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Biomedical subjects

K F Brown

Publications and source records attributed to K F Brown.

At least 55 records · Page 3Linked to original sources
PubMed1983

Determinants of d-tubocurarine plasma protein binding in health and disease.

d-Tubocurarine protein binding was determined in plasma from normal surgical patients; patients with renal dysfunction; patients with alcoholic cirrhosis; and patients scheduled for coronary artery surgery and was compared with binding determined in solutions of isolated human serum albumin (HSA). The free fraction of d-tubocurarine was independent of plasma drug concentration throughout the range 0.1-3.0 micrograms/ml. The free fraction of d-tubocurarine in renal disease (0.44 +/- 0.05), liver disease (0.53 +/- 0.05), and cardiac disease (0.49 +/- 0.05) was not significantly different from that in normal patients (0.50 +/- 0.04). Furthermore, the free fraction of d-tubocurarine was unrelated to plasma concentrations of total protein, total globulin, albumin, total lipids, or alpha 1-acid glycoprotein in the four patient groups. The free fraction of d-tubocurarine (0.55 +/- 0.02, n = 7) in solutions of HSA (0.58 mM) was similar to that observed in plasma. Albumin, therefore, appears to be the major plasma binding protein for d-tubocurarine.

Adolescent↗
PubMed1982

Diazepam plasma binding in the perinatal period: influence of nonesterified fatty acids.

The plasma binding of diazepam was determined serially in 24 women undergoing either elective induction of labour (vaginal or emergency caesarean delivery) or elective caesarean section at term and in 5 nonpregnant women requiring abdominal surgery. In the majority of pregnant patients, a marked increase in diazepam percentage free was observed during labour or prior to caesarean section, reaching a maximum, 1.6 to 3.2 fold increase at delivery or within 4 h postpartum; by the fifth day postpartum, diazepam percentage free was lower than on admission to hospital. In contrast, little change in diazepam percentage free was observed during the perisurgical period in nonpregnant patients. In parturient and surgical patients, the time courses of diazepam percentage free and plasma nonesterified fatty acid (NEFA) concentration were parallel. Bivariate regression analyses of pooled data demonstrated a strong correlation (r = 0.642, p = less than 0.010 between diazepam percentage free and corresponding NEFA concentration and a weaker correlation between diazepam percentage free and both albumin (r = 0.319, p less than 0.02) or total protein (r = 0.438, p less than 0.01). From multiple linear regression it was demonstrated that 54% of the variability in diazepam percentage free could be attributed to plasma NEFA and albumin concentrations. NEFA displacement of plasma bound diazepam was substantiated using crystalline human serum albumin. An approximate 65% increase in plasma alpha 1 acid glycoprotein levels was observed posttrauma in both parturient and surgical patients but was unrelated to diazepam binding events. A relationship between diazepam plasma binding changes and concurrently altered disposition of diazepam during parturition is postulated.

Adult↗
PubMed1981

Ultrafiltration in serum protein binding determinations.

the ultrafiltration technique was evaluated theoretically and experimentally for use in clinical serum binding determinations. It is apparent from free energy considerations that the ultrafiltrate concentration approaches the true free concentration only as the pressure gradient causing flow reduces to zero. The theory presented accounts for the previously unexplained lower ultrafiltrate concentration observed at higher filtration pressures. Mathematical simulations of the molecular separation show that the ultrafiltrate concentration remains constant during filtration, and, thus, binding equilibria are not disturbed by this procedure, suggesting that an arbitrary restriction on the volume filtered is unnecessary. This finding greatly extends the value of the ultrafiltration technique in clinical binding determinations, especially for strongly bound, potent drugs where assays may be insufficiently sensitive to detect the extremely small free fraction reliably. These theoretical findings were verified experimentally by ultrafiltration of salicylate, ibuprofen, and carprofen in buffer, purified proteins, and whole serum.

Blood Proteins↗
PubMed1981

Transsynovial distribution of ibuprofen in arthritic patients.

