Lidia J. Notarianni

Plasma Protein Binding of Drugs in Pregnancy and in Neonates

SummaryPlasma protein binding of drugs has important implications for drug disposition and action since it is the first, and controlling, step in drug distribution. Physiological changes in pregnancy include significant changes in plasma composition which affect drug binding and subsequent drug response; the extent of these changes depends on the stage of gestation. Both albumin and α1-acid glycoprotein fractions are reduced, and consequently the binding of both acidic and basic drugs may be affected. This may lead to difficulties in maintaining adequate plasma concentrations of highly protein-bound drugs, since the measurement of total drug concentration in plasma may no longer be a valid indicator for dose adjustment.The newborn infant displays a continually changing plasma profile. The presence of fetal proteins and endogenous substrates known to interfere with drug binding can lead to unexpected complications due to a higher than expected ‘free’ drug fraction. Furthermore, a decrease in the affinity of albumin for bilirubin during this period may lead to bilirubin displacement by drugs such as diazepam, sulphonamides and salicylate, resulting in clinical jaundice which would not occur beyond the neonatal period. Plasma composition and its effect on drug binding should be taken into account when prescribing highly protein bound drugs with narrow therapeutic: toxic ratios.

Crystallization behaviour and drug release from bacterial polyhydroxyalkanoates

Abstract Crystalline polyhydroxyalkanoates (PHAs) such as poly- d (−)3-hydroxybutyrate (PHB) and its copolymers with poly-3-hydroxyvalerate (P(HB-HV)) are produced by a wide variety of bacteria and have uses in controlled drug delivery systems. The crystallization kinetics and morphology of P(HB-HV) polyesters both with and without the incorporation of a model drug, Methyl Red, have been investigated, as they are thought to influence drug release characteristics. The influence of copolymer composition and incorporation of Methyl Red on radial growth rates, G, of PHB and P(HB-HV) copolymer spherulites were investigated using polarized light video-microscopy. Growth curves could be obtained over a wide range of undercoolings for all the copolymers studied. At a given crystallization temperature, G decreased with increasing HV content and with increasing drug concentration in polymer spherulites. Spherulite morphology appeared to be a complex function of polymer molecular weight, copolymer composition, drug loading and crystallization temperature (Tc). Release of Methyl Red from melt-crystallized matrices of these PHAs was a function of Tc and copolymer composition. Drug release from isothermally crystallized copolymer films occurred progressively more rapidly with increasing HV content. This could be explained by the progressively poorer drug entrapment within copolymer matrices with increasing HV content. In PHB, Methyl Red was thought to be largely entrapped within spherulites (interlamellar regions) but for copolymers with increasing HV content, progressively greater amounts of drug were excluded at the spherulite surface and at interspherulitic boundaries.

Rapid and simple chromatographic method for the determination of diazepam and its major metabolites in human plasma and urine

A simple, rapid, sensitive and selective HPLC method has been developed for the analysis of diazepam (DZP) and its major metabolites, N-desmethyldiazepam (DMDZP), temazepam (TZP) and oxazepam (OZP), in plasma and urine, using clonazepam (CZP) as the internal standard and chloroform as the extracting solvent, with a 10 ng/ml limit of quantitation for the four assayed drugs, and an average (+/-S.D.) recovery of 87.7+/-6.46%, 92.9+/-5.31%, 91.4+/-4.01% and 91.7+/-2.68% for DZP, DMDZP, TZP and OZP, respectively (from plasma), and 89.6+/-2.26%, 90+/-4.24%, 87.45+/-0.64% and 94.50+/-0.71% for DZP, DMDZP, TZP and OZP, respectively (from urine). The method has also proved to be selective and reproducible.

Rapid method for the routine determination of caffeine and its metabolites by high-performance liquid chromatography.

Caffeine is a popular compound for phenotyping individuals for CYP4501A2, xanthine oxidase (XO) and N-acetyltransferase (NAT) utilising urinary metabolites. The analysis is complex since at least thirteen metabolites are excreted by man. Past methods have been less than satisfactory in that either not all the metabolites have been resolved and/or extractions selective for particular groups of metabolites are required prior to chromatography. We report a method for the rapid analysis of caffeine and metabolites in urine that negates the requirement for an extraction step, and also a method for plasma analysis.

