Search

It has previously been reported that a prototypical compound (AGN 211377), which blocks pro-inflammatory prostanoid receptors (DP 1 , DP 2 , EP 1 , EP 4, FP, TP) and leaves open IP and EP 2 receptors so that their anti-inflammatory properties could be exerted, produced superior inhibitory effects on cytokine release from human macrophages compared to cyclooxygenase (COX) inhibitors. This favorable activity profile translated into animal studies, with AGN 211377 exceeding the level of inhibition afforded by COX inhibition. AGN 211377 was not, however, a practical drug candidate, having poor bioavailability and cost of goods concerns. Compound 1 (designated AGN 225660) represents a second-generation compound with an entirely different "druggable" core structure. Such a dramatic change in chemical scaffold created uncertainty with respect to matching the effects of AGN 211377. AGN 225660 inhibited RANTES, IL-8, and MCP-1 secretion by at least 50%, from TNFα activated human macrophages. Although AGN 225660 reduced TNFα-evoked MCP-1 release from human monocyte-derived macrophages, it increased LPS-induced MCP-1 secretion (up to 2-fold) from human monocyte-derived dendritic cells. However, AGN 225660 inhibited the release of IL12p 70 and IL-23 from human monocyte-derived dendritic cells stimulated by LPS by more than 70%. This effect of AGN 225660 was reproduced in part by the prototype compound AGN 211377 and a combination of selective DP 1 , EP 1 , EP 4 , FP, and TP antagonists. These findings suggest important effects on T cell skewing and disease modification by this class of therapeutic agents. AGN 225660 exhibited good ocular bioavailability and was active in reducing ocular inflammation associated with phacoemulsification surgery, LPS, and arachidonic acid induced uveitis., Competing Interests: The authors declare the following competing financial interest(s): N. J. Poloso remains an Allergan Inc. employee., (© 2020 American Chemical Society.)

Retailers are strategically positioned to leverage environmental improvement over product supply chains through actions targeted at suppliers and consumers. Informed by scientific evidence on environmental hotspots and control points across 14 priority product groups, and a review of 25 major European retailers' actions, this paper proposes a framework to guide and assess retailer best practice in supply chain environmental improvement. Commonly used product standards and improvement measures are classified into "basic" or "good" levels of environmental protection. A hierarchy of eight Best Environmental Management Practices (BEMPs) is proposed to systematically identify and improve the most environmentally damaging supply chains across retail assortments. Widespread third party environmental certification is the most transparent and verifiable mechanism of improvement but may not be appropriate for some supply chains. The enforcement of retailer-defined environmental requirements, and supplier improvement programmes based on performance benchmarking and dissemination of better management practices, are alternative BEMPs that may be used in combination with third party certification. Facilitating consumer selection of frontrunner ecological products is a lower priority BEMP owing to the well documented limitations of this approach. From available data, the highest current or credible-target sales shares of products improved according to the highest priority BEMP and environmental protection level were used to derive "benchmarks of excellence" for each of the 14 product groups. The assessment framework is demonstrated through application to three retailers., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: Despite structural similarity with prostaglandin F(2 alpha), the ocular hypotensive agent bimatoprost (Lumigan; Allergan, Inc., Irvine, CA) shows unique pharmacology in vitro and functional activity in vivo. Unfortunately, the precise mechanisms that underlie bimatoprost's distinctive impact on aqueous humor dynamics are unclear. The purpose of the present study was to investigate the effects of bimatoprost and a novel prostamide-selective antagonist AGN 211334 on human conventional drainage., Methods: Two model systems were used to test the consequences of bimatoprost and/or AGN 211334 treatment on conventional drainage. Human anterior segments in organ culture were perfused at a constant flow rate of 2.5 microL/min while pressure was recorded continuously. After stable baseline facilities were established, segments were treated with drug(s), and pressure was monitored for an additional 3 days. In parallel, the drugs' effects on hydraulic conductivity of human trabecular meshwork (TM) cell monolayers were evaluated. Pharmacological properties of AGN 211334 were characterized in isolated feline iris preparations in organ culture and heterologously expressed G-protein-coupled receptors were examined in vitro., Results: Bimatoprost increased outflow facility by an average of 40% +/- 10% within 48 hours of treatment (n = 10, P < 0.001). Preincubation or coincubation with AGN 211334 significantly blunted bimatoprost's effects by 95% or 43%, respectively. Similar results were obtained in cell culture experiments in which bimatoprost increased hydraulic conductivity of TM cell monolayers by 78% +/- 25%. Pretreatment with AGN 211334 completely blocked bimatoprost's effects, while coincubation decreased its effects on average by 74%. In both models, AGN 211334 alone significantly decreased fluid flux across trabecular tissues and cells., Conclusions: The findings indicate that bimatoprost interacts with a prostamide receptor in the trabecular meshwork to increase outflow facility.