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PubMed1976

Blocking of olive oil induced plasma protein escape from the intestinal circulation by histamine antagonists and by a diamine oxidase releasing agent.

Earlier studies have shown that feeding of olive oil to rats substantially increased the plasma protein in the intestinal lymph. The possibility of histamine mediating this response was examined. The plasma protein escape from intestinal circulation after olive oil feeding was measured in rats in terms of the amount of Evans Blue labelled plasma protein found in the intestinal lymph. Animals treated with histamine antagonists (H1-receptor antagonist pyrilamine, 16-22 mg/kg i.p., plus H2-receptor antagonist Burimamide, 12-16 mg/kg i.p.) did not show an increase in the quantity of lymphatic plasma protein. Heparin pretreatment which releases the histaminolytic enzyme, diamine oxidase, into the interstitial space also prevented the increased accumulation of labelled plasma protein in the lymph after olive oil ingestion. Based on these observations, histamine appears to act on the intestinal microcirculation during olive oil absorption and allows larger quantities of plasma proteins to leave the intestinal circulation.

Amine Oxidase (Copper-Containing)↗
PubMedDate not supplied

Plasma protein binding of drugs in pregnancy.

The degree of binding to plasma proteins is an important determinant of drug disposition and response. Normal human pregnancy is associated with concentration of plasma proteins, free fatty acids and possibly other endogenous substances interfering with drug binding. The possibility of an associated change in plasma binding capacity therefore needs to be taken into consideration. Experimental studies conducted mostly in vitro have shown that the plasma protein binding of many (but not all) drugs is decreased during pregnancy, particularly during the last trimester. This phenomenon should be taken into account when interpreting serum concentrations of total (free + protein-bound) drug in clinical practice. Notable examples of drugs whose unbound fraction increases during pregnancy include diazepam, valproic acid, phenytoin, phenobarbitone, salicylic acid, pethidine, lignocaine, dexamethasone, sulphafurazole and propranolol. For many drugs, important differences have been demonstrated in the degree of protein binding between maternal and cord plasma. In some cases, this may provide an explanation for the finding of marked differences in total drug concentration between maternal and fetal plasma at the time of delivery.

Adrenal Cortex Hormones↗
PubMed1953

The localization of homolgous plasma proteins in the tissues of young human beings as demonstrated with fluorescent antibodies.

Employing fluorescent antibodies for the detection of homologous plasma proteins in tissue sections, the distribution of plasma albumin, gamma-globulin, beta-lipoprotein, beta(1)-metal-combining globulin, and fibrinogen has been studied in the tissues of infants and children. Plasma albumin, gamma-globulin, and beta(1)-metal-combining globulin were found in many cells and particularly cell nuclei, connective tissues and interstitial spaces, lymphatics, and blood vessels. beta-Lipoprotein was found mostly in the nuclei of all cell types while fibrinogen was restricted largely to the lymphatic and vascular channels, connective tissues and the interstitial spaces. The widespread distribution of these plasma proteins in cells and connective tissues indicates the magnitude of the extravascular plasma protein pool which is in equilibrium with circulating plasma. Unfortunately, these results do not permit accurate localization of the sites of production of these plasma proteins, but do give some idea of their intimate relationship to the tissues.

Antibodies↗
PubMed1991

Influence of the plasma protein concentration on renal function.

1. The effect of the plasma protein concentration on renal function remains controversial. Most, but not all, experimental studies suggest that a reduced plasma protein concentration perfusing the kidney may reduce tubular sodium reabsorption. Hypoproteinaemic disease states are usually associated with sodium retention, which is not always volume-dependent. 2. We induced a 21% and 24% reduction in plasma total protein and plasma albumin, respectively, in unanaesthetized sheep by acute extracorporeal plasmapheresis. Arterial pressure did not change, and changes in circulatory volume were minimised by infusion of crystalloid to maintain pulmonary artery occlusion pressure, measured using a Swann-Ganz pulmonary artery catheter. 3. After plasmapheresis, there was no significant change in creatinine clearance, sodium excretion, plasma renin activity or urinary kallikrein excretion. 4. After plasmapheresis, there was no significant reduction in plasma osmolality, increase in urine osmolality and fall in free water clearance. 5. The results suggest that in the absence of detectable changes in circulating volume or arterial pressure, acute hypoproteinaemia is associated with significant changes in renal water handling, but has no direct effect on sodium excretion or on renal release of renin and kallikrein.

Acute Disease↗
PubMed1993

Rapid steady-state analysis of blood-brain transfer of L-Trp in rat, with special reference to the plasma protein binding.

We estimated constants for the binding of tryptophan (Trp) to plasma proteins, and for the transfer of Trp from plasma to brain in rat. The measurements were made under conditions in which the plasma and brain concentrations of Trp were raised to new steady-states for at least 10 min before being measured. The concentration of other competing amino acids were also at a steady-state. The plasma Trp concentration was elevated by i.p. injection of different doses of L-tryptophan methyl ester 60 min before the measurement of the plasma-brain transfer. We simultaneously measured blood flow with [14C]-butanol, and the brain tissue Trp uptake with [3H]Trp. The maximal velocity (Vmax), apparent half-saturation Michaelis-Menten constant (Km(app)), and diffusion constant (PdS) for Trp transport from plasma into brain were found to be 7.0 +/- 2.1 nmol g-1 min-1, 36 +/- 17 microM, and 0.065 +/- 0.006 ml g-1 min-1, respectively. The maximum plasma protein binding (Bmax) and dissociation constant (KD) for Trp were estimated at 360 +/- 16 nmol/ml-plasma and 81 +/- 10 microM, respectively. We conclude that the plasma protein binding of Trp inhibits the blood-brain transfer in inverse proportion to the plasma free Trp concentration.

Animals↗
PubMed1980

Effect of heparin on bilirubin clearance in rats: pharmacokinetic consequences of extensive hepatic extraction of plasma protein binding inhibitors.

The purpose of this investigation was to determine the effect of heparin-induced endogenous inhibitors of plasma protein binding on the plasma concentrations of total (free plus bound) and free bilirubin in rats with experimental hyperbilirubinemia. Adult male rats received constant-rate intravenous infusions of bilirubin and, after attaining steady state, were given either an intravenous injection of heparin, 500 units/kg, or this injection plus a maintenance infusion of hepatin. Control animals received normal saline solution instead of heparin. The free fraction of bilirubin in plasma increased substantially within 2 min after heparin injection and remained elevated when heparin concentrations were sustained by infusion of the anticoagulant. Despite the decreased plasma protein binding of bilirubin, the plasma concentration of total bilirubin did not decrease (as it does, consistent with pharmacokinetic theory, following injection or infusion of certain other inhibitors of bilirubin binding) and the plasma concentration of free bilirubin did not return to normal (as observed previously after administration of other binding inhibitors) but remained elevated. These results are consistent with the recently demonstrated rapid and extensive hepatic extraction of heparin-induced endogenous inhibitors of plasma protein binding. The heparin interaction with bilirubin may be particularly serious because of the sustained elevation of free bilirubin concentrations in plasma and the potential neurotoxicity of free bilirubin.

Animals↗
PubMed1988

Inhibition of platelet [3H]-imipramine binding by human plasma protein fractions.

Inhibition of high-affinity [3H]-imipramine binding to platelet membranes by human plasma fractions and isolated plasma proteins was investigated. Several plasma proteins were found to contribute to the observed apparent inhibition and this contribution was assessed in terms of inhibitor units. Alpha 1 acid glycoprotein, high density and low density lipoprotein, IgG and alpha 1-antitrypsin were identified as effective non-specific inhibitors. Alpha-1-acid glycoprotein was confirmed to be the most potent plasma protein inhibitor. Cohn fractions were evaluated for the presence of the postulated endocoid of [3H]-imipramine binding site.

Binding Sites↗
PubMed1980

Biosynthesis of plasma proteins in serum-free medium by primary monolayer culture of rat hepatocytes.

Morphologically intact rat hepatocytes separated by collagenase perfusion were cultured in L-15/fetal calf serum medium to form a monolayer. Thereafter the hepatocytes were grown in serum-free L-15 medium in which they produced and continuously released plasma proteins. The secreted plasma proteins were collected, separated and characterized by crossed immunoelectrophoresis. Most of the newly biosynthesized plasma proteins secreted into the medium during incubation for thirty hours had the same electrophoretic mobility, antigenicity and staining characteristics as their counterparts in rat serum. The addition of tritium labelled amino acid mixture to the culture medium revealed that the release of radioactively labelled plasma proteins into the culture medium was essentially linear during the thirty hour incubation period. However, saturation of the intracellular pool took place after ca. ten hours of incubation. Addition of leukocytic endogenous mediator, LEM, to cultures of rat hepatocytes caused a profound increase in the relative concentration of acute-phase proteins secreted into the culture medium.

Amino Acids↗
PubMed1988

Purification of plasma protein.

The purification of coagulation proteins from plasma milieu is a complex and sometimes difficult task. Most clotting factors are present in plasma in trace amounts. They are sensitive to proteolytic degradation and adsorption to surfaces. Thus for most coagulation proteins it was not until the seventies that highly purified preparations were available. Nowadays, most coagulation proteins are isolated from plasma using combinations of ion exchange, molecular sieve and affinity chromatographies. Sometimes, e.g. for Vitamin K dependent factors, specific adsorption properties are utilized. During affinity chromatography, proteins may be bound to specific immobilized receptors, antibodies, substrates, or inhibitors. An example for the latter is the use of bezamidine-Sepharose for the purification of thrombin. Immunoadsorption to immobilized monoclonal antibodies allowed the isolation of highly purified factor VIII:C. For factor XI and prekallikrein the binding of these proteins to the immobilized cofactor high molecular weight kininogen is utilized for an effective separation of contaminations. Antithrombin III can be isolated by linkage to its cofactor, heparin, on heparin-Sepharose. Using affinity chromatography on lysine-Sepharose it is possible to isolate plasminogen from plasma, serum or urine in a one step procedure with high yield and quality. This, of course, is an ideal situation, where the goal of a purification, namely the separation of a highly purified, biologically active product with high yield can be accomplished in a simple, fast procedure.

Blood Coagulation Factors↗
PubMedDate not supplied

Sequential changes in insulin-like growth factor 1, plasma proteins, and total body protein in severe sepsis and multiple injury.

BACKGROUND: Our group wanted to test the hypothesis that plasma levels of insulin-like growth factor 1 (IGF-1), transferrin, and prealbumin are useful markers of nutritional progress in severe sepsis and multiple injury. METHODS: Measurements of IGF-1 and plasma proteins were made in critically ill patients as soon as they were hemodynamically stable and 5, 10, 15, and 21 days later. The magnitude and direction of the measured changes were compared with the magnitude and direction of the change in total body protein in the same time period. RESULTS: Fourteen patients with severe sepsis and 10 multiply injured patients were studied. As a group they had an increased metabolic expenditure that peaked at 153% of normal and lost approximately 12.0% of total body protein. An early fall in IGF-1 and plasma proteins accompanied a marked acute phase response, and recovery occurred while hypermetabolism and net proteolysis continued. No correlation existed between changes in IGF-1 or plasma proteins and the change in total body protein. CONCLUSIONS: Plasma levels of IGF-1, transferrin, and prealbumin are not useful for following changes in protein stores early in the course of critical illness.

APACHE↗
PubMed1956

A study of plasma protein alterations in rabbits infected with type I pneumococci.

An investigation of the plasma protein changes in rabbits infected intradermally with Type I pneumococci has been carried out, utilizing a cationic detergent method of protein fractionation. A consistent pattern of change was observed. There was an increase in the alpha globulins and fibrinogen concentration which reached maximal levels at the height of the infection. Albumin fell to a minimal concentration when the increment of alpha globulins and fibrinogen was greatest. The beta-gamma concentration showed a significant decrease during the most severe phase of the infection but returned to normal several days after spontaneous subsidence of bacteremia. The magnitude of these plasma protein alterations depended on the severity of the infection and the response of the host. Significantly greater changes were observed in rabbits severely bacteremic than in those with mild bacteremia. Administration of penicillin suppressed the infection and decreased the usual plasma protein alterations. Injection of cortisone prior to the onset of the Type I pneumococcus infection caused an early inhibition of the expected plasma protein changes, but later the protein pattem developed in the same manner as it did in the severely infected animals.

Animals↗
PubMed1990

Interaction between endogenous circulating sulfated-glycosaminoglycans and plasma proteins.

Interaction between endogenous 35S-labelled plasma glycosaminoglycans and proteins in murine plasma was demonstrated by coelution from gel chromatography of circulating 35S-labelled glycosaminoglycans with a wide range of plasma proteins. Autoradiography of electrophoretic tracing of proteins from 35S-sulfate labelled plasma showed that labelled glycosaminoglycans were associated with alpha 1, alpha 2, beta globulins and albumin, but not with gamma globulins. Analysis by gel chromatography on Sepharose CL-6B of delipidated 35S-labelled plasma after either proteolysis or beta-elimination, suggested that 35S-labelled glycosaminoglycan chains were covalently bound to proteins. Lipids were probably involved in the supramolecular assembly of GAGs with plasma proteins, as shown by hydrophobic interaction chromatography. In addition, strong, non-covalent interaction between glycosaminoglycan chains and proteins was responsible for the difficulty in extracting 'free' glycosaminoglycans from plasma. Consistently, ion-exchange chromatography of 35S-sulfate labelled delipidated plasma after alkali treatment, revealed that the anionic properties of glycosaminoglycans were hampered when plasma proteins were present.

Animals↗
PubMed1989

Determination of cis-diamminedichloroplatinum (II) in plasma proteins and hemoglobin of cancer patients.

A study was conducted to determine the levels of cis-diamminedichloroplatinum (II) (cisplatin) in plasma proteins and hemoglobin of cancer patients after cisplatin chemotherapy. Thirty-seven cancer patients with different type of cancers (lung, esophageal, urinary tract, and testicular cancer, melanoma, osteosarcoma etc) received cisplatin 32-110 mg/m2 either as a single intravenous infusion or as infusions given on 5 consecutive days. Blood samples were classified according to time from previous cisplatin infusion. They included a total of 103 samples taken before the cisplatin infusion, immediately after infusion, 1, 2 or 3-5 days after infusion or 2-3, 4, or 5-7 weeks after infusion. Platinum (Pt) concentration in plasma proteins and hemoglobin was measured by atomic absorption spectroscopy (AAS). The data showed a correlation between the dose of cisplatin and the concentrations of Pt in plasma proteins and hemoglobin of cancer patients. Plasma proteins bound more cisplatin than hemoglobin, the respective maxima in the patients receiving greater than 50 mg/m2 being 27.7 and 1.6 ng/mg protein in samples drawn immediately after treatment. The kinetics of disappearance of Pt from plasma proteins showed several components; the initial half-life was about 5-7 days. The disappearance of Pt from hemoglobin showed a single component of a half-life of 12-14 days.

Adolescent↗
PubMed2000

Adsorption kinetics of plasma proteins on oil-in-water emulsions for parenteral nutrition.

The plasma protein adsorption patterns on colloidal drug carriers are regarded as an important factor for their in vivo fate. In this study the adsorption kinetics on oil-in-water emulsions were determined and compared to the adsorption kinetics on polystyrene particles. In addition, the adsorption kinetics on the same systems after surface-modification with a hydrophilic polymer were also investigated. The protein adsorption was determined by means of two dimensional polyacrylamide gel electrophoresis (2D-PAGE). The determination of the plasma protein adsorption kinetics was carried out using different concentrations of human plasma in the incubation medium to prolong the residence time of the more abundant plasma proteins on the surface. Proteins which are likely to be displaced in a split second are thus accessible to analysis. The oil-in-water emulsion showed a distinctly different adsorption behavior from the one previously described for solid surfaces, where initially adsorbed proteins are displaced by others, having a higher affinity to the surface ('Vroman effect'). No competitive protein adsorption could be observed on the emulsions. Moreover, the predominantly adsorbed apolipoproteins A-I, A-IV, C-II and C-III increase in amount with increasing plasma concentration. The knowledge of the adsorption kinetics of colloidal carriers might be helpful for a better understanding of the in vivo behavior of such systems and for the transfer of principles already known from other carrier systems to the controlled development of emulsions for site specific drug delivery.

Adsorption↗
PubMed2002

Purity of spiking agent affects partitioning of prions in plasma protein purification.

Prions are not detectable in the blood or plasma of persons afflicted with classical or variant Creutzfeldt-Jakob disease, and they have never been shown to be transmitted by blood or plasma products. Despite the uncertainty as to the presence and biophysical properties of prions in plasma, prion removal studies have been conducted using brain homogenate or microsomes prepared from prion-infected rodent brains as model prions. In this study, we compare the partitioning of different prion spiking agents, having different biophysical properties, in the processes used for plasma protein purification. We have found that membrane-bound prion spiking agents partition similarly, whereas purified, unbound pathogenic prion proteins can have significantly different partitioning properties depending on the conditions in the production process. We conclude that prion spiking studies for the evaluation of prion reduction in plasma protein purification should employ spiking agents with different biophysical properties to mimic partitioning of the theoretical prion contaminant. This will give greater assurance as to the prion safety margins of the life-saving plasma protein therapeutics and excipients.

Animals↗
PubMed2002

Predicting plasma protein binding of drugs: a new approach.

In spite of the large amount of plasma protein binding data for drugs, it is not obvious and there is no clear consensus among different disciplines how to deal with this parameter in multidimensional lead optimization strategies. In this work, we have made a comprehensive study on the importance of plasma protein binding and the influencing factors in order to get new insights for this molecular property. Our analysis of the distribution of percentage plasma protein binding among therapeutic drugs showed that no general rules for protein binding can be derived, except for the class of chemotherapeutics, where a clear trend towards lower binding could be observed. For the majority of indication areas, however, empirical rules are missing. We present here an extensive list of multiply determined primary association constants for binding to human serum albumin (HSA) for 138 compounds from the literature. Correlating these binding constants with the percentage fraction of protein bound showed that the percentage data above 90%, corresponding to a binding constant below 6 microM, are of insufficient accuracy. Furthermore, it could be demonstrated that the lipophilicity of drugs, traditionally felt to dominate binding to HSA, is not the only relevant descriptor. Here, we report a generic model for the prediction of drug association constants to HSA, which uses a pharmacophoric similarity concept and partial least square analysis (PLS) to construct a quantitative structure-activity relationship. It is able to single out the submicromolar to nanomolar binders, i.e. to differentiate between 99.0 and 99.99% plasma protein binding. Depending on the system, this can be important in medicinal chemistry programs and may together with other computed physicochemical and ADME properties assist in the prioritization of synthetic strategies.

Humans↗
PubMed1986

Plasma protein alterations in AIDS and hemophilia A.

Plasma proteins of patients with AIDS, ARC, hemophilia A, and some viral infections were studied using various electrophoretic techniques, and compared to healthy control subjects. On isoelectric focusing (IEF) gels the most prominent and consistent finding was a marked increase in a basic protein band (AABP) at pI approximately equal to 9.0 in plasma samples derived from AIDS and hemophilia A patients. Using SDS gels, we noted an increased amount of protein in the 90 KD region in AIDS patients as compared to control subjects. On two dimensional gels (2D gels) basic protein(s) with pI congruent to 8.1-9.0 and molecular weight of approximately 90 KD were noted to be increased. In addition, a basic protein of 27 KD along with two acidic proteins in the low molecular weight region were also elevated in AIDS plasma. Although a limited number of samples were analyzed, it seems probable that a number of proteins are altered in AIDS plasma. AABP stained positive with periodic acid Schiff (PAS) reagent, indicating that it is a glycoprotein. This protein did not bind to an anti-IgG sepharose column, suggesting that it is not an immunoglobulin. The purified protein also did not react with antibody to fibrinogen and hemoglobin beta-chain. There are many changes in the plasma protein pattern of AIDS and hemophilia A patients as compared to normal controls.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Phenotypic variation in human HepG2 hepatoma cells: alterations in cell growth, plasma protein synthesis and heme pathway enzymes.

1. Growth rates, morphology, plasma protein synthesis and the level of heme pathway enzymes were examined in six sublines of HepG2 cells obtained from various laboratories. 2. Five sublines represented by G2a display the known characteristics of HepG2 cell type, including morphology, plasma protein synthesis and an increase in delta-aminolevulinic acid (ALA) dehydratase activities in response to Me2SO treatment. 3. In contrast, cells of the G2f subline failed to secrete significant quantities of plasma proteins. There was also no increase in ALA dehydratase activity following Me2SO treatment. These findings suggest that G2f cells represent a variant of HepG2 cells with an altered phenotype.

Blood Proteins↗