Optical barcoding of colloidal suspensions: applications in genomics, proteomics and drug discovery

The enormous amount of information generated through sequencing of the human genome has increased demands for more economical and flexible alternatives in genomics, proteomics and drug discovery. Many companies and institutions have recognised the potential of increasing the size and complexity of chemical libraries by producing large chemical libraries on colloidal support beads. Since colloid-based compounds in a suspension are randomly located, an encoding system such as optical barcoding is required to permit rapid elucidation of the compound structures. We describe in this article innovative methods for optical barcoding of colloids for use as support beads in both combinatorial and non-combinatorial libraries. We focus in particular on the difficult problem of barcoding extremely large libraries, which if solved, will transform the manner in which genomics, proteomics and drug discovery research is currently performed.

Cationic drug pharmacokinetics in diseased livers determined by fibrosis index, hepatic protein content, microsomal activity, and nature of drug

The disposition kinetics of six cationic drugs in perfused diseased and normal rat livers were determined by multiple indicator dilution and related to the drug physicochemical properties and liver histopathology. A carbon tetrachloride (CCl4)induced acute hepatocellular injury model had a higher fibrosis index (FI), determined by computer-assisted image analysis, than did an alcohol-induced chronic hepatocellular injury model. The alcohol-treated group had the highest hepatic alpha(1)- acid glycoprotein, microsomal protein (MP), and cytochrome P450 (P450) concentrations. Various pharmacokinetic parameters could be related to the octanol-water partition coefficient (log P-app) of the drug as a surrogate for plasma membrane partition coefficient and affinity for MP or P450, the dependence being lower in the CCl4-treated group and higher in the alcohol-treated group relative to controls. Stepwise regression analysis showed that hepatic extraction ratio, permeability-surface area product, tissue-binding constant, intrinsic clearance, partition ratio of influx (k(in)) and efflux rate constant (k(out)), and k(in)/k(out) were related to physicochemical properties of drug (log P-app or pK(a)) and liver histopathology (FI, MP, or P450). In addition, hepatocyte organelle ion trapping of cationic drugs was evident in all groups. It is concluded that fibrosis-inducing hepatic disease effects on cationic drug disposition in the liver may be predicted from drug properties and liver histopathology.

Macrolides in cystic fibrosis. Is there a role?

A spectrum of anti-inflammatory properties, evidence of anti-infective action against Pseudomonas aeruginosa at sub-inhibitory concentrations and positive clinical experience in patients with diffuse panbronchiolitis, a disease with features in common with cystic fibrosis (CF), has prompted research to evaluate the role of macrolide therapy in patients with CF. Newer macrolides such as azithromycin have the advantage of improved tolerability and a prolonged intracellular half-life requiring an infrequent dosing regimen. Results from initial studies suggest a benefit from several months of macrolide therapy in patients with CF. An improvement in lung function was initially shown in a small open study in children, while maintenance of lung function compared with placebo, reduced acute respiratory exacerbations, and reduced systemic markers of inflammation were demonstrated in a randomized, placebo-controlled study of macrolide therapy in adult patients with CF. Additional controlled studies are required to determine optimal drug, dosage, and duration of therapy, and long-term adverse effects of prolonged therapy with macrolides in patients with CF. The potential, with long-term use, to induce resistance against other bacteria colonizing the upper respiratory tract e.g. pneumococci has not been explored. Measurement of cytokines and inflammatory mediators from the sputum of patients with CF is technically difficult and does not correlate with disease activity. There is a need for easily measurable, reproducible and clinically meaningful end-points for evaluation of new therapies in CF. The choice of appropriate outcome measures, apart from lung function, to monitor disease activity needs careful consideration in clinical trials determining the efficacy of macrolides in patients with CF. Evidence-based recommendations for the use of macrolides in the treatment of CF are not expected for some years although macrolides are already being prescribed for long-term use in some centers. There is a need for further research into mechanisms of anti-inflammatory action of macrolides in the lungs of patients with CF and whether or not such therapy may be beneficial in the long term. Copyright 2002 Adis International

The cyclotides: Novel macrocyclic peptides as scaffolds in drug design

Cyclotides are a novel class of circular, disulfide-rich peptides (similar to 30 amino acids) that display a broad range of bioactivities and have exceptionally high stability. Their physical properties, which include resistance to thermal and enzymatic degradation, can be attributed to their unique cyclic backbone and knotted arrangement of disulfide bonds. The applicability of linear peptides as drugs is potentially limited by their susceptibility to proteolytic cleavage and poor bioavailability. Such limitations may be overcome by using the cyclotide framework as a scaffold onto which new activities may be engineered. The potential use of cyclotides for drug design is evaluated here, with reference to rapidly increasing knowledge of natural cyclotides and the emergence of new techniques in peptide engineering.

Some new killing trick: Welfare reform and drug markets in a U.S. urban ghetto

Ethnographic data collected over a 5-year period is analyzed to determine how the Personal Responsibility & Work Opportunity Reconciliation Act of 1996 (PRWORA) has affected the lives of young male drug dealers from AIDS-afflicted families residing in Detroit. The data analysis indicated that the participants perceived drug dealing as the only viable employment opportunity for meeting the quotidian & health care needs of their families. The findings also revealed that the participants were highly aware of local political processes & the necessities of caring for relatives living with AIDS. Additional attention is dedicated to exploring the state of MI's rationale for ending the General Assistance Program, the sociocultural foundations of the PRWORA, various stipulations of the PRWORA, & how the PRWORA has augmented the legal vulnerability of welfare recipients. It is concluded that the PRWORA will force many welfare recipients to engage in illicit activities & will generally decrease recipients' health. 59 References. J. W. Parker