ET in rat plasma over a concentration range of 150 to 4000 ng/mL of each enantiomer. A stereospecific assay was used to measure concentrations of ET enantiomer. RESULTS: No stereoselectivity was observed in plasma or tissues after iv dosing. Area under the concentration vs. time curves indicated that highest uptake of ET occurred in brain tissue, followed by heart tissues, then plasma. There was no noticeable difference between concentrations of ET enantiomers in different parts of brain (substantia nigra, cortex, or striatum). There was no observed stereoselectivity in plasma protein binding of ET enantiomers in rat plasma. Saturation of binding to plasma proteins was observed between 500 and 2000 ng/mL of each ET enantiomer, but unbound fraction was constant at concentrations below and above that range. CONCLUSION: Ethopropazine displays nonstereoselectivity in its pharmacokinetics. The drug shares distribution features similar to those of other phenothiazine derivatives. Based on the in vitro plasma protein binding results, there appears to be saturation of some, but not all, plasma binding proteins of ET within the range of concentrations studied.

Animals↗
PubMed1982

Drug protein conjugates--I. A study of the covalent binding of [14C]captopril to plasma proteins in the rat.

The metabolism of [14C]captopril has been investigated in vitro and in vivo in male Wistar rats. The formation of conjugates of [14C]captopril with plasma proteins was observed both in vitro and in vivo: 180 min after intravenous infusion of [14C]captopril 35 +/- 5% of total radioactivity was covalently bound to plasma proteins. The fate of [14C]captopril-plasma protein conjugates was investigated in vivo. [14C]Captopril was incubated in vitro with rat and human plasma and the resulting captopril-protein conjugates were infused into male rats. The plasma concentration of [14C]captopril-rat plasma protein conjugates declined monoexponentially with a half-life of 71.1 +/- 2.2 min. After 180 min 28 +/- 3% of the radioactivity was excreted in urine, largely as [14C]captopril-cysteine mixed disulphide (67%). Thus although captopril readily forms covalent bonds with plasma proteins the resulting conjugates dissociate in vivo. The toxicological implications of these findings are discussed.

Animals↗
PubMed1978

Adsorption of plasma proteins on hydrophobic surfaces. III. Serum, plasma, and blood.

Liquid-air and liquid-liquid interfaces were used as models for the liquid-solid system of plasma proteins and hydrophobic surfaces in the study of adsorption of serum, plasma, and blood onto these surfaces. The interfacial tension is determined for three phases: air, methylene iodide, and isooctane. Curves of interfacial tension versus time for the various systems are given from which a triple-intersection point, where the protein solution is in equilibrium with each surface, is found. It is shown that albumin, gamma-globulin, and a mixed solution of these at in vivo concentrations behave in characteristic and constant manners at the three interfaces of air, methylene iodide, and isooctane. A range of synthetic surfaces which have constant behavior at equilibrium is deduced and it is concluded that any soft tissue response differences between such surfaces could not be the result of albumin or gamma-globulin.

Adsorption↗
PubMed2002

Proteolysis in severe sepsis is related to oxidation of plasma protein.

OBJECTIVE: To test the hypothesis that the oxidation of proteins is part of the mechanism of proteolysis in catabolic states. DESIGN: Prospective, observational study. SETTING: Critical care unit at a university teaching hospital, New Zealand. PATIENTS: 13 patients (6 male, 7 female; median age 61, range 26-76 years) who were admitted to the Department of Critical Care Medicine at Auckland Hospital with a diagnosis of severe sepsis. The median APACHE II score during the first 24 hours after admission was 22 (range 15-34). Control values of protein carbonyl in plasma were established in 15 healthy volunteers. INTERVENTIONS: We made serial measurements of total body protein (by neutron activation analysis) and plasma protein carbonyl (by ELISA) concentrations over a period of 10 days. MAIN OUTCOME MEASURE: Plasma protein carbonyl concentration and total body protein. RESULTS: The total amount of body protein decreased significantly over the 10 days (p < 0.001). Plasma protein carbonyl concentrations were significantly higher in the septic patients than in the control group throughout the study period (p < 0.0001). There was a significant reduction in plasma protein carbonyl concentration over the study period (p < 0.008). The early increase in the concentration of protein carbonyl formation was followed by an ongoing loss of body protein. There was a significant positive correlation between total body protein and plasma protein carbonyl (p < 0.03). CONCLUSIONS: Severe sepsis results in oxidation of plasma proteins and this precedes and is related to the loss of body protein.

