PKQuest: a general physiologically based pharmacokinetic model. Introduction and application to propranolol

BACKGROUND: A "physiologically based pharmacokinetic" (PBPK) approach uses a realistic model of the animal to describe the pharmacokinetics. Previous PBPKs have been designed for specific solutes, required specification of a large number of parameters and have not been designed for general use. METHODS: This new PBPK program (PKQuest) includes a "Standardhuman" and "Standardrat" data set so that the user input is minimized. It has a simple user interface, graphical output and many new features: 1) An option that uses the measured plasma concentrations to solve for the time course of the gastrointestinal, intramuscular, intraperotineal or skin absorption and systemic availability of a drug – for a general non-linear system. 2) Capillary permeability limitation defined in terms of the permeability-surface area products. 4) Saturable plasma and tissue protein binding. 5) A lung model that includes perfusion-ventilation mismatch. 6) A general optimization routine using either a global (simulated annealing) or local (Powell) minimization applicable to all model parameters. RESULTS: PKQuest was applied to measurements of human propranolol pharmacokinetics and intestinal absorption. A meal has two effects: 1) increases portal blood flow by 50%; and 2) decreases liver metabolism by 20%. There is a significant delay in the oval propranolol absorption in fasting subjects that is absent in fed subjects. The oral absorption of the long acting form of propranolol continues for a period of more than 24 hours. CONCLUSIONS: PKQuest provides a new general purpose, easy to use, freely distributed and physiologically rigorous PBPK software routine

Collagen-Like Proteins in Pathogenic E. coli Strains

The genome sequences of enterohaemorrhagic E. coli O157:H7 strains show multiple open-reading frames with collagen-like sequences that are absent from the common laboratory strain K-12. These putative collagens are included in prophages embedded in O157:H7 genomes. These prophages carry numerous genes related to strain virulence and have been shown to be inducible and capable of disseminating virulence factors by horizontal gene transfer. We have cloned two collagen-like proteins from E. coli O157:H7 into a laboratory strain and analysed the structure and conformation of the recombinant proteins and several of their constituting domains by a variety of spectroscopic, biophysical, and electron microscopy techniques. We show that these molecules exhibit many of the characteristics of vertebrate collagens, including trimer formation and the presence of a collagen triple helical domain. They also contain a C-terminal trimerization domain, and a trimeric α-helical coiled-coil domain with an unusual amino acid sequence almost completely lacking leucine, valine or isoleucine residues. Intriguingly, these molecules show high thermal stability, with the collagen domain being more stable than those of vertebrate fibrillar collagens, which are much longer and post-translationally modified. Under the electron microscope, collagen-like proteins from E. coli O157:H7 show a dumbbell shape, with two globular domains joined by a hinged stalk. This morphology is consistent with their likely role as trimeric phage side-tail proteins that participate in the attachment of phage particles to E. coli target cells, either directly or through assembly with other phage tail proteins. Thus, collagen-like proteins in enterohaemorrhagic E. coli genomes may have a direct role in the dissemination of virulence-related genes through infection of harmless strains by induced bacteriophages

Merchants, Smugglers, and Pirates: Multinational Clandestine Trade on the South China Coast, c. 1520-1550'

Texture (preferred orientation) has a significant influence on the formability of metals. This was shown experimentally for rolled steel sheet by Stickels and Mould [1]. They found a correlation between the in-plane angular variation of r-value and the anisotropy of Young’s modulus, E, as measured by ultrasonics. The r-value is a measure of plastic strain on deep drawing, defined as ϵyy/(∈yy + ∈zz), with ∈yy the in-plane strain and ∈zz the strain in the thickness direction

Does the 5-HT1A rs6295 polymorphism influence the safety and efficacy of citalopram therapy in the oldest old?

Major depressive disorder (MDD) in older people is a relatively common, yet hard to treat problem. In this study, we aimed to establish if a single nucleotide polymorphism in the 5-HT1A receptor gene (rs6295) determines antidepressant response in patients aged > 80 years (the oldest old) with MDD. Nineteen patients aged at least 80 years with a new diagnosis of MDD were monitored for response to citalopram 20 mg daily over 4 weeks and genotyped for the rs6295 allele. Both a frequentist and Bayesian analysis was performed on the data. Bayesian analysis answered the clinically relevant question: ‘What is the probability that an older patient would enter remission after commencing selective serotonin reuptake inhibitor (SSRI) treatment, conditional on their rs6295 genotype?’ Individuals with a CC (cytosine–cytosine) genotype showed a significant improvement in their Geriatric Depression Score (p = 0.020) and cognition (p = 0.035) compared with other genotypes. From a Bayesian perspective, we updated reports of antidepressant efficacy in older people with our data and calculated that the 4-week relative risk of entering remission, given a CC genotype, is 1.9 [95% highest-density interval (HDI) 0.7–3.5], compared with 0.52 (95% HDI 0.1–1.0) for the CG (cytosine–guanine) genotype. The sample size of n = 19 is too small to draw any firm conclusions, however, the data suggest a trend indicative of a relationship between the rs6295 genotype and response to citalopram in older patients, which requires further investigation