Lipid-based drug delivery systems (LBDDS) are one of the most studied bioavailability enhancement technologies and are utilized in a number of U.S. Food and Drug Administration (FDA) approved drugs. While researchers have used several general rules of thumb to predict which compounds are likely to benefit from LBDDS, formulation of lipid systems is primarily an empiric endeavor. One of the challenges is that these rules of thumb focus in different areas and are used independently of each other. The Developability Classification System attempts to link physicochemical characteristics with possible formulation strategies. Although it provides a starting point, the formulator still has to empirically develop the formulation. This article provides a review and quantitative analysis of the molecular properties of these approved drugs formulated as lipid systems and starts to build an approach that provides more directed guidance on which type of lipid system is likely to be the best for a particular drug molecule. ARTICLE HISTORY
Abstract. Novel erythropoiesis stimulating protein (NESP) is a hyperglycosylated analogue of recombinant human erythropoietin (Epoetin) which has an increased terminal half-life in animal models. The aim of this study was to extend these observations to humans. Using a double-blind, randomized, cross-over design, the single-dose pharmacokinetics of Epoetin alfa (100 U/kg) and an equivalent peptide mass of NESP were compared following intravenous bolus in 11 stable peritoneal dialysis patients. This was followed by an open-label study to determine the single-dose pharmacokinetics of an equivalent peptide mass of NESP by subcutaneous injection in six of these patients. The mean terminal half-life for intravenous NESP was threefold longer than for intravenous Epoetin (25.3 versus 8.5 h), a difference of 16.8 h (95% confidence interval, 9.4 to 24.2 h, P = 0.0008). The area under the serum concentration—time curve was significantly greater for NESP (291.0 ± 7.6 ng · h per ml versus 131.9 ± 8.3 ng · h per ml; mean ± SEM; P < 0.0005), and clearance was significantly lower (1.6 ± 0.3 ml/h per kg versus 4.0 ± 0.3 ml/h per kg; mean ± SEM; P < 0.0005). The volume of distribution was similar for NESP and Epoetin (52.4 ± 2.0 ml/kg versus 48.7 ± 2.1 ml/kg; mean ± SEM). The mean terminal half-life for subcutaneous NESP was 48.8 h. The peak concentration of subcutaneous NESP was approximately 10% of that following intravenous administration, and bioavailability was approximately 37% by the subcutaneous route. The longer half-life of NESP is likely to confer a clinical advantage over Epoetin by allowing less frequent dosing in patients treated for anemia.
To date, human studies in a dialysis population have confirmed the pharmacokinetic differences in half life and clearance between NESP and r- HuEPO (Macdougall, 1999). However, studies in humans using NESP have shown an efficacy profile that is comparable to r-HuEPO (Coyne et al, 2000; Nissenson et al, 2000; Locatelli et al, 2001). These studies reinforce the fact that results garnered from animal models are not necessarily indicative of what is to be ascertained in humans. REFERENCES
The Inter-American Agency for Cooperation and Development is currently funding a project focused on groundwater management in coastal karst environments in the Caribbean. The islands of Jamaica, Antigua, and Barbados are currently the primary regional participants in this project. Geophysical characterization of pilot sites on each of these islands is being used to provide input into conceptual groundwater flow models, which in turn will be used to support the development of sustainable groundwater management strategies for these coastal aquifers.Geophysical fieldwork at a pilot site located in the northeast portion of the island of Antigua took place in April 2004. Data from the survey support mapping the geology and hydrology of the region and locating the freshwater-seawater interface. Geophysical methods used in the fieldwork included time-domain electromagnetic (TEM) central-loop soundings, Schlumberger-array resistivity soundings, EM-31 terrain conductivity profiling, and multi-electrode resistivity profiling. In-field analysis of data collected at a regional scale led to a conceptual understanding of seawater intrusion into the study area. This conceptual understanding led to concentrated data collection efforts in specific areas.The first area surveyed in-depth to confirm our conceptual understanding of seawater intrusion at the site was Mercers Creek channel that runs from west of the Collins and Potworks reservoirs to Mercers Creek Bay located along the north coast of the island. TEM soundings, assembled into an eastwest profile across the channel, reveal a conductive region, thought to represent seawater migrating inland in response to the reduced freshwater head caused by pumping at the Collins well field. The second area surveyed in-depth was the Ayres Creek channel that runs by the Collins and Bristol well fields before draining into the extensive tidal flat at Nonsuch Bay located along the northeast coast of the island. This channel contains a secondary dam that captures outflow from the Potworks and Collins dams during periods of high rainfall and flooding, but is otherwise dry. This area was studied in detail using a high-density geophysical data collection strategy. Subsequent data interpretation led to the identification of a conductive zone that appears to be the result of seawater intrusion. The extent of the intrusion in the vicinity of the channel is controlled by the groundwater pumping at the Collins and Bristol w ell fields and storm surge/tidal fluctuations. This conceptual model has groundwater management implications that are being evaluated using groundwater flow models.
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