APACHE↗
PubMed2000

Plasma protein carbonyls in nonpregnant, healthy pregnant and preeclamptic women.

Increased reactive oxygen species (ROS) and lipid peroxidation may be implicated in the pathogenesis of preeclampsia by causing cell (membrane) damage and impaired endothelial function. Carbonyl derivatives of proteins, or protein carbonyls, may be sensitive biomarkers of ROS-mediated damage. The aim of the study was to compare levels of protein carbonyls in plasma of preeclamptic, healthy pregnant and healthy nonpregnant women. Plasma protein carbonyls were measured in 47 preeclamptic, 45 healthy pregnant and 22 healthy nonpregnant women by using a sensitive ELISA-method. ANOVA, the unpaired t-test and Pearson's correlation were used for statistical analysis. Preeclamptic women had significantly higher plasma protein carbonyl levels than healthy pregnant women (P < 0.0001). Healthy pregnant women showed significantly higher protein carbonyl levels (P < 0.001) as compared to nonpregnant controls. The higher levels of protein carbonyls as compared to nonpregnant controls suggest that increased oxygen free radical damage occurs in normal pregnancy and to a much higher extent in preeclampsia.

Adult↗
PubMedDate not supplied

Pharmacokinetic effects of altered plasma protein binding of drugs in renal disease.

The measurement of plasma drug concentrations provides no insight into the relationship between the free and the plasma-protein-bound fractions of drugs. Plasma protein binding may decrease in renal disease due to uremia, hypoalbuminemia, or due to drug interactions. Decreased plasma protein binding leads to an increase in free plasma fraction causing an increase in volume of distribution and a shorter elimination half life. The increase in the apparent volume of distribution and the shorter elimination half life cause a decrease in total plasma concentration. Therefore, the free drug concentration is more reliable than the total plasma concentration for therapeutic drug monitoring. However, the free amount in plasma and in tissue and the tissue-bound amount remain unchanged under steady state conditions. Thus, a decrease in plasma protein binding in renal disease usually does not lead to increased drug toxicity, and alteration of drug dosage is not required, although the total plasma concentration may be found to be considerably lower than normal. In addition to plasma protein binding, alteration of tissue binding must also be considered for the determination of the appropriate dosage of some drugs in renal disease.

Biological Availability↗
PubMed1975

Snythesis and differentiation of plasma proteins in cultured embryonic chicken liver cells: a system for study of regulation of protein synthesis.

A new system is described for studying the control of protein synthesis. In a monolayer culture of chick embryo liver cells, plasma proteins are synthesized for three days at in vivo rates. The plasma proteins are secreted into the culture medium and without concentration are detected there simply and sensitively by a modified Laurell electronimmunoassay. Secretion of the newly synthesized plasma proteins occurs within 30 min of their synthesis. Thus, rates of synthesis of the plasma proteins can be followed readily from rates of their accumulation in the culture medium. This system has the following advantages for the study of protein synthesis: cells do not have to be disrupted for the assay; the cell population can be followed over several days; it is not necessary to label the proteins radioactively; and turnover of plasma proteins is negligible and need not be taken into account. The usefulness of the system is illustrated by a number of findings. The spectrum of plasma proteins synthesized in culture changed qualitatively and quantitatively. Albumin synthesis steadily decreased with culture time and stopped at the third day, whereas the synthesis of some new plasma proteins ("adult") was induced. These qualitative changes suggest differential gene expression in culture and a special control of albumin synthesis in vivo, different from the synthesis of the other plasma proteins. Quantitative changes in the rates of synthesis of specific plasma proteins suggest a competition among their messenger RNAs for components of the translational machinery. Insulin has a differential effect on the synthesis of specific plasma proteins at concentrations within the physiological range of the hormone.

Animals↗
PubMed1983

Applications of fast protein liquid chromatography TM in the separation of plasma proteins in urine and cerebrospinal fluid.

