The Intestinal Absorption of a Prodrug of the mGlu2/3 Receptor Agonist LY354740 is Mediated by PEPT1: In Situ Rat Intestinal Perfusion Studies

LY354740 is a potent mGlu2/3 agonist with a limited oral bioavailability. Its alanyl prodrug, LY544344, showed high affinity to the intestinal peptide transporter PEPT1, and improved the oral bioavailability of LY354740 in various animal models. The aim of the present study was to investigate the mechanism of in vivo absorption of the dipeptidic prodrug LY544344. The permeabilities of LY544344 and LY354740 were examined in the rat in situ single‐pass intestinal perfusion model. The intestinal absorptive flux of LY354740 was shown to be very low in comparison with LY544344. The absorptive flux of LY544344 could best be described by a Michaelis–Menten process in parallel with a linear process. The estimated parameters were: J_max = 26.7 × 10^?5 µmol/(cm²‐s), K_m = 2.6 mM. The absorptive permeability of LY544344 was reduced to approximately 5% of control in the presence of excess Gly‐Sar, a known PEPT1 substrate. Intracellular accumulation of LY354740 and LY544344, estimated postperfusion, showed high levels of LY354740 over LY544344 at all perfusate concentrations studied. However, there was a decline in the intracellular ratio of LY354740 to LY544344 at higher concentrations, suggesting that the metabolic activation to release LY354740 is saturable. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1574–1581, 2010     

Epidemiologic observations of operating room infections resulting from variations in ventilation and temperature.

Over a period of years the ventilation system of a community hospital progressively deteriorated until it no longer met regulatory guidelines. The hospital, a publicly funded military facility, requested funding to repair the ventilation system, but funds were not forthcoming because of budget austerity. When an increase in infections was documented, high-risk operations were curtailed and funding was expedited. With the new improved ventilation system the operating rooms once again met regulatory guidelines and infections returned to baseline rates. Throughout the period infections remained below recognized national levels.     

In situ saphenous vein bypass grafts: angiographic evaluation and interventional repair of complications

In situ saphenous vein grafts are being used with increasing frequency for bypass procedures involving the femoral and popliteal arteries. Complications of these procedures include anastomotic stenoses and persistent arteriovenous fistulae that may result in failure of the graft. Balloon angioplasty and embolotherapy with detachable balloons were employed successfully in three or four recent cases of patients with complications from in situ grafts. Tailored angiography is essential for evaluating in situ grafts, and interventional techniques are extremely useful for managing complications.