A Reassessment of the Treatment of Salicylate Poisoning

SummaryThe treatment of salicylate poisoning is ased on the prevention of further absorption, and enhancement of excretion of already absorbed drug. A variety of methods based on this rationale have been used over the years. One of the more popular and successful treatments has been forced alkaline diuresis to encourage excretion. This technique, however, is not without risk and has now been replaced with alkalinisation alone, which has been shown to be safer and equally successful. The use of activated charcoal as an acute adsorbing agent for drug still in the upper gastrointestinal tract is beneficial in minimising further absorption. A recent development in the use of activated charcoal is the administration of multiple doses which are believed to enhance elimination of absorbed drug. The charcoal adsorbs salicylate diffusing back into the gut from the coeliac and mesenteric blood vessels thereby effectively eliminating it — a form of ‘internal peritoneal dialysis’. Multiple-dose activated charcoal and alkalinisation are currently the most popular methods of treatment.

The influence of crystalline morphology and copolymer composition on drug release from solution cast and melt-processed P(HB-HV) copolymer matrices

Abstract Crystalline poly- D (−)-3-hydroxybutyrate (PHB) and its copolymers with poly-3-hydroxyvalerate [P(HB-HV)] are biodegradable polyhydroxyalkanoates with potential application in controlled drug delivery systems. Matrices of PHB and P(HB-HV) copolymers containing a model drug, methyl red, were prepared by solvent casting and melt-processing. Drug release from P(HB-HV) copolymer matrices produced by any given fabrication technique was dependent on copolymer composition. Progressively faster rates of drug release were obtained on increasing HV content. This could be explained by the different crystallization behaviour of P(HB-HV) copolymers. Evidence from polarized light microscopy of copolymer spherulites suggests that copolymer films with increasing HV content exhibit morphologies with decreasing abilities to entrap the model drug.

Evidence for the Internalization of [125I-TYR2, NLE4, D-PHE7] α-MSH following Binding to the MSH Receptor of B16 Murine Melanoma Cells

The mechanism of action of a-melanocyte stimulating hormone (a-MSH) is thought to be receptor-mediated induction of CAMP, which in turn produces an increase in tyrosinase and melanin content. a-MSH is a 13 amino acid peptide that binds to melanoma cells. Previous studies have suggested that binding occurs at the cell surface without internalization,’ In this study, the internalization of [‘251-Tyr2,Nle4,~-Phe7]a-MSH following binding by B 16 mouse melanoma cells has been investigated. The amount of peptide internalized was differentiated from surface-bound ligand by acid dissociation (pH 2.5) of surface-bound radiolabeled [1251-Tyr2,Nle4,~-Phe7]~-MSH.

Lignocaine kinetics in the rat.

After intravenous injection of lignocaine 2·5, 5·0 or 10·0 mg kg−1 in the rat blood concentration declined in a bi‐exponential manner. The data were analysed according to a two‐compartment open model with elimination from the central compartment. Analysis of variance revealed no significant differences in k12, k21, k13, t1/2α, t1/2β, AUC or in the volume constants for the different doses used. After lignocaine 50·0, 70·0 or 90·0 mg kg−1 by mouth there was no significant change in t1/2β for the different doses or in peak plasma concentration normalized for dose. For both routes of administration blood concentration‐time curves were superimposible and AUC was linearly related to dose. Renal excretion was negligible. Systemic availability of lignocaine was the lowest of species so far studied (mean 0·019 ± 0·001) did not alter with dose, and was very similar to the values in the literature quoted for the isolated perfused liver. Clearance of lignocaine related to anticipated liver mass was almost identical to the values for liver blood flow quoted using other techniques. The data indicated high hepatic extraction of lignocaine by the intact rat and the absence of dose dependency within the range studied.

A Conformational Study of Two Cyclic Peptide Analogues of α‐MSH

The design of new a-melanocyte-stimulating hormone (a-MSH) agonists has recently received great impetus with the discovery that cyclic lactam analogues of a-MSH4-,, and a-MSH,-,,, bridged between positions 5 and 10, and with D-Phe at position 7, have melanotropic activity. Cyclic disulfide a-melanotropin analogues have long been known to be a class of a-MSH agonists. The discovery of a second group of cyclic agonists has great implications in the molecular modeling and computer-assisted design of new analogues: for example, the structurally

A Cleavable Biotinylated Photoactivable Derivative of α‐MSH: Its Application to the Characterization and Isolation of the α‐MSH Receptora

The presence of a-melanocyte-stimulating hormone (a-MSH) receptors on various mouse and human melanoma cell lines has been demonstrated by photoaffinity labeling.I.* The objective of this investigation was to develop an efficient method for the characterization and purification of the a-MSH receptor from B16 munne melanoma cells. The method described comprises three elements: (a) The synthesis of a cleavable biotinyiated photoactivable derivative of a-MSH. (b) The application of the streptavidin-biotin affinity system. (c) The use of magnetic beads as an immobilized support in place of conventional affinity columns.