[Spinal cord injuries and corticotherapy. The NASCIS II study and feasibility].
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Acute Disease↗
Biomedical subjects
J Barré
Publications and source records attributed to J Barré.
[Intraoperative posture in the surgery of lumbar disk hernia].
For surgery of the lumbar disc, with a posterior route, the patient is placed either in a prone, or a knee-chest, or a lateral position. They aim at facilitating the surgical access in decreasing local bleeding and collapsing the dural sheath. This benefit, as a result of the maintenance of the pressure in the epidural venous system at a low level, is obtained through the absence of any abdominal compression as well as the posture. In the prone position, the abdominal compression and the increase of the physiologic lordosis impair the systemic venous return and carry the risk of cardiac arrest. In addition to these adverse effects, the conventional knee-chest position increases the haemodynamic repercussions in modifying the distribution of blood volume and increasing the potential risk of mediastinal compression and air embolism. The lateral position generates only minor haemodynamic modifications, except in the obese. However it is difficult to stabilize the patients' position and to maintain the alignment of the spine. Therefore it is used the less one. The postural risks of all three positions are numerous and include mainly the compression of nerves, vessels and skin. Finally the selection of the position depends basically on morphological criteria and the adaptative capacities of the patient. The optimal position is the one offering a low pressure level in the spinal venous system, while maintaining the venous return.
Anesthesia, General↗
Effects of plasma lipid levels on blood distribution and pharmacokinetics of cyclosporin A.
The present study attempted to characterize the distribution of cyclosporin A (CsA) among the lipoprotein fractions, very-low-, intermediate-, low-, and high-density (VLDL, IDL, LDL, and HDL, respectively) in the plasma of patients awaiting heart transplantation and the influence of plasma lipid constituents on the pharmacokinetics of CsA. Major fractions of a therapeutic concentration of CsA were found in HDL and in LDL. In addition, plasma lipid concentrations (total cholesterol, triglycerides, phospholipids, VLDL-cholesterol--TC, TG, PL, VLDLc, respectively) are positively correlated with the CsA distribution within the LDL fraction, and negatively correlated with the CsA distribution within the HDL fraction. Thus, the percentage of CsA in each type of lipoproteins was shown to vary with the lipid levels among individuals. A significant negative correlation was found between apparent distribution volume at steady state (Vss) in plasma and TC, PL, and LDLc and between the area under the curve measured in blood (AUCB) for whole blood and PL.
Adult↗
Dextromethorphan O-demethylation and dextrorphan glucuronidation in a French population.
The dextromethorphan (DMP) O-demethylation and the dextrorphan (DRP) glucuronidation distributions were studied in 120 French Caucasian subjects. After a single 25 mg DMP oral administration, DMP, free and total DRP concentrations were measured in 8h-urine collection, using an HPLC technique with fluorescent detection. The DMP and free DRP concentrations ratio, in log form, was used to estimate the oxidative demethylation phenotype of the subjects. Two different populations were found. The first one consisted of the extensive metabolizers (90.8%, 95% confidence interval from 85.6 to 95.9%) and the second one consisted of poor metabolizers (9.2%, 95% confidence interval from 4.0 to 14.4%). The antimode value of the distribution was estimated at approximately 0.7 corresponding to a ratio of 5. Moreover, this ratio was compared to the DMP and total DRP concentrations ratio, usually defined to DMP O-demethylation phenotyping. On the other hand, the glucuronide DRP concentration was calculated by subtracting the free DRP concentration from the total DRP concentration. Consequently, the free DRP and glucuronide DRP concentrations ratio was also used to estimate the DRP glucuronidation in the present population. This ratio in log form reflected the UDP-glucuronyltransferase(s) capacity(ies). This log ratio appeared to be normally distributed in the population studied. These results show that log DMP/free DRP ratio can be used, as well as log DMP/total DRP ratio, to determine the oxidative phenotype of subjects and that the DRP conjugation does not exhibit any apparent genetic polymorphism.
Administration, Oral↗
pH titration curves of the desialylated human alpha 1-acid glycoprotein variants by combined isoelectrofocusing-electrophoresis: utilization in the development of a fractionation method for the protein variants by chromatography on immobilized metal affinity adsorbent.
