Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression.

We analyzed aging parameters using a mechanistic target of rapamycin (mTOR) hypomorphic mouse model. Mice with two hypomorphic (mTOR(Δ/Δ)) alleles are viable but express mTOR at approximately 25% of wild-type levels. These animals demonstrate reduced mTORC1 and mTORC2 activity and exhibit an approximately 20% increase in median survival. While mTOR(Δ/Δ) mice are smaller than wild-type mice, these animals do not demonstrate any alterations in normalized food intake, glucose homeostasis, or metabolic rate. Consistent with their increased lifespan, mTOR(Δ/Δ) mice exhibited a reduction in a number of aging tissue biomarkers. Functional assessment suggested that, as mTOR(Δ/Δ) mice age, they exhibit a marked functional preservation in many, but not all, organ systems. Thus, in a mammalian model, while reducing mTOR expression markedly increases overall lifespan, it affects the age-dependent decline in tissue and organ function in a segmental fashion.

Factors of hyperlipidemia medication adherence in a nationwide health plan.

OBJECTIVES: To evaluate the factors associated with nonadherence in a nationally representative sample of patients receiving lipid-lowering therapy (LLT). STUDY DESIGN: Retrospective database analysis of treatment-naive (1 year without LLT claim) hyperlipidemia patients evidenced by a new pharmacy claim for lipid-lowering therapy. METHODS: Pharmacy and medical claims data were analyzed for currently enrolled members receiving a new LLT from 2007 to 2008. Adherence was defi ned as percentage of days covered (PDC) and values %lt;80% were used to categorize nonadherent patients. Independent variables included patient demographics, pharmacy utilization, and medical conditions. Stepwise logistic regression was used to predict the odds of nonadherence. Laboratory data variables were incorporated in an exploratory sub-analysis to test the robustness of the original model. RESULTS: Adherence with LLT was estimated in 88,635 patients. Sixty-fi ve percent of patients were nonadherent (mean PDC = 0.33). Compared with statins, patients treated with bile acid sequestrants were 6.75 times as likely to be nonadherent (P <.001). Significant (P <.05) predictors of nonadherence included age 45 to 55 years (ref: age >75 y) (odds ratio [OR]: 1.11); prior diabetes diagnosis (OR: 1.15); and unique pharmacies used (OR = 1.10). Significant factors reducing nonadherence include male gender (OR: 0.77); previous heart attack (OR: 0.82); prior adherent behavior (OR: 0.89); and unique physicians seen (OR: 0.97). Compared with no copayment, patients with $5 to $30 copayments had a significant reduction in the likelihood of nonadherence. CONCLUSIONS: Medication adherence remains poor in patients receiving LLT. Treatment outcomes and healthcare resource use may be improved by prioritizing adherence programs in at-risk patient populations.

Effect of volume- and time-based constraints on capture of analytes in microfluidic heterogeneous immunoassays.

Despite the prevalence of microfluidic-based heterogeneous immunoassays (where analytes in solution are captured on a solid surface functionalized with a capture molecule), there is incomplete understanding of how assay parameters influence the amount of captured analytes. This study presents computational results and corresponding experimental binding assays in which the capture of analytes is studied under variations in both mass transfer and surface binding, constrained by real-world assay conditions of finite sample volume, assay time, and capture area. Our results identify: 1) a "reagent-limited" regime which exists only under the constraints of finite sample volume and assay time; 2) a critical flow rate (e.g. 0.5 microL min(-1) under our assay conditions) to gain the maximum signal with the fastest assay time; 3) an increase in signal by using a short concentrated plug (e.g. 5 microL, 100 nM) rather than a long dilute plug (e.g. 50 microL, 10 nM) of sample; 4) the possibility of spending a considerable fraction of the assay time out of the reaction-limited regime. Overall, an improved understanding of fundamental physical processes may be particularly beneficial for the design of point-of-care assays, where volumes of reagents and available samples are limited, and the desired time-to-result short.

Modeling of adhesion in tablet compression. II. Compaction studies using a compaction simulator and an instrumented tablet press.

Adhesion problems are usually not identified until prolonged compression runs are studied near the end of the drug development process. During tablet manufacturing, adhesion problems encountered are usually addressed by statistically designed experiments based on experience. It would be a significant benefit for the pharmaceutical industry if adhesion problems could be identified early in drug development based on molecular considerations of the drug substance and/or prototype formulations. Drug substance-punch face interactions were reported in the first of the articles in this series, and focused on the elucidation of adhesion problems in tablet compression. It was hypothesized that the intermolecular interactions between drug molecules and the punch face was the first step (or criterion) in the adhesion process, and that the rank order of adhesion during tablet compression should correspond with the rank order of these energies of interaction. That is, the interaction between the molecular structure of the drug and the metal surface determines the primary interaction event or relative potential for adhesion, while the mechanical processes and/or lubrication effects may subsequently impact the extent of adhesion. Molecular simulations and atomic force microscopy were used to establish the rank order of the work of adhesion of a series of profen compounds. The results predicted that the relative degree of drug substance-punch face adhesion should decrease in the order of ketoprofen > ibuprofen > flurbiprofen. In this study, the authors investigated whether the rank order of the work of adhesion established on the molecular level and interparticulate level holds true in the tableting environment by measuring tablet take-off force, ejection force, and visual observation of the punch surfaces for both pure drug compacts and formulated tablets. The compaction simulator was used for pure profen compacts, while the instrumented tablet press for formulated tablets. Due to the inability to extract the adhesion force component from the total ejection force measurement, tablet ejection force was not used as a criterion to judge the adhesion behavior of the model compounds. The criteria used for judgement of punch face adhesion were tablet take-off force and visual observation of the punch faces. The rank order of adhesion for both pure drug and formulated tablets was determined to follow the order of ketoprofen > ibuprofen > flurbiprofen. The effect of run time on adhesion behavior was also investigated. Therefore, the rank order of the punch-face adhesion tendencies for the series of profen compounds was determined, and found to agree with the data from the predictive methods reported in the first article.

Modeling of adhesion in tablet compression--I. Atomic force microscopy and molecular simulation.

Adhesion problems during tablet manufacturing have been observed to be dependent on many formulation and process factors including the run time on the tablet press. Consequently, