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Biomedical subjects

J Barre

Publications and source records attributed to J Barre.

At least 55 records · Page 3Linked to original sources
PubMed1987

Effect of erythrocytes and plasma protein binding on the transport of progabide and SL 75102 through the rat blood-brain barrier.

Brain extraction of two antiepileptic compounds, progabide and its acid metabolite, SL 75102, was investigated using the carotid injection technique in the rat. The extent to which drug binding to plasma proteins could inhibit the brain extraction was measured. Equilibrium dialysis at 4 degrees showed that both drugs were highly bound to human serum proteins, mainly to serum albumin. Progabide is also bound to red blood cells and to lipoproteins. The free dialyzable drug fraction was inversely related to the protein concentration. Similarly, the brain extraction of the drugs in the presence of either albumin, or red blood cells for progabide was inversely related to their respective concentrations. However, the rat brain extraction of both drugs was higher than expected from the in vitro measurement of dialyzable fraction. Furthermore, despite a significant degree of progabide binding to lipoproteins, no significant reduction in the brain extraction of the drug was observed. These data indicate that the amount of circulating progabide or SL 75102 available for penetration in a peripheral tissue such as brain exceeds the dialyzable fraction of drug. However, the in vivo exchangeable drug fraction still parallels the dialyzable fraction, except if the drug is lipoprotein-bound.

Biological Transport, Active↗
PubMed1987

Comparative pharmacokinetics of intravenous propranolol in obese and normal volunteers.

Plasma pharmacokinetics of a single IV dl-propranolol dose (8 mg) were investigated in 12 obese subjects (mean +/- SD: 110.3 +/- 20.4 kg; 198.7 +/- 32.5% of ideal body weight) and compared with those of 12 healthy subjects (66.7 +/- 6.8 kg; 94.5 +/- 7.8% of ideal body weight). In obese subjects plasma alpha-1 glycoprotein acid concentrations and propranolol protein binding capacity did not differ significantly from control subjects. When compared with controls, obese subjects showed a significant increase (P less than .01) in AUC (161.0 +/- 67.0 vs 109.6 +/- 23.1 hr.micrograms/L), and significant decreases (P less than .01) in Vss (208.9 +/- 71.9 vs 318.6 +/- 91.8 L), V beta (234.3 +/- 70.4 vs 340.7 +/- 89.1 L), and total clearance (57.5 +/- 18.3 vs 75.9 +/- 15.4 L/hr). Elimination half-life was similar for the two populations (3.5 +/- 0.9 hr in obese subjects vs 3.1 +/- 0.9 hr in controls). Therefore, neither lipophilicity of propranolol nor drug plasma protein binding can explain these data. Altered hepatic function and tissue blood flow in obese subjects are proposed as an explanation for the decrease in total clearance and volume of distribution.

Adult↗
PubMed1987

A double-peak phenomenon in the pharmacokinetics of veralipride after oral administration: a double-site model for drug absorption.

Equal doses of veralipride have been given to 12 healthy volunteers by three different administrations--intravenous infusion, oral solution, and oral capsules--in a randomized cross-over design. After the intake of the solution, but not after infusion or capsules, two maximum plasma concentrations have been observed and interpreted, according to a double-site model for drug absorption.

Administration, Oral↗
PubMed1987

Pharmacokinetics of erythromycin in patients with severe cirrhosis. Respective influence of decreased serum binding and impaired liver metabolic capacity.

Pharmacokinetic parameters were studied after i.v. infusion of erythromycin (500 mg) in five patients with alcoholic cirrhosis and six normal subjects. Serum AAG levels were 4.7 +/- 2.4 mumol l-1 in cirrhotics and 10.3 +/- 2.1 +/- mumol l-1 in normals. The unbound fraction (fu) of erythromycin was significantly higher in cirrhotic patients (58.3 +/- 17.7%) than in normal subjects (30.5 +/- 2.8%, P less than 0.01), and a negative correlation was found between fu values and serum AAG (r = -0.867, P less than 0.01). Due to increase in fu, volume of distribution (Vss) was significantly augmented in cirrhotics (85.5 +/- 23.8 l vs 57.6 +/- 14.8 l, P less than 0.05). Serum clearance of unbound erythromycin (CLu) was significantly reduced in cirrhotic patients (42.2 +/- 10.1 l h-1 vs 113.2 +/- 44.2 l h-1 in normal subjects, P less than 0.01). This led to marked elevation of serum concentrations of unbound drug and was entirely explained by the decrease of non renal (i.e. hepatic intrinsic) clearance (31.6 +/- 7.5 l h-1 in cirrhotics, 98.6 +/- 41.5 l h-1 in normals, P less than 0.02); renal clearance remained unchanged. It is concluded that in cirrhotic patients, low serum AAG levels and reduced liver metabolic capacity may lead to marked changes in pharmacokinetics of erythromycin, and that similar results might be expected for drugs which exhibit the same serum binding and pharmacokinetic behaviour as erythromycin.