Fast Protein Liquid Chromatography TM (FPLC), in which an anion-exchange column is used, provides rapid separation and reproducible profiling of the plasma proteins in urine and cerebrospinal fluid (CSF). Chromatographic separation of the proteins takes 1 h for urine specimens and 45 min for CSF. The elution sequence from the anion-exchange column is similar to the electrophoretic mobility. Individual proteins have the same retention times independently of which type of specimen is used. The elution characteristics of 21 plasma proteins have been identified. We illustrated some applications of this system, including the profiling of tubular protein-uria, the isolation of Bence Jones proteins from urine, and the investigation of hemoglobin-derived products in the CSF.

Adult↗
PubMed2006

In vivo measurement of synthesis rate of multiple plasma proteins in humans.

Advances in quantitative proteomics have facilitated the measurement of large-scale protein quantification, which represents net changes in protein synthesis and breakdown. However, measuring the rate of protein synthesis is the only way to determine the translational rate of gene transcripts. Here, we report a technique to measure the rate of incorporation of amino acids from ingested protein labeled with stable isotope into individual plasma proteins. This approach involves three steps: 1) production of stable isotope-labeled milk whey protein, oral administration of this intrinsically labeled protein, and subsequent collection of blood samples; 2) fractionation of the plasma and separation of the individual plasma proteins by a combination of anion exchange high-pressure liquid chromatography and gel electrophoresis; and 3) identification of individual plasma proteins by tandem mass spectrometry and measurement of stable isotopic enrichment of these proteins by gas chromatography-mass spectrometry. This method allowed the measurement of the fractional synthesis rate (FSR) of 29 different plasma proteins by using the same precursor pool. We noted a 30-fold difference in FSR of different plasma proteins with a wide range of physiological functions. This approach offers a tremendous opportunity to study the regulation of plasma proteins in humans in many physiological and pathological states.

Adult↗
PubMedDate not supplied

Changes with respect to time in the in vivo adsorption of plasma proteins onto artificial heart blood pumps.

The distribution of adsorbed plasma proteins (albumin, IgG, and fibrinogen) on 10 artificial heart blood pumps coated with 2 segmented polyurethanes was evaluated quantitatively after long-term in vivo experiments with goats to determine how the adsorption of plasma proteins on the pumps was affected by the kinds of biomaterials used, and by the pumping duration. The adsorbed plasma proteins on the materials were determined quantitatively using the iodine-125 conjugated antibody method. Microscopically, the adsorbed plasma proteins were marked by the gold colloid conjugated antibody method, and analyzed using a field emission scanning electron microscope. The macroscopic results showed that: 1) the adsorbed plasma proteins on KP-13 were more evenly and finely distributed than those on Cardiothane; 2) with KP-13, the adsorption of IgG and albumin at the center of the pumps was significantly less than in the peripheral areas, and the adsorbed IgG and albumin decreased significantly as the pumping duration increased; 3) in contrast, the adsorbed fibrinogen increased significantly with time; and 4) with Cardiothane, the tendencies for adsorbed IgG and albumin to decrease, and for adsorbed fibrinogen to increase, were less significant than with KP-13. Microscopically, the gold colloids marking plasma proteins were found to not cover the whole of the surface, but were found scattered randomly or in clusters, with no relationship observed between the distributions of the three plasma proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗
PubMed2005

Volume expansion and plasma protein clearance during intravenous infusion of 5% albumin and autologous plasma.

Autologous plasma may be used to replace plasma volume and plasma proteins during surgery, but its effectiveness is largely unknown. In the present study, the characteristics of predonated frozen and thawed autologous plasma were compared with those of 5% albumin in 15 male volunteers who received 10 ml/kg of body weight of these colloids as intravenous infusions over 30 min. Venous blood was sampled and urine was collected over 8 h to outline the volume expansion and blood-interstitial fluid space transport of three plasma proteins (albumin, fibrinogen and antithrombin) by means of mass balance analysis. The maximum plasma dilution of 5% albumin and autologous plasma averaged 17 and 21% respectively, and their half-lives were 2.5 and 2.9 h respectively (P<0.03). The between-subject variability in dilution was most pronounced for autologous plasma. Transport of protein from blood to the interstitial space occurred faster when the infused fluid contained the protein in question. The rate was highest at 60 min, and the process was still in progress at 8 h when approx. 60% of the infused albumin, 45% of the fibrinogen and 75% of the infused antithrombin had been translocated to the interstitial fluid space. In contrast with the proteins, excess plasma water was removed by urinary excretion. It is concluded that the volume expansion is equivalent for the two colloid fluids, although it is more predictable for 5% albumin. The transport of protein outlasted the volume expansion.

