Prodrugs of perzinfotel with improved oral bioavailability.

Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1 (3-5%), prodrug derivatives (3a-h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by a 30 mg/kg oral dose of 1. Consistent with these results, 3a was significantly more potent and had a longer duration of activity than 1 following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1.

Building a statewide knowledge network for clinicians in intensive care units: knowledge brokering and the NSW Intensive Care Coordination and Monitoring Unit (ICCMU).

PURPOSE: This paper describes the initial establishment of the Intensive Care Coordination and Monitoring Unit (ICCMU), and reports on the implementation of a state-based intensive care Listserv, ICUConnect, for staff in ICUs in New South Wales, Australia. The aim of the Listserv was to decrease professional isolation in smaller and less resourced ICUs by developing a network based on professional peer support. The Listserv was launched in December 2003 with 130 clinical nurse consultants and nurse managers. The emphasis was on exchange of both codified and experiential information. MATERIAL AND METHODS: Evaluation of the Listserv was undertaken with a user survey piloted in 2004 and conducted in 2005. The survey explored the penetration, activity patterns and opinions of members of the Listserv. Members of the Listserv were mostly Australian intensive care clinicians and academics. RESULTS: At the time of the survey, Listserv membership had grown to over 433 users. As expected rural members tended to ask questions of clinical support and advice, while nurse educators in metropolitan ICUs were the most active members on-list. The free exchange of information, especially in the form of policies and procedures, has led to the development of an information repository on the ICCMU website. CONCLUSIONS: The Listserv has created a beginning community of practice with ICCMU taking an active approach to knowledge management by facilitating exchange of information. The creation of ICCMU as a clinician-led resource has developed a structure that is ideally placed to act as a knowledge broker within a network of ICUs. A collaborative process to produce generic guidelines is now underway.