Pent-up demand for care among dual-eligible victims of elder financial exploitation in Maine.

Elder financial exploitation (EFE), the misuse of a vulnerable adult's property or resources for personal gain, is a form of elder abuse. This study addresses whether dual-eligible EFE victims were experiencing pent-up demand for health services alleviated through investigation by Adult Protective Services (APS). A quasi-experimental design addressed health service utilization and costs for 131 dual-eligible Maine APS clients over age 60 with substantiated allegations of EFE relative to comparable non-APS controls. APS case files spanning 2007-2012 were linked to 2006-2014 Medicare and Medicaid claims data. Service utilization and costs were analyzed 1 year prior, during, and 2 years after the initial APS investigation. Difference in differences logistic regression and generalized linear models addressed the likelihood of incurring costs and expenditure levels relative to matched controls, respectively. Victims of EFE had higher overall odds of using inpatient and long-term services and supports (LTSS) and higher odds of using LTSS post-investigation than controls. Higher overall levels of outpatient and prescriptions expenditures and higher inpatient expenditures during the APS event year contributed toward APS clients incurring $1,142 higher PMPM total costs than controls. Victims of EFE were experiencing significant pent-up demand for health services post-APS involvement.

Robust Translation of γ-Secretase Modulator Pharmacology across Preclinical Species and Human Subjects.

The amyloid-ß peptide (Aß)-in particular, the 42-amino acid form, Aß1-42-is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming to inhibit Aß synthesis or increase the clearance of Aß have entered clinical trials, including γ-secretase inhibitors, anti-Aß antibodies, and amyloid-ß precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aß1-42 production, and may also decrease Aß1-40 while simultaneously increasing one or more shorter Aß peptides, such as Aß1-38 and Aß1-37. GSMs are particularly attractive because they do not alter the total amount of Aß peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, ß-C-terminal fragment. This report describes the translation of pharmacological activity across species for two novel GSMs, (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (BMS-932481) and (S,Z)-17-(4-chloro-2-fluorophenyl)-34-(3-methyl-1H-1,2,4-triazol-1-yl)-16,17-dihydro-15H-4-oxa-2,9-diaza-1(2,4)-cyclopenta[d]pyrimidina-3(1,3)-benzenacyclononaphan-6-ene (BMS-986133). These GSMs are highly potent in vitro, exhibit dose- and time-dependent activity in vivo, and have consistent levels of pharmacological effect across rats, dogs, monkeys, and human subjects. In rats, the two GSMs exhibit similar pharmacokinetics/pharmacodynamics between the brain and cerebrospinal fluid. In all species, GSM treatment decreased Aß1-42 and Aß1-40 levels while increasing Aß1-38 and Aß1-37 by a corresponding amount. Thus, the GSM mechanism and central activity translate across preclinical species and humans, thereby validating this therapeutic modality for potential utility in AD.

The utility of stable isotope labeled (SIL) analogues in the bioanalysis of endogenous compounds by LC-MS applied to the study of bile acids in a metabolomics assay.

The growing field of biomarker bioanalysis by liquid chromatography mass spectrometry (LC-MS) is challenged with the selection of suitable matrices to construct relevant and valid calibration curves resulting in not only precise but also accurate data. Because surrogate matrices are often employed with the associated concerns about the accuracy of the obtained data, here we present an assay using surrogate analytes in naive biological matrices. This approach is illustrated with the analysis of endogenous bile acids (e-BAs) in serum and plasma using stable isotope-labeled (SIL) analogues as calibration standards to address the matrix concerns. Several deuterated BAs (d-BAs) were used as standards representing respectively grouped e-BAs with structural similarity allowing for the simultaneous bioanalysis of 16 e-BA. The utility of this LC-MS assay employing d-BAs is demonstrated with the analysis of samples resultant of a controlled metabolomics study where a cohort of rats was fed/fasted to investigate the change of e-BAs dependent on food consumption and fasting time.

Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors.

GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.

Contributions of a long side chain to the binding affinity of an anthracene derivative to DNA.

Systematic studies on the DNA binding of a new anthracene derivative, carrying a 1,8-octyldiamine side chain, were carried out. Calorimetric, spectroscopic, and helix melting studies show that the side chain, consisting of eight methylene groups, enhances the binding constant by a factor of approximately 35 when compared to the binding of a probe lacking the long side chain. Furthermore, the enthalpy of binding of the long-chain derivative to calf thymus DNA (Delta H = 4.1 +/- 0.1 kcal/mol) is far greater than the sum of the enthalpy changes associated with the binding of the probe lacking the long side chain, and the enthalpy for the binding of 1,8-octyldiamine.2HCl. Strong synergistic effects, therefore, are seen with the long-chain derivative. Spectroscopic data indicate bathochromism, strong hypochromism, and quenching of anthryl fluorescence when the above ligand binds to calf thymus DNA. Fluorescence energy transfer studies and circular dichroism data strongly suggest intercalation of the anthryl ring system. The binding stabilizes the double helix, and the helix melting temperature is increased from 78 degrees C to >90 degrees C. The binding to DNA is reversible, depended on the ionic strength, and the major binding mode was suppressed at high ionic strengths and a new mode begins to dominate binding. Substitution of the anthracene ring with 1,8-octyldiamine chain provided a simple method to enhance the binding constant by nearly a factor of 35.

Identification and Preclinical Pharmacology of the γ-Secretase Modulator BMS-869780.

Alzheimer's disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-ß peptide (Aß), particularly the 42-amino acid Aß1-42, in the brain. Aß1-42 levels can be decreased by γ-secretase modulators (GSM), which are small molecules that modulate γ-secretase, an enzyme essential for Aß production. BMS-869780 is a potent GSM that decreased Aß1-42 and Aß1-40 and increased Aß1-37 and Aß1-38, without inhibiting overall levels of Aß peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ-secretase and lowered brain Aß1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and Aß1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aß1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aß1-42 without Notch-related side effects.