Characterization of ZK 245186, a novel,selective glucocorticoid receptor agonist for the topical treatment of inflammatory skin diseases

Background and purpose:

Glucocorticoids are highly effective in the therapy of inflammatory diseases. Their value, however, is limited by side effects. The discovery of the molecular mechanisms of the glucocorticoid receptor and the recognition that activation and repression of gene expression could be addressed separately opened the possibility of achieving improved safety profiles by the identification of ligands that predominantly induce repression. Here we report on ZK 245186, a novel, non-steroidal, low-molecular-weight, glucocorticoid receptor-selective agonist for the topical treatment of inflammatory dermatoses.

Experimental approach:

Pharmacological properties of ZK 245186 and reference compounds were studied in terms of their potential anti-inflammatory and side effects in functional bioassays in vitro and in rodent models in vivo.

Key results:

Anti-inflammatory activity of ZK 245186 was demonstrated in in vitro assays for inhibition of cytokine secretion and T cell proliferation. In vivo, using irritant contact dermatitis and T cell-mediated contact allergy models in mice and rats, ZK 245186 showed anti-inflammatory efficacy after topical application similar to the classical glucocorticoids, mometasone furoate and methylprednisolone aceponate. ZK 245186, however, exhibits a better safety profile with regard to growth inhibition and induction of skin atrophy after long-term topical application, thymocyte apoptosis, hyperglycaemia and hepatic tyrosine aminotransferase activity.

Conclusions and implications:

ZK 245186 is a potent anti-inflammatory compound with a lower potential for side effects, compared with classical glucocorticoids. It represents a promising drug candidate and is currently in clinical trials.This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009     

Genetic analysis of avian influenza A viruses isolated from domestic waterfowl in live-bird markets of Hanoi, Vietnam, preceding fatal H5N1 human infections in 2004

The first known cases of human infection with highly pathogenic avian influenza (HPAI) H5N1 viruses in Vietnam occurred in late 2003. However, HPAI H5N1 and low-pathogenic avian influenza (LPAI) H5N2 and H9N3 viruses were isolated from domestic waterfowl during live-bird market (LBM) surveillance in Vietnam in 2001 and 2003. To understand the possible role of these early viruses in the genesis of H5N1 strains infecting people, we performed sequencing and molecular characterization. Phylogenetic analysis revealed that the hemagglutinin (HA) genes of two geese HPAI H5N1 strains belonged to clade 3, and their surface glycoprotein and replication complex genes were most closely related (98.5–99.7% homologous) to A/duck/Guangxi/22/01 (H5N1) virus, detected contemporarily in southern China, whilst the M and NS genes were derived from an A/duck/Hong Kong/2986.1/00 (H5N1)-like virus. The H5 HA gene of the duck HPAI H5N1 strain belonged to clade 5 and acquired a gene constellation from A/quail/Shantou/3846/02 (H5N1), A/teal/China/2978.1/02 (H5N1) and A/partridge/Shantou/2286/03 (H5N1)-like viruses. The phylogenetic analysis further indicated that all eight gene segments of goose and duck HPAI H5N1 and LPAI H5N2 viruses were distinct from those of H5N1 clade-1 viruses known to have caused fatal human infections in Vietnam since late 2003. The duck H9N3 isolates derived genes from aquatic-bird influenza viruses, and their H9 HA belonged to the Korean lineage. The PB2 gene of A/duck/Vietnam/340/01 (H9N3) virus had lysine at position 627. Based on the molecular characterization of specific amino acid residues in the surface and relevant internal protein-coding genes, the Vietnamese H5N1 and H9N3 virus isolates indicated specificity to avian cell surface receptor and susceptibility for currently licensed anti-influenza A virus chemotherapeutics. Our findings suggest that the H5N1 and H5N2 viruses that circulated among geese and ducks in LBMs in Hanoi, Vietnam, during 2001 and 2003 were not the immediate ancestors of the clade-1 viruses associated with fatal human infections in Vietnam. The clade-1 HPAI H5N1 viruses were independently introduced into Vietnam.     

Universal influenza vaccination in the United States: are we ready? Report of a meeting

Universal influenza vaccination has been proposed as one strategy to improve vaccination coverage and disease prevention. In October 2005, influenza and vaccination experts, public health practitioners, representatives from medical professional societies, influenza vaccine manufacturers, and managed care organizations met to assess whether current data were sufficient to support an expansion of universal influenza vaccination and to define information gaps and potential barriers to implementation. Presenters at the meeting documented the substantial burden of influenza disease among all age groups, the major role of children in transmission, and the effectiveness of vaccine, especially in healthy children and adults. Observational studies and a mathematical model suggested that indirect protection, or "herd immunity," resulting from vaccination of school-age children would substantially reduce the incidence of disease in other age groups. Economic analyses generally showed that vaccination of healthy children and adults is cost-effective and is sensitive to vaccine cost, population group, and season. Influenza vaccination received annually over several years is safe and effective, but data on long-term use are limited. Challenges to expanded recommendations include maintenance of the vaccine supply, implementation of a feasible and effective strategy for vaccine delivery, the burden on the public health infrastructure, public acceptability, and financing. Overall, meeting attendees favored incremental expansion of recommendations, potentially toward universal influenza vaccination. They preferred to expand recommendations among children first, because children have a higher risk of illness, compared with healthy adults; because there is greater feasibility of implementation of the recommendations among children; and because of the potential for herd immunity decreasing morbidity and mortality among adults.     

Respiratory syncytial virus and other respiratory virus infections in residents of homeless shelters – King County,Washington, 2019–2021

Respiratory syncytial virus (RSV) causes disproportionate morbidity and mortality in vulnerable populations. We tested residents of homeless shelters in Seattle, Washington for RSV in a repeated cross-sectional study as part of community surveillance for respiratory viruses. Of 15 364 specimens tested, 35 had RSV detected, compared to 77 with influenza. The most common symptoms for both RSV and influenza were cough and rhinorrhea. Many individuals with RSV (39%) and influenza (58%) reported that their illness significantly impacted their ability to perform their regular activities. RSV and influenza demonstrated similar clinical presentations and burden of illness in vulnerable populations living in congregate settings.