Adult↗
PubMed1987

Binding parameters and microbiological activity of macrolides, lincosamides and streptogramins against Staphylococcus aureus.

Parameters of erythromycin binding to Staphylococcus aureus were measured in-vitro using an equilibrium method with [3H]erythromycin. The dissociation constant of the complex, erythromycin-S. aureus sensitive strain, was KD = 0.11 microM. The maximal binding, representing the density of binding sites was 14,847 molecules/cell. No binding was detectable on the constitutive resistant strain. Macrolides, streptogramins and lincosamides displaced bound [3H]erythromycin by a competitive process indicating that these compounds share common binding sites on the bacteria, i.e. 50 S ribosomal subunits. A good correlation (r = 0.99) was demonstrated between the corresponding inhibition constants (Ki) and the minimal inhibitory concentration. It is proposed that knowledge of the binding parameters provides a good indication of bacterial susceptibility and may serve as a useful adjunct in developing new compounds.

Anti-Bacterial Agents↗
PubMed1987

[Comparison of the efficacy and tolerance of Kabi 2165 and standard heparin in the prevention of deep venous thrombosis in total hip prosthesis].

A series of 80 patients operated for total hip prosthesis under epidural anesthesia was randomly allocated to treatment with Kabi 2165 (n = 40): 2,500 U anti-Xa preoperatively and evening of operation and 2,500 U anti-Xa morning and evening daily up to the 9th or 10th day postoperatively, or standard heparin (n = 40): 3,750 U preoperatively and then 8 hourly, at a dose adjusted with thrombin time and cephalin + activator time, daily up to the 9th or 10th day. Phlebography was performed routinely on the 9th or 10th day. Venous thrombosis occurred in 7 patients (17.5%) in the Kabi 2165 group, including two high, potentially emboligenic, localizations (5%), and in 4 patients (10%) in the standard heparin group, including 2 potentially emboligenic clots (5%). The difference is not statistically significant (total number: p = 0.5; potentially emboligenic: p = 0.33). Pulmonary embolism did not occur. Overall tolerance, evaluated from hemoglobin and hematocrit values, intra- and post-operative bleeding and operation wound hematoma and at injection site was comparable in the two groups.

Aged↗
PubMed1987

Progabide and SL 75102 binding to plasma proteins and red blood cells in humans.

The binding of progabide and its metabolite, SL 75102, was studied in vitro by equilibrium dialysis. The progabide binding percentage in serum remained constant (approximately equal to 96%) over a wide range of concentrations. Binding of progabide was characterized by one class of sites to human serum albumin (HSA) (n = 3.8 +/- 0.2; K = 2.5 X 10(4) M-1). The binding to alpha 1 acid glycoprotein (AAG) was also shown to be saturable with n = 1.7 +/- 0.2 and K = 3.1 X 10(4) M-1. Progabide was bound to a lesser extent to red blood cells (RBC), lipoproteins and gamma-globulins. The SL 75102 binding percentage in serum remained constant (approximately equal to 98%), over a range of concentrations exceeding therapeutic levels. SL 75102 showed two saturable classes of binding sites to HSA: the first one with n1 = 0.8 +/- 0.1 and K1 = 10(6) M-1 and the second one with n2 = 7.9 +/- 0.2 and K2 = 8.1 X 10(3) M-1. The binding to AAG was also shown to be saturable with n = 0.7 +/- 0.1 and K = 1.6 X 10(4) M-1. SL 75102 was bound to a lesser extent to RBC, lipoproteins and gamma-globulins. The binding parameters were used to calculate the distribution of progabide and SL 75102 among the components in whole blood over the therapeutic range. The calculations showed that serum albumin was the major binding component for the parent drug and its metabolite.

