Literature Review: Investigating Drug Transport at the Blood-Brain Barrier and the Effects of P-glycoprotein on the Brain Distribution of Drugs.

The blood-brain barrier (BBB) is a unique barrier that strictly regulates the entry of endogenous substrates and xenobiotics into the brain. This is due to its tight junctions and the array of transporters and metabolic enzymes that are expressed. The determination of brain concentrations in vivo is difficult, laborious and expensive which means that there is interest in developing predictive tools of brain distribution. Predicting brain concentrations is important even in early drug development to ensure efficacy of central nervous system (CNS) targeted drugs and safety of non-CNS drugs. The literature review covers the most common current in vitro, in vivo and in silico methods of studying transport into the brain, concentrating on transporter effects. The consequences of efflux mediated by p-glycoprotein, the most widely characterized transporter expressed at the BBB, is also discussed. The aim of the experimental study was to build a pharmacokinetic (PK) model to describe p-glycoprotein substrate drug concentrations in the brain using commonly measured in vivo parameters of brain distribution. The possibility of replacing in vivo parameter values with their in vitro counterparts was also studied. All data for the study was taken from the literature. A simple 2-compartment PK model was built using the Stella™ software. Brain concentrations of morphine, loperamide and quinidine were simulated and compared with published studies. Correlation of in vitro measured efflux ratio (ER) from different studies was evaluated in addition to studying correlation between in vitro and in vivo measured ER. A Stella™ model was also constructed to simulate an in vitro transcellular monolayer experiment, to study the sensitivity of measured ER to changes in passive permeability and Michaelis-Menten kinetic parameter values. Interspecies differences in rats and mice were investigated with regards to brain permeability and drug binding in brain tissue. Although the PK brain model was able to capture the concentration-time profiles for all 3 compounds in both brain and plasma and performed fairly well for morphine, for quinidine it underestimated and for loperamide it overestimated brain concentrations. Because the ratio of concentrations in brain and blood is dependent on the ER, it is suggested that the variable values cited for this parameter and its inaccuracy could be one explanation for the failure of predictions. Validation of the model with more compounds is needed to draw further conclusions. In vitro ER showed variable correlation between studies, indicating variability due to experimental factors such as test concentration, but overall differences were small. Good correlation between in vitro and in vivo ER at low concentrations supports the possibility of using of in vitro ER in the PK model. The in vitro simulation illustrated that in the simulation setting, efflux is significant only with low passive permeability, which highlights the fact that the cell model used to measure ER must have low enough paracellular permeability to correctly mimic the in vivo situation.

Mutation analysis of the SLC4A11 gene in Indian families with congenital hereditary endothelial dystrophy 2 and a review of the literature

Purpose: Congenital hereditary endothelial dystrophy 2 (CHED2) is an autosomal recessive disorder caused by mutations in the solute carrier family 4, sodium borate transporter, member 11 (SLC4A11) gene. The purpose of this study was to identify the genetic cause of CHED2 in six Indian families and catalog all known mutations in the SLC4A11 gene. Methods: Peripheral blood samples were collected from individuals of the families with CHED2 and used in genomic DNA isolation. PCR primers were used to amplify the entire coding region including intron-exon junctions of SLC4A11. Amplicons were subsequently sequenced to identify the mutations. Results: DNA sequence analysis of the six families identified four novel (viz., p.Thr262Ile, p.Gly417Arg, p.Cys611Arg, and p.His724Asp) mutations and one known p.Arg869His homozygous mutation in the SLC4A11 gene. The mutation p.Gly417Arg was identified in two families. Conclusions: This study increases the mutation spectrum of the SLC4A11 gene. A review of the literature showed that the total number of mutations in the SLC4A11 gene described to date is 78. Most of the mutations are missense, followed by insertions-deletions. The present study will be helpful in genetic diagnosis of the families reported here.

A literature survey on the real-time computational simulation of biological organs

This paper lists some references that could in some way be relevant in the context of the real-time computational simulation of biological organs, the research area being defined in a very broad sense. This paper contains 198 references.

Peptide delta-Turn: Literature Survey and Recent Progress

Among the various types of a-peptide folding motifs, delta-turn, which requires a central cis-amide disposition, has been one of the least extensively investigated. In particular, this main-chain reversal topology has been studied in-depth neither in linear/cyclic peptides nor in proteins. This Minireview article assembles and critically analyzes relevant data from a literature survey on the d-turn conformation in those compounds. Unpublished results from recent conformational energy calculations and a preliminary solution-state analysis on a small model peptide, currently ongoing in our laboratories, are also briefly outlined.

Revenue management in remanufacturing: perspectives, review of current literature and research directions

The pace of development in the world has increased over the years and with it, the use of hi-tech gadgets, consumer durables, automobiles, etc. has also gone up. In this context, as resources become more and more scarce, there are multiple challenges that emerge both from a sustainable development perspective, and from the perspective of meeting profitability objectives of a firm. Remanufacturing has come up in a big way as an answer to these challenges, but firms are struggling with respect to revenue management of this nascent area. We assess the current literature and distil the key factors that firms need to consider as they assimilate remanufacturing in their operations and revenue management strategy. We provide an assessment of white spaces in research in this area and also outline the directions for future research.

Una visión argentina de España a principios del siglo XX : los caminos peninsulares de Ernesto Mario Barreda

Número monográfico: El viaje y sus discursos

Unamuno y América, una intensa relación

Resumen: Miguel de Unamuno tenía gran interés por y hacia los temas de América, sobre todo de la América hispánica. El objetivo de este artículo es refl exionar sobre la recepción y la acogida que dio a la literatura hispanoamericana coetánea, sobre cómo se aproximó a la obra de los escritores americanos, especialmente los argentinos. A través de un análisis crítico, se profundizará en esta relación considerando que América estuvo presente en su refl exión y su preocupación. Asimismo, se tratarán brevemente las colaboraciones literarias del escritor vasco en La Nación y otras revistas americanas para demostrar su interés respecto a la temática.

Altruism with Social Roots: An Emerging Literature

Revised: 2007-01.-- Published as an article in: Revista Desarrollo y Sociedad (2006), Semestre II, pp. 245-260.

Contemporary mormon literature: Phyllis Barber's writing

612 p.