Using a two-dimensional isoelectrofocusing (IEF)-electrophoresis technique, the pH titration curves of the three main desialylated variants (F1, S and A) of human alpha 1-acid glycoprotein (AAG) were studied to assist in the development of a fractionation method for the AAG variants. For this purpose, different AAG samples, each corresponding to one of the three main phenotypes of the protein (F1S/A, F1/A and S/A), were first purified by chromatographic separation of individual human plasma samples on immobilized Cibacron Blue F3G-A. The purified AAG samples were then disialylated and their heterogeneity was checked by analytical IEF. The pH-mobility curves of the desialylated AAG samples were displayed in polyacrylamide gel slabs, under a constant set of experimental conditions, by carrying out electrophoresis of the protein samples perpendicularly to two stationary pH gradients: a large gradient (pH 3.5-9.5) and a narrow gradient (pH 5-8). The curves showed that all the desialylated variants of AAG exhibited small charge differences and moved closely together between about pH 3.5-5.5 and pH 7.5-9.5. However, the variants were found to show microheterogeneity in their total charge between about pH 5.5 and 7.5 due to the titrated ionizable groups involved along this pH zone. This microheterogeneity was assumed to be accounted for by the existence of differences between the titratable histidyl residues of the AAG variants. Consequently, the interactions of the variants with immobilized transition metal ions were studied at pH 7, using affinity chromatography on an iminodiacetate Sepharose-Cu(II) gel. It was found that the A variant was strongly bound by immobilized Cu(II) ions, whereas the F1 and S variants interacted non-specifically with the immobilized ligand. This finding allowed the development of a rapid and effective fractionation method for desialylated AAG into its A and F1 or S variants, depending on the AAG phenotype, by chromatography on an immobilized affinity Cu(II) adsorbent. The quantitative relationships between immobilized Cu(II) ions and desialylated AAG (the apparent association constant and gel protein-binding capacity) were also determined using a non-chromatographic equilibrium binding technique.
Chromatography, Affinity↗
Pharmacokinetics of cefodizime: a review of the data on file.
Cefodizime is a new aminothiazolyl cephalosporin which may be administered iv or im. The absolute bioavailability im is almost 100%. The mean volume of distribution is approximately 6.2-8.51. Protein binding of cefodizime is 73-89% over the plasma concentration range. Cefodizime penetrates into several tissues and body fluids such as lung, sputum, pleural and ascitic fluids, prostate, kidney, and urine to give concentrations often exceeding the MICs of susceptible pathogens. Total body clearance is low (35-52 ml/min) and clearance is predominantly renal with up to 80% of an iv dose recovered unchanged in the urine. The pharmacokinetics are linear within the range of doses studied (0.5-2 g). The plasma concentration profile is best described by a triple exponential function. The ranges of half-lives reported are as follows: the distribution half-life is 0.2-0.5 h (accounting for 6-15% of the AUC), the beta half-life is 1.5-2.1 h (accounting for 56-76% of the AUC), and the terminal (gamma) half-life is 3.9-7.9 h (accounting for 18-43% of the AUC) After 2 g bd for five days in healthy volunteers, steady state was reached on the second administration, and no accumulation of the drug was noted. The total clearance is about 20% less in elderly subjects than in young adults, but no dosing adjustment is needed in the elderly. The pharmacokinetic profile is significantly altered in patients with a creatinine clearance less than 30 ml/min (three- to five-fold increase in half-life). Accordingly, the dose should be reduced to 50% of normal, at the same dosing interval.(ABSTRACT TRUNCATED AT 250 WORDS)
Biological Availability↗
Measurement of free drug in phase I: is it useful?
Early investigation of protein binding of a new drug is mandatory. The following questions have to be answered: is unbound fraction constant over tested concentrations? Which proteins are involved? What are the binding parameters? Can the drug compete with other therapeutic agents for the binding sites or in other words can drug displacements be predicted? What is the interindividual variability in protein binding? Is the binding stereoselective? All this information is necessary in predicting the pharmacokinetic behaviour of the drug and in assisting in the design of future pharmacokinetic protocols in phases II and III. The use of free drug concentration should also be considered when comparing the bioavailability of regular vs sustained release dosage forms of drugs exhibiting concentration-dependent binding and when studying concentration-effect relationships.
Drug Evaluation↗
Comparison of propranolol and sotalol pharmacokinetics in obese subjects.