Anticonvulsants↗
PubMed1986

In vitro [3H]-erythromycin binding to Staphylococcus aureus.

Characteristics of erythromycin binding to Staphylococcus aureus were determined by using kinetics and equilibrium binding experiments. Both methods yielded identical values of the dissociation constant, i.e. 0.1 muM. This value was in accord with that found with a bacterial extract of ribosomes which are the organelles where erythromycin exerts its action. This good agreement shows that the dissociation constant of erythromycin determined with intact bacteria is a good reflect of specific bacterial receptors of macrolides, i.e. ribosomes. In addition, mechanism of uptake of the antibiotic by Staphylococcus aureus was investigated. Passive diffusion process was shown to be mainly responsible for this phenomenon.

Erythromycin↗
PubMed1986

Influence of bile salts and lipids on intestinal absorption of griseofulvin in man.

The influence of bile salts and lipids on the intestinal absorption of griseofulvin has been studied in 11 healthy male volunteers by the intestinal perfusion technique. The drug in a nutrient solution (Realmentyl) was perfused into the second part of duodenum at 5 ml/min. Intestinal samples were taken continuously at 1 ml/min, 20 cm (at the angle of Treitz) and 45 cm distal to the perfusion point. To study the effect of lipids on griseofulvin absorption, the drug was perfused with solutions A and B, of which B contained a total lipid and caloric load three times that of A. The influence of bile salts on griseofulvin absorption was examined by perfusing the drug on Day 1 with bile salts and again on the following day after bile salt depletion. Bile salts and a varying quantity of lipid perfusate had no significant influence on the duodeno-jejunal griseofulvin absorption rate per cm of intestine. Lipids, however, may still play a role in griseofulvin absorption along the entire intestine.

Adult↗
PubMed1986

[Post-transfusion thrombopenia treated with gammaglobulins].

Thrombopenia and a haemorrhagic syndrome occurring on the eighth postoperative day were probably related to a post-transfusion purpura, confirmed by the discovery of antiplatelet antibodies not belonging to the PLA1 antigen system. The stabilization of this haemorrhage and a full recovery were obtained by giving high doses of intravenous human gammaglobulins. Blood replacement only rarely induces postoperative immuno-allergologic thrombopenia; heparin is the best known causative agent. It is concluded that platelets should never be given so long as the responsible agent is not formally identified.

Diagnosis, Differential↗
PubMed1986

In vitro binding study of gemfibrozil to human serum proteins and erythrocytes: interactions with other drugs.

The binding of gemfibrozil to human serum, isolated proteins and erythrocytes was studied in vitro by equilibrium dialysis. Our results show that this drug is highly bound to serum (99%) at therapeutic levels. Human serum albumin was shown to be mainly responsible for this binding (98.6%) with a saturable process characterized by two binding sites with a moderate affinity. Like many acidic drugs with a carboxylic acidic group, gemfibrozil showed none or negligible binding to alpha 1 acid glycoprotein, lipoproteins and gamma-globulins. The drug binding to erythrocytes is very low (0.8%). The unbound fraction in blood remains constant (0.8%) within the range of therapeutic concentrations. Moreover, interactions were studied with bilirubin and palmitic acid at pathophysiological concentrations and acenocoumarol, salicylic acid, valproic acid, furosemide, phenylbutazone, tolbutamide, warfarin and sulfamethoxazol at therapeutic concentrations. Neither endogenous compounds nor the other drugs studied altered gemfibrozil binding in serum. Likewise, the binding of warfarin to serum and to human serum albumin (600 microM) is not influenced by gemfibrozil.

Blood Proteins↗
PubMed1986

[Rational posology and drug dosage].

Serum level monitoring of drugs allows an optimal drug therapy, because it can take into account individual pharmacokinetic (and metabolic) variations. Some special conditions in drugs and in patients are highly suggestive of drug monitoring. These include mainly physiological but also pharmacological situations and apply to drugs with low therapeutic indices. However, for some drugs, highly bound to proteins or to blood cells, another more specific measurements will take in the future the place of serum level monitoring.

Aged↗
PubMed1986

Pharmacokinetics of warfarin in the nephrotic syndrome and effect on vitamin K-dependent clotting factors.

