Expanding clinical applications of population pharmacodynamic modelling

Population pharmacokinetics or pharmacodynamics is the study of the variability in drug concentration or pharmacological effect between individuals when standard dosage regimens are administered. We provide an overview of pharmacokinetic models, pharmacodynamic models, population models and residual error models. We outline how population modelling approaches seek to explain interpatient variability with covariate analysis, and, in some approaches, to characterize the unexplained interindividual variability. The interpretation of the results of population modelling approaches is facilitated by shifting the emphasis from the perspective of the modeller to the perspective of the clinician. Both the explained and unexplained interpatient variability should be presented in terms of their impact on the dose-response relationship. Clinically relevant questions relating to the explained and unexplained variability in the population can be posed to the model, and confidence intervals can be obtained for the fraction of the population that is estimated to fall within a specific therapeutic range given a certain dosing regimen. Such forecasting can be used to develop optimal initial dosing guidelines. The development of population models (with random effects) permits the application of Bayes's formula to obtain improved estimates of an individual's pharmacokinetic and pharmacodynamic parameters in the light of observed responses. An important challenge to clinical pharmacology is to identify the drugs that might benefit from such adaptive-control-with-feedback dosing strategies. Drugs used for life threatening diseases with a proven pharmacokinetic-pharmacodynamic relationship, a small therapeutic range, large interindividual variability, small interoccasion variability and severe adverse effects are likely to be good candidates. Rapidly evolving changes in health care economics and consumer expectations make it unlikely that traditional drug development approaches will succeed in the future. A shift away from the narrow focus on rejecting the null hypothesis towards a broader focus on seeking to understand the factors that influence the dose-response relationship--together with the development of the next generation of software based on population models--should permit a more efficient and rational drug development programme.     

Comparison of protein adsorption isotherms and uptake rates in preparative cation-exchange materials

Adsorption isotherms and effective diffusivities of lysozyme in a set of six preparative cation-exchange stationary phases were determined from batch uptake data in a stirred vessel. Both a pore diffusion and a homogeneous diffusion model were used in estimating diffusivities, with the isotherms fitted to a non-Langmuirian analytical isotherm equation. The capacities inferred from the isotherms are found to be correlated with the surface area accessible to lysozyme, the effective surface concentrations obtained being in agreement with values measured by different methods in various non-chromatographic systems. The pore diffusivities show systematic trends with protein and salt concentration, and effects of pore size and connectivity are also evident. Some trends in the homogeneous diffusivities are quite different to those in the pore diffusivities, but these differences largely disappear when the homogeneous diffusivities are rescaled to account for adsorption equilibrium behavior. Additional information is required to elucidate further the mechanisms of coupled diffusion and adsorption in stationary phases.     

Early modifications of chemokine production and mRNA expression during rush venom immunotherapy

The mechanism by which specific immunotherapy exerts its beneficial effect remains unclear. Chemokines are implicated in inflammatory and allergic diseases, in particular via their ability to induce histamine release from basophils, a potential early target of rush venom immunotherapy (RVIT), In this study, the authors evaluated ex vivo regulated upon activation normal T-cell expressed and secreted (RANTES), interleukin 8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) production and mRNA expression by mononuclear cells (MNC) from nine patients undergoing a 3.5-h ultra rush treatment, before treatment at Day 0 (D0), at the end of the 3.5-h of the rush at Day 4h (D4h), at Day 15 (D15) and Day 45 (D45) after treatment. Increased RANTES release and mRNA expression were observed in 24-h culture of peripheral blood MNC collected at D4h. This was followed by a decrease in the production of RANTES, IL-8 and MCP-1, 45 days after initiation of RVIT. The same pattern was observed after in vitro venom stimulation of MNC. At the mRNA level, similar profiles were observed except for IL-8 mRNA which inversely increased during RVIT. These results suggest that RVIT is associated with a general decrease in chemokines which may explain, in part, the clinical efficacy of specific immunotherapy.     

Reconstitution of DNA topoisomerase VI of the thermophilic archaeon Sulfolobus shibatae from subunits separately overexpressed in Escherichia coli

DNA topoisomerase VI from the hyperthermophilic archaeon Sulfolobus shibatae is the prototype of a novel family of type II DNA topoisomerases that share little sequence similarity with other type II enzymes, including bacterial and eukaryal type II DNA topoisomerases and archaeal DNA gyrases. DNA topoisomerase VI relaxes both negatively and positively supercoiled DNA in the presence of ATP and has no DNA supercoiling activity. The native enzyme is a heterotetramer composed of two subunits, A and B, with apparent molecular masses of 47 and 60 kDa, respectively. Here wereport the overexpression in Escherichia coli and the purification of each subunit. The A subunit exhibits clusters of arginines encoded by rare codons in E.coli . The expression of this protein thus requires the co-expression of the minor E.coli arginyl tRNA which reads AGG and AGA codons. The A subunit expressed in E.coli was obtained from inclusion bodies after denaturation and renaturation. The B subunit was overexpressed in E.coli and purified in soluble form. When purified B subunit was added to the renatured A subunit, ATP-dependent relaxation and decatenation activities of the hyperthermophilic DNA topoisomerase were reconstituted. The reconstituted recombinant enzyme exhibits a specific activity similar to the enzyme purified from S.shibatae . It catalyzes transient double-strand cleavage of DNA and becomes covalently attached to the ends of the cleaved DNA. This cleavage is detected only in the presence of both subunits and in the presence of ATP or its non-hydrolyzable analog AMPPNP.     

Hickman catheter-related infections in patients with cancer

There is strong evidence to support the hypothesis that the rapid effects of steroids on neurons are membrane-mediated. Rapid steroid effects have been demonstrated in the absence of intracellular receptors, in the presence of RNA or protein synthesis inhibitors, and in response to steroids coupled to large proteins that block access to intracellular receptors. This study selectively reviewed the emerging body of evidence suggesting that steroids have multiple sites of cellular actions, and explored in depth one possible membrane-mediated mechanism of action, the membrane-intercalation model.     

Synthesis and characterization of block copolymers from D,L-lactide and poly(tetramethylene ether glycol)

The copolymer from D ,L -lactide and poly(tetramethyene ether glycol) (PTMG) was prepared in bulk with an isotributyl aluminum–water–phosphoric acid complex catalyst as the initiator and characterized by H-NMR, GPC, and DSC. The effects of the temperature and the amount of PTMG on the polymerization rate and the molecular weight of copolymers were studied. The behavior of the degradation and delivery rate of Levonorgestrel microspheres in vitro was observed. The results show that the degradation and the delivery rate can be controlled by adjusting the molar rate of hydrophilic and hydrophobic segments of the copolymer © 1995 John Wiley & Sons, Inc.     

Synthesis ofE,E-diene hydroperoxides via photoisomerization of protected hydroperoxides

A general approach toE,E-diene hydroperoxides is described based upon photoisomerization of readily availableZ,E-diene monoperoxyketals. Protection of aZ,E-diene hydroperoxide as the 2-methoxypropyl peroxyketal is followed by iodine-mediated photoisomerization to produce a mixture enriched in theE,E isomer. After chromatographic purification, deprotection of the peroxyketal with mild acid furnishes theE,E-diene hydroperoxide.