Six obese subjects (mean +/- s.d. : 145.1 +/- 16.7% of ideal body weight) were randomly assigned to a single i.v. dose either of (+/-)-propranolol base (0.108 mg kg-1 of ideal body weight) or of (+/-)-sotalol base (1.06 mg kg-1 of ideal body weight). Each subject received the other drug 7 days later. Pharmacokinetic parameters were compared with those obtained previously in non-obese control subjects. In obese subjects, the pharmacokinetic data calculated for sotalol were comparable with those measured in controls (total body clearance = 9.4 +/- 2.9 L h-1; volume of distribution during the terminal phase = 79.8 +/- 19.8 L or 0.9 +/- 0.2 L kg-1; terminal half-life = 6.2 +/- 1.6 h). For propranolol, total clearance (44.3 +/- 15.9 L h-1) and volume of distribution (230.5 +/- 48.2 L or 2.7 +/- 0.7 L kg-1) were significantly less than control values. The terminal half-life (3.9 +/- 1.1 h), was not significantly increased. These results could be explained by altered tissue blood flow and a decreased metabolic capacity of the liver in obese subjects.
Adult↗
Disease-induced variations in plasma protein levels. Implications for drug dosage regimens (Part I).
Many diseases appear to lead to a decrease of drug plasma binding due either to hypoalbuminaemia or to a modification of albumin structure. In other diseases, the binding of a drug may increase due to elevated concentrations of alpha 1-acid glycoprotein or lipoproteins. However that may be, the free fraction of a drug may vary in different pathologies. But an increase or decrease of the drug free fraction does not automatically mean an increase or decrease of the free drug concentration. Whatever the drug, a variation in the volume of distribution more or less proportional to the variation in the plasma free fraction can be expected. With respect to the clearance, the problem is much more complex and depends on the hepatic extraction ratio of drug. If the extraction is related to the free fraction (fu) of drug, a variation in fu will lead to a variation in the total drug concentration but no variation in the free drug concentration and no change in the pharmacological effect. If the extraction of a drug is dependent on hepatic flow, a variation in fu will lead to a change in the free drug concentration (with no change in the total drug concentration) and hence changes in the pharmacological effect. The aim of this article is to review the literature concerning disease-induced variations in plasma protein levels during the past 10 years. Finally, possible implications for drug dosage regimens are discussed generally from examples studies in the literature.
Animals↗
Disease-induced variations in plasma protein levels. Implications for drug dosage regimens (Part II).
Part I of this article, which appeared in the previous issue of the Journal, discussed the implications of variations in plasma protein levels in a number of diseases: hepatic and renal disease, acute myocardial infarction, burns, cancer, diabetes mellitus, hyperlipidaemia and inflammatory diseases. In Part II the authors continue their review with a further range of disease states, and consider their import for drug dosages.
Animals↗
[Pharmacokinetic properties of cefixime].
After a 200 mg intravenous or oral dose, the absolute bioavailability of cefixime, evaluated by comparison of areas under the serum concentration-time curve values, is 50 per cent. Because food has no effect on peak serum concentrations or on the extent of drug absorption, cefixime can be taken with or without meals. Protein binding is 70 per cent. Cefixime is cleared, mainly unchanged, partly by the liver (60 per cent) and partly by the kidneys (40 per cent). The elimination half-life varies between 3 and 4 hours. Plasma concentrations increase linearly but not proportionally to doses. No significant accumulation was observed after repeated administration in young and elderly subjects. The pharmacokinetic profile of cefixime is significantly altered in patients with marked renal impairment (creatinine clearance less than 20 ml/min), and in such cases dosage should be reduced from 400 to 200 mg/day. Haemodialysis or peritoneal dialysis do not remove significant amounts of the drug from the body. In cirrhotic patients, no dosage adjustment is needed, although the elimination half-life is increased twofold (congruent to 6.5 hours). The extravascular and tissue diffusion of cefixime is satisfactory in those areas where the organisms need to be eradicated.
Administration, Oral↗
In vitro studies on the blood distribution of almitrine.