Adult↗
PubMed2006

Determination of drug plasma protein binding by solid phase microextraction.

The plasma protein binding of drugs has been shown to have significant effects on the quantitative relationship between clinical pharmacokinetics and pharmacodynamics. In many clinical situations, measurement of the total drug concentration does not provide the needed information concerning the unbound fraction of drug in plasma, which is available for pharmacodynamic action. Therefore, the accurate determination of unbound plasma drug concentrations is important in understanding drug action. Many methodologies exist for determining the extent of plasma protein binding, but different methods produce a rather wide range of results for the same compound at the same concentration level. The solid phase microextraction (SPME) method reported in the present study attempts to eliminate many experimental variables that could lead to the lack of reproducibility, such as the variable content of organic solvent or ionic strength in plasma, pH shifts, and volume shifts. Five well-known drugs were chosen to study plasma protein binding: ibuprofen, warfarin, verapamil, propranolol, and caffeine, with high, intermediate and low binding properties. Dilution of plasma with isotonic PBS or incubation with 10% CO(2) in the atmosphere was found to compensate for changes in pH during incubation. The data obtained using these pH-controlled methods correlate well with the average values of plasma protein binding found in the literature. SPME, which uses an extraction phase that dissolves or adsorbs the drug of interest and rejects proteins, overcomes several limitations of currently available techniques and is a thermodynamically sound method, since the measurements are always performed at equilibrium. Compared to other methods, SPME offers several advantages: small sample size, short analysis time, possibility to automate, and ability to directly study complex samples.

Blood Proteins↗
PubMed1989

Apolipoprotein A-I binds to a family of bovine seminal plasma proteins.

Bovine seminal plasma contains four similar acidic proteins, previously designated as BSP (bovine seminal plasma)-A1, BSP-A2, BSP-A3, and BSP-30-kDa, that when added to pituitary cell cultures result in the immediate secretion of gonadotropins (follitropin and lutropin). However, when calf or horse serum was included in the culture medium the secretion of gonadotropins was completely prevented. This effect was seen at levels up to 200 micrograms of BSP protein/ml while the presence of more than 200 micrograms of BSP protein/ml in the serum medium continued to release gonadotropins. This could be explained by the presence in the sera of a binding factor to the BSP proteins which prevents their action. This binding factor has been detected in all the sera tested, including human serum, in dot-blot experiments using 125I-labeled BSP-A1, -A2, -A3, or -30-kDa protein. Thus, it was of interest to isolate this binding factor from human serum by affinity chromatography on a column of BSP-A1/-A2-agarose. The purified binding factor was then identified as apolipoprotein A-I (apoA-I) by the following criteria: (a) it has a molecular mass of 27,000 daltons, (b) the amino acid composition is similar to apoA-I, (c) the first 25 residues at the amino-terminal end of this binding factor are identical to apoA-I, and (d) the binding factor cross-reacts in the radioimmunoassay of apoA-I. Furthermore, BSP proteins also bind to purified plasma apoA-I and apoA-I associated with high density lipoprotein. ApoA-I is the major protein of plasma high density lipoprotein and plays an important role in lipid transport and metabolism. Thus, the binding of bovine seminal plasma proteins to apoA-I suggests some physiological significance in lipoprotein function or vice versa.

Amino Acid Sequence↗
PubMed1983

Diabetes-induced alterations in liver protein synthesis. Changes in the relative abundance of mRNAs for albumin and other plasma proteins.

