ABSTRACT
Preclinical pharmacological characterization of a novel inhibitor (UM8190) of prolylcarboxypeptidase (PRCP) was investigated. We synthesized and evaluated a library of proline-based analogs as prospective recombinant PRCP (rPRCP) inhibitors and inhibitors of PRCP-dependent prekallikrein (PK) activation on human pulmonary artery endothelial cells (HPAEC). Among the newly synthesized compounds, UM8190 was further characterized in vivo using methods that encompassed a mouse carotid artery thrombosis model and animal model of food consumption. (S)-N-dodecyl-1-((S)-pyrrolidine-2-carbonyl) pyrrolidine-2-carboxamide [Compound 3 (UM8190)] was selected for further evaluation from the initial assessment of its PRCP inhibitory action (K(i)= 43 µM) coupled with its ability to block PRCP-dependent PK activation on HPAEC (K(i)= 34 µM). UM8190 demonstrated excellent selectivity against a panel of carboxypeptidases and serine proteases and blocked bradykinin (BK) generation and BK-induced permeability by 100%, suggesting that it may be useful in preventing the local production of large amounts of BK. Furthermore, UM8190 showed an anorexigenic effect when systemically administered to fasted mice, reducing food intake in a dose- and time-dependent manner. In a mouse carotid artery thrombosis model, it also demonstrated an antithrombotic effect. UM8190 is a selective PRCP inhibitor and it may represent a new anorexigenic, and antithrombotic drug, that works by inhibiting PRCP-mediated mechanisms.
Subject(s)
Appetite/drug effects , Carboxypeptidases/antagonists & inhibitors , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Animals , Appetite Depressants/chemical synthesis , Appetite Depressants/chemistry , Appetite Depressants/pharmacology , Bradykinin/metabolism , Carboxypeptidases/metabolism , Cell Line , Disease Models, Animal , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Fibrinolytic Agents/therapeutic use , Humans , Mice , Mice, Inbred C57BL , Nitric Oxide/metabolism , Prekallikrein/metabolism , Proline/chemistry , Proline/pharmacology , Proline/therapeutic use , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Thrombosis/drug therapy , Thrombosis/pathologyABSTRACT
A prospective bacteriologic study on 67 women undergoing either vaginal or abdominal hysterectomy was done to elucidate causes of debrile morbidity. Forty-one percent of the vaginal and 35% of the abdominal hysterectomy patients met the criteria for febrile morbidity postoperatively. Preoperative and 24-hour postoperative urine samples were obtained by transvaginal bladder tap, and the freshly cut edge of the vaginal cuff was routinely swabbed following removal of the uterus. In addition, the subcutaneous layer was cultured during closure of the abdominal wound. Escherichia coli, Enterococcus, and alpha- and beta-Streptococcus were the predominant organisms recovered. The importance of routine vaginal cuff cultures at the time of surgery for the treatment of postoperative morbidity is discussed.
Subject(s)
Bacteria/isolation & purification , Fever/etiology , Hysterectomy , Postoperative Complications/etiology , Vagina/microbiology , Adult , Anaerobiosis , Animals , Escherichia coli/isolation & purification , Escherichia coli Infections/etiology , Female , Fever/epidemiology , Fever/microbiology , Humans , Middle Aged , Postoperative Complications/microbiology , Prospective Studies , Sheep , Streptococcal Infections/etiology , Streptococcus/isolation & purification , Texas , Urinary Tract Infections/etiology , Urine/microbiologyABSTRACT
The aerosol stability of St. Louis encephalitis (SLE) virus was studied over a 6-hr period at a temperature of 21 C and relative humidity values of 23, 46, 60, and 80%. Aerosols were generated from and collected in 0.75% bovine albumin-buffered saline, and spores of Bacillus subtilis var. niger were used as the tracer to determine the physical decay of the aerosols. Aerosol samples were titrated in BHK-21 cell monolayers for surviving SLE virus. The results of this study indicated that, under the test conditions employed, relative humidity had no influence on the stability of SLE virus in the airborne state.
