Novel pyrrolidine heterocycles as CCR1 antagonists.

A novel series of pyrrolidine heterocycles was prepared and found to show potent inhibitory activity of CCR1 binding and CCL3 mediated chemotaxis of a CCR1-expressing cell line. A potent, optimized triazole lead from this series was found to have acceptable pharmacokinetics and microsomal stability in rat and is suitable for further optimization and development.

Mucoid Pseudomonas in cystic fibrosis.

Pseudomonas aeruginosa is a frequent and virulent pulmonary pathogen in patients with cystic fibrosis. If colonization is not prevented, P aeruginosa becomes permanently established and nearly always mutates into a mucoid strain. The alginate-containing matrix of the mucoid strain is thought to allow the formation of protected microcolonies and provide increased resistance to opsonization, phagocytosis, and destruction by antibiotics. As a result, conversion to the mucoid phenotype is associated with a significant increase in morbidity and mortality. In the microbiology laboratory, mucoid P aeruginosa has a distinct Gram stain and culture appearance that can expedite its identification and facilitate appropriate patient management. Important aspects of the mucoid phenotype are reviewed.

The NJ SEED project: evaluation of an innovative initiative for ethics training in nursing homes.

OBJECTIVES: This article reports the results of an evaluation of the New Jersey Stein Ethics Education and Development (NJ SEED) project--a statewide initiative to create, organize and educate a statewide network of regional long-term care ethics committees. The main focus of the evaluation was to measure utilization of the committees, describe how facilities have benefited from the project, and identify potential barriers to the use of this resource. METHODS: Based on administrative records from the NJ SEED project, 225 facilities were identified and asked to complete a facility survey. Ninety-three surveys were received, resulting in a 41% response rate. An additional survey of the regional ethics committees (RECs), as well as several focus groups and individual interviews were conducted to supplement the survey data. RESULTS: Fifty-eight percent of the facility respondents reported current participation in an NJ regional ethics committee. About one third (30%) of participating facilities had requested a formal case consultation (on at least one occasion) on behalf of a resident, but two thirds had consulted with their RECs on a more informal basis. Facilities that reported participating in the REC Network were more likely to have formally written policies than nonparticipants. CONCLUSIONS: Many NJ nursing homes find the statewide REC Network to be an important resource; however continued efforts need to be expended for recruiting and training facilities that are not taking full advantage of this important source of peer support and professional expertise.

Novel pyrrolidine ureas as C-C chemokine receptor 1 (CCR1) antagonists.

Monocyte infiltration is implicated in a variety of diseases including multiple myeloma, rheumatoid arthritis, and multiple sclerosis. C-C chemokine receptor 1 (CCR1) is a chemokine receptor that upon stimulation, particularly by macrophage inflammatory protein 1alpha (MIP-1alpha) and regulated on normal T-cell expressed and secreted (RANTES), mediates monocyte trafficking to sites of inflammation. High throughput screening of our combinatorial collection identified a novel, moderately potent CCR1 antagonist 3. The library hit 3 was optimized to the advanced lead compound 4. Compound 4 inhibited CCR1 mediated chemotaxis of monocytes with an IC(50) of 20 nM. In addition, the compound was highly selective over other chemokine receptors. It had good microsomal stability when incubated with rat and human liver microsomes and showed no significant cytochrome P450 (CYP) inhibition. Pharmacokinetic evaluation of the compound in the rat showed good oral bioavailability.