Mechanisms responsible for diabetes-induced alterations in liver protein synthesis were investigated in vivo and in perfused liver using Bio-Breeding Worcester (BB/W) control rats, spontaneously diabetic BB/W rats maintained on insulin therapy, and diabetic BB/W rats withdrawn from insulin therapy for 48 h. Withdrawal of insulin therapy in the diabetic rats resulted in marked alterations in a number of parameters related to liver protein synthesis compared to BB/W control or insulin-maintained diabetic rats. Alterations seen in vivo following withdrawal of insulin included changes in the relative concentrations of several plasma proteins, a 40% reduction in total liver RNA relative to DNA, a 5-fold reduction in albumin synthesis relative to the synthesis of total liver proteins, a 5-fold reduction in albumin mRNA relative to total RNA, reductions in the relative abundance of mRNAs for at least four plasma proteins other than albumin, and a relative increase in mRNA for at least one plasma protein. Alterations observed in perfused liver included reductions in total liver protein synthesis (60% of control), albumin production (24% of control), and total secretory protein production (44% of control). All parameters studied were essentially unchanged from BB/W control values when the diabetic rats were maintained on insulin therapy. The results indicate that insulin deficiency leads to marked reductions in liver protein synthesis, particularly the synthesis of albumin and other plasma proteins. The mechanisms responsible for these alterations include changes in the relative abundance of specific mRNAs and a decrease in total cellular RNA.

Animals↗
PubMed1987

Non-enzymic glycation of individual plasma proteins in normoglycemic and hyperglycemic patients.

Diabetic patients in poor glycemic control show increased glycation of total plasma proteins, but little is yet known about the relative extents to which the various individual proteins are glycated. Thus, we studied the non-enzymic glycation of several major plasma proteins and plasma protein fractions in normal and diabetic patients. In vivo glycation for most plasma proteins was very low in non-diabetic patients, only gamma globulin showing more than 5% glycation. In diabetic plasmas, glycation was much greater, immunoglobulins again showing the greatest proportion, followed in descending order by albumin, complement C3, fibrinogen, transferrin, haptoglobin, and alpha-1-antitrypsin. When plasma proteins were glycated in vitro, this order was IgG greater than complement C3 greater than albumin greater than transferrin greater than haptoglobin greater than alpha-1-antitrypsin. In general, proteins with the longest biological half-lives, such as IgG and albumin, showed the greatest in vivo glycation. On the other hand, proteins with high intrinsic glycability, such as complement C3, showed moderate glycation, despite a short half-life. Except for albumin, more basic proteins showed greater glycation than acidic proteins, but there was poor correlation between mole percent lysine and glycation. Evidently the relative extents of glycation of different plasma proteins are a complex function of integrated glucose concentrations over time and of the half-life and chemical characteristics of each protein.

Blood Protein Electrophoresis↗
PubMed1988

Plasma protein binding of ketanserin and its distribution in blood.

The in vitro plasma protein binding and distribution in blood of ketanserin ((+/-)-3-[2-[4-(4-fluorobenzoyl)-1- piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione, R 41 468), a novel serotonin S2-receptor antagonist used in hypertension, was studied in rats, dogs and humans. Plasma protein binding of ketanserin amounted to 95.1% in healthy subjects, 88.1% in dogs and 98.8% in rats. Its blood to plasma concentration ratio was 0.70 in humans, 0.78 in dogs and 0.65 in rats. Plasma protein binding of ketanserin-ol, the main plasma metabolite of ketanserin, was 81.2% in humans and its blood to plasma concentration ratio was 1.04. The plasma protein binding of both ketanserin and ketanserin-ol was highly dependent on pH. Albumin was by far the main binding protein for ketanserin in human plasma and binding was independent of the ketanserin concentration within a very wide range. Plasma protein binding of ketanserin in elderly hypertensive patients was not significantly different from that in healthy adults. In chronic renal failure patients, whether on haemodialysis or not, the free ketanserin fraction was 40% higher than in healthy subjects. High therapeutic levels of ketanserin (0.25 microgram/ml) did not influence the plasma protein binding of diphenylhydantoin, hydrochlorothiazide, imipramine, ketoconazole, propranolol or warfarin. Out of 12 drugs, only tolbutamide at therapeutic concentrations decreased significantly the plasma protein binding of ketanserin. However, the resulting 5-20% increase of the free ketanserin fraction is hardly clinically relevant.

Administration, Oral↗
PubMed1998

Plasma protein binding of gyrase inhibitors.

Plasma protein binding of a wide range of gyrase inhibitors in clinical practice or trials has been determined by ultrafiltration to determine structure-protein binding relationships. The protein binding was independent of overall lipophilicity. In particular, the "western" part of the "quinolone" skeleton, consisting of a heterocyclus at position 7 and varying substituents at position 8, strongly influences the extent of protein binding, indicating that this part interacts with the plasma protein. In contrast, substituents in position N1 do not show an effect on the protein binding in this series of compounds.

Adsorption↗