The behavior of warfarin, a drug tightly bound to albumin, was studied in patients with nephrotic syndrome (NS) to assess the influence of hypoalbuminemia on its pharmacokinetics and its effect on vitamin K-dependent coagulation factors. A single dose of warfarin (8 mg) was given orally to 11 nephrotic patients with normal or nearly normal renal function and to 11 controls. In every subject the following measurements were performed: albuminemia before (t0) warfarin administration; plasma warfarin and vitamin K-dependent coagulation factors (FII, FVII, FIX, FX) levels, before and at time intervals from 0 to 48 h after drug administration; warfarin urinary excretion from 0 to 24 h. Urinary warfarin excretion was null in 19 out of the 22 subjects and very low in two nephrotic patients and in one control. Low serum albumin in NS patients induced a twofold increase of unbound warfarin vs controls (3.5% vs 1.8%, p less than 0.001) which led to a threefold increase in plasma clearance of warfarin (9.70 vs 3.26 ml X min-1, p less than 0.001); as warfarin distribution volume showed only a slight (non significant) increase in NS patients, the elimination half-life was thus markedly shortened in NS patients vs controls (18 vs 36 h, p less than 0.01). Maximum warfarin effect on vitamin K-dependent factor levels occurred at 18 h in controls and 24 h in nephrotics, and these lowest values were similar, in spite of a higher level at 0 in NS patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Binding of bornaprolol to human serum proteins and blood cells.

The binding of 14C-bornaprolol to human serum proteins and to blood cells and platelets was studied by equilibrium dialysis and centrifugation. Bornaprolol binding to alpha 1-acid glycoprotein (n = 1.89, K = 433,900 M-1) was found to be a saturable phenomenon. By contrast, a non-saturable binding was observed with serum albumin (nK = 6.4 X 10(3) M-1), HDL (nK = 205 X 10(3) M-1), LDL (nK = 1,530 X 10(3) M-1), VLDL (nK = 2,342 X 10(3) M-1) and gamma globulins (nK = 25 X 10(3) M-1). The binding to blood cells was negligible. All the binding parameters were used to simulate the distribution of bornaprolol between serum proteins and blood cells over the range of therapeutic concentrations and showed that serum albumin, red blood cells and alpha 1 acid glycoprotein were the major binding components.

Blood Cells↗
PubMed1986

[Plasma binding of drugs in chronic renal failure].

As in many pathological states, changes in the plasma protein binding of drugs are observed in uremia. Renal failure reduces the fraction of many acidic drugs bound to serum albumin. This decreased binding is due to many factors: variations of protein concentrations, structural changes of proteins, competitive displacers in plasma of chronic uremic patients. When the margin between pharmacological and toxic doses is narrow, drug monitoring by measurement of plasma free drug concentrations seems necessary to adjust the dosage regimen in uremic patients.

Binding, Competitive↗
PubMed1985

Diclofenac binding to albumin and lipoproteins in human serum.

The binding of diclofenac to human serum albumin (HSA) and to lipoproteins was studied in vitro by equilibrium dialysis. Binding to HSA is characterized by two classes of sites with one site each (K1 = 5 X 10(5) M-1 and K2 = 0.6 X 10(5) M-1). The binding to lipoproteins was shown to be saturable with a larger number of binding sites and low association constants. The evidence of two specific binding sites on HSA was confirmed by circular dichroism data. In addition, an identification of those sites was performed by displacement of fluorescent probes. The data show that the high affinity site (K1 = 5 X 10(5) M-1) is likely to be shared by benzodiazepines while the second one (K2 = 0.6 X 10(5) M-1) is common with the warfarin site.

Binding Sites↗
PubMed1985

Protein binding of propisomide.

This paper describes the protein binding of propisomide to human serum and isolated proteins using equilibrium dialysis. The drug is exclusively bound to alpha1-acid glycoprotein with high affinity. The binding is saturable even at low concentrations of the drug. Thus, the fraction unbound varied from 0.05 to 0.60 with decreasing serum concentration. The major metabolite of the drug or other drugs with affinity for alpha1-acid glycoprotein can displace propisomide from its binding site only when present in serum at high levels. Two ultrafiltration techniques are compared to equilibrium dialysis for the determination of serum protein binding of propisomide. Ultrafiltration does not give reliable results. Equilibrium dialysis is retained as an accurate method for the determination of the fraction unbound of propisomide.

Adult↗