Free and total ibuprofen levels in serum and synovial fluid (SF) were determined in one male and 14 female arthritic patients (mean age 56 yr, range 19 to 77) after 400 mg three times daily for 2 days. Free drug was separated by ultrafiltration and assayed by a new highly sensitive and precise gas chromatographic-mass spectrometric technique. Total protein and albumin were assayed by automatic analyzer, and the routine serum biochemical profile obtained. Serum and SF nonesterified fatty acids (NEFAs) were methylated and assayed by gas chromatography. While both total protein and albumin levels were lower (P less than 0.01) in SF, NEFA levels did not differ (p greater than 0.05). Ibuprofen readily partitions into and binds strongly to joint fluid, the total level being about half that in serum. The ratio of total ibuprofen in SF to that in serum (x = 0.41 +/- 0.17) correlated with the albumin concentration ratio (r = 0.886) indicating that albumin binding is an important determinant of ibuprofen transsynovial distribution. A low total ibuprofen SF/serum ratio, apparent for three patients on concomitant aspirin therapy, is consistent with reports of an ibuprofen-salicylate interaction. Free ibuprofen in SF (0.192 +/- 0.086 microgram ml-1) did not differ (p greater than 0.05) from serum free levels (x = 0.251 +/- 0.139 microgram ml-1), supporting the concept of the synovial cavity as a compartment readily accessible to unbound drug species. Multiple regression analyses revealed relative independence of free concentration on total levels, and the small positive and negative influences of NEFAs and albumin concentrations. Bilirubin, uric acid, cholesterol, triglycerides, and chloride ion did not correlate with serum free concentration.

Adult↗
PubMed1977

General class of multiparticulate dissolution models.

The dissolution of multiparticulate systems under sink and nonsink conditions can be described rigorously according to a generally applicable formula on the basis of the single-particle dissolution model and the initial particle distribution. The kinetic model for log-normal systems dissolving under sink conditions is extended to nonsink conditions as a specific example. The equation presented describes a general class of multiparticulate models for various values of the dispersion parameter and the dissolution capacity coefficient.

Kinetics↗
PubMed1977

Method of obtaining drug-macromolecule binding parameters directly from dynamic dialysis data.

A new method of treating dynamic dialysis data to obtain binding parameters for drug-macromolecule interactions is presented. This method allows the determination of binding parameters directly from dialysis data according to a theoretical model. It is not necessary to determine the dialysis rate constant accurately in a separate experiment, and bias is not introduced due to differentiation. The proposed method should be applicable where the drug is substantially bound to the dialysis membrane.

Albumins↗
PubMed1976

Theoretical isotropic dissolution of nonspherical particles.

Equations are derived for the isotropic dissolution of single particles, considering simple forms of the six crystal systems. These can be summarized by three basic equations which are approximated well, and in some cases exactly, by the dissolution equation for a hypothetical spherical particle of specified diameter. Formulas are given to enable calculation of this diameter and to minimize the weighted errors in the approximations. Spherical approximations provide a simple basis for calculating the dissolution profile of real multiparticulate systems which are difficult to describe otherwise. Spherical approximations based on equal surface area or volume result in large errors.

Crystallization↗
PubMed1976

Experimental evaluation of three single-particle dissolution models.

The dissolution of the 60-85-mesh fraction os recording, flow-through dissolution apparatus equipped with a dissolution cell; it was particularly suitable for kinetic analysis of multiparticulate systems. By using a time-scaling approach, experimental data are compared with theoretical calculations to evaluate, quantitatively, which of three single-particle dissolution models best describes the data and how well the multiparticulate kinetics can be explained mathematically. The nonspherical tolbutamide particles are replaced in the calculations by a hypothetical system of spherical particles that appears to be log-normally distributed. This procedure permits the calculation of the intrinsic dissolution profile, considering both size distribution and particle shape effects.

Kinetics↗
PubMed1975

Dissolution profile in relation to initial particle distribution.

A general equation was derived describing the complete and exact dissolution profile of powders under sink conditions. It is applicable to powders having any initial particle-size distribution, with particles dissolving according to any explicit equation. It was applied to develop an equation for the dissolution of log-normal powders that is more generally applicable than previous approaches. The effect of change in initial particle-size distribution parameters on the dissolution profile is illustrated.

Computers↗
PubMed1975

Size distribution effects in multiparticulate dissolution.

The evaluation of models for single-particle dissolution, based on multiparticulate dissolution data, is complicated by the distribution effect present when the particles are not truly monodispersed. By using simulated data, it is shown that remarkably good linearity can be obtained with log-normal powders using an incorrect model. It is suggested that particle-size analysis is necessary to enable calculation of the distribution effect and to prevent this type of misinterpretation. The change in particle-size distribution during dissolution is calculated and shows potential for distinguishing between two, but not all three, of the models investigated. Four theoretical rules for multiparticulate dissolution are stated and discussed. The concept of "time scaling" is presented. By using this procedure, it should be possible to reduce considerably computational errors arising from nonlinear dissolution data. It is demonstrated that dissolution profiles can be transformed to a standard form, enabling the distribution effect to be evaluated without interference from rate or particle-size parameters.

Kinetics↗