BACKGROUND: Long-term peritoneal dialysis (PD) causes peritoneal morphological and functional changes, resulting in high transport status featuring increased peritoneal permeability. High transport status is diagnosed by peritoneal equilibration test (PET), a reliable but time-consuming method. We identifed a reliable biomarker in peritoneal effluent to predict high transport status in PD patients. METHODS: We collected peritoneal effluent and serum from 33 PD patients and measured common laboratory test parameters. High transport status was determined by PET if the dialysate/plasma ratio of creatinine at 4h dwell (D/P Cr 4h) was >/=0.81. RESULTS: There were significant correlations between D/P Cr 4h and some laboratory parameters in overnight effluent (pancreatic lipase activity, r=0.65, p<0.001; beta2-microglobulin concentration, r=0.59, p<0.001; IL-6 concentration, r=0.53, p<0.001; and CA125 concentration, r=0.29, p=0.027). In a multivariate logistic regression analysis, the pancreatic lipase activity in overnight effluent was identified as an independent predictor of high transport status even after adjusting for age, PD duration, and glomerular filtration rate [OR=1.43 (95% CI: 1.11-1.83), p=0.005]. CONCLUSIONS: The pancreatic lipase activity in overnight effluent is an independent predictor of high transport status in PD patients.
Title: The simulated binding of (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]m eth yl] -1H-inden-1-one hydrochloride (E2020) and related inhibitors to free and acylated acetylcholinesterases and corresponding structure-activity analyses Inoue A, Kawai T, Wakita M, Iimura Y, Sugimoto H, Kawakami Y Ref: Journal of Medicinal Chemistry, 39:4460, 1996 : PubMed
The simulated binding profiles of acetylcholine, ACh, and the inhibitor (+/-)-2,3-dihydro-5,6- dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-on e hydrochloride (E2020), 1, and some of its analogs to acetylcholinesterase, AChE, were determined using full force field energetics and allowing complete conformational flexibility in both the ligand and receptor. A new mode of binding of ACh to AChE was found which involves the carboxyl oxygen of ACh interacting with Gly 118 and 119. Multiple modes of binding of 1 and some of its analogs were found which include alignment models observed in previous more restricted modeling studies. The key ligand-receptor interactions identified, and the corresponding energetics, are consistent on a relative basis, with observed binding constants for both the individual isomers of each of the inhibitors, as well as among the inhibitors themselves. The multiple modes of binding of 1 to AChE arises from small changes in binding at a single subsite and also from multiple subsite changes. Thus, an independent subsite model for ligand-receptor binding holds for some modes of binding, but not for others. A comparison of the simulated AChE-1 (and analog inhibitors) binding models to the receptor-independent 3D-QSARs previously developed for this class of inhibitors reveals extensive mutual consistency. The findings from these two modeling studies provides greater guidelines for inhibitor design than can be realized from either one. The combined docking and 3D-QSAR studies permit a detailed understanding of the SAR of more than 100 compound 1 analog inhibitors. A simple molecular recognition model can also be gleaned from the docking studies. A cylindrical "plug" (the inhibitor) having a large dipole moment must sterically fit into a cylindrical hole (the active site gorge of AChE), the lining of which also has a large dipole moment. Our simulations suggest that the dynamic "back door" to the active site of AChE does not form a large enough opening for sufficiently long time periods so as to be an effective entrance/exit pathway.
The phase III drug-candidate, E2020, developed for treatment of Alzheimer's disease, and possibly other demenitas, and its analogues have been the focus of extensive molecular pharmacological and structural studies. The potency and selectivity of E2020 as an inhibitor of acetylcholinesterase, AChE, in the brain is established. A combination of molecular modeling and QSAR studies have been used throughout the evolution of the AChE inhibitor program leading to the benzylpiperidine series, and, ultimately, E2020. QSAR studies have identified requirements of optimize inhibition activity as a function of substituent choice on both the indanone and benzyl rings in the E2020 class of inhibitors. A combination of X-ray crystal structure studies of E2020 isomers and the molecular shape analysis, MSA, of E2020 and its analogues has led to a postulated active conformation, and molecular shape, for these AChE inhibitors. The active molecular shape corresponds to a high degree of shape similarity between the two E2020 isomers which, in turn, is consistent with the observed high inhibition potencies of both of these compounds. Intermolecular docking studies were carried out for E2020 and some analogues with the crystal structure of AChE when it became available. The docking simulations involving E2020 analogues suggest these inhibitors do not bind at the acetylcholine, ACh, active site, but rather at the most narrow location of the long channel leading to the active site. Intermolecular binding geometries are consistent with the postulated active conformations derived from structure-activity (receptor geometry independent) information.