Blood binding of almitrine, a highly lipophilic drug, was investigated in vitro. [3H]-Almitrine was incubated in a serum pool and isolated protein and lipoprotein fractions. The investigations were performed by using ultracentrifugation and another method which measures the uptake by proteins from glass beads coated with almitrine. Our results with ultracentrifugation show that the distribution of almitrine in serum takes place predominantly in the lipoprotein fraction (78%) and to a minor extent (22%) in the fraction of d greater than 1.20 (albumin-rich fraction). Experiments using glass beads coated with almitrine were then conducted to measure the binding of almitrine to isolated plasma proteins. The maximal uptake values (mol almitrine/mol lipoprotein) of almitrine by isolated lipoproteins decrease from VLDL (260) to LDL (20) to HDL (3) and seem to be related to the lipid content of the particles. The uptake by albumin and alpha 1-acid glycoprotein was low. The molar ratios of [almitrine]/[lipoprotein] are roughly proportional to almitrine concentrations within the therapeutic range. When almitrine was incubated in erythrocytes suspended in several dilutions of serum, almitrine partitioned less in erythrocytes as the serum protein concentration increased in the suspension.
Almitrine↗
Blood binding and tissue transfer of drugs: the influence of alpha 1 acid glycoprotein binding.
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Animals↗
[In vitro study of ceftriaxone binding to blood].
Binding of ceftriaxone, a new third generation cephalosporin, to blood was studied in vitro. Steady state dialysis with 14C-ceftriaxone was used. Percentages of ceftriaxone bound to plasma within the range of therapeutic concentrations (10 to 1,000 microM) varied widely (80 to 50%). Indicating that the binding process is saturable, investigations performed with various isolated plasma proteins in physiologic concentrations show that ceftriaxone binds mainly to albumin, and marginally or not at all to alpha-1-acid glycoprotein, gammaglobulins, transferrin, haptoglobin, and lipoproteins. Albumin has a single binding site (n = 0.7) with moderate affinity (Ka = 72,000 M-1) for ceftriaxone. The presence of this site explains why ceftriaxone binds to plasma according to a saturable process. Only a small proportion (5%) of ceftriaxone (75-450 microM) binds to red blood cells in whole blood with a 50% hematocrit. A strongly significant inhibition of ceftriaxone (520 microM) binding to plasma was found with high bilirubin levels (230 microM) (24% decrease; p less than 0.01). A small but significant decrease in ceftriaxone (380 microM) binding to plasma was found with high serum oleic acid (1014 microM) or uric acid (1,800 microM) concentrations (2% decrease; p less than 0.05).
Bilirubin↗
Binding of minaprine to human serum proteins and erythrocytes.
The binding of minaprine to human serum, isolated proteins and erythrocytes was studied in vitro. This drug shows both a saturable and a nonsaturable binding process in serum. The drug is bound to alpha 1-acid glycoprotein in a saturable fashion with a moderate affinity whereas albumin is involved in the nonsaturable and major binding. The combination of these two processes results in a slight decrease (7%) in the drug binding to serum within the range of therapeutic concentrations. Competitive binding with metabolites of minaprine or with other basic drugs seems unlikely when these compounds are present in serum at therapeutic levels. The binding of minaprine to erythrocytes remains constant within the range of therapeutic concentrations.
Blood Proteins↗
Equilibrium dialysis, ultrafiltration, and ultracentrifugation compared for determining the plasma-protein-binding characteristics of valproic acid.
Equilibrium dialysis, ultrafiltration, and ultracentrifugation were compared to determine their reliability and applicability in the study of binding of an anticonvulsant drug, valproic acid, by plasma proteins. We studied drug binding with pooled serum and with solutions of human serum albumin at physiological concentrations. We compared binding characteristics such as number of binding sites, affinity constants, and percent of binding as measured by each method in the therapeutic range for valproic acid. Results by ultracentrifugation differed from those by equilibrium dialysis and ultrafiltration, which agreed reasonably well with each other.
Blood Proteins↗
Liquid-chromatographic determination of propisomide and its mono-N-dealkylated metabolite in plasma and urine.
We describe a "high-performance" liquid-chromatographic assay for simultaneously determining propisomide and its mono-N-dealkylated metabolite in plasma and urine. After extraction with dichloromethane at alkaline pH, the unchanged drug, its metabolite, and the internal standard are separated by liquid chromatography on a reversed-phase column and the absorbance of the eluate is measured at 254 nm. Selectivity, sensitivity, and reproducibility are excellent. Results are similar to those by gas chromatography for propisomide but, in addition, the metabolite can be simultaneously measured in the same clinical sample. We also report results by this method for blood and plasma samples from a volunteer receiving a single 200-mg dose of propisomide.
Anti-Arrhythmia Agents↗
Effect of hyperbilirubinaemia on the plasma protein binding of chlorophenoxyisobutyric acid in neonates.
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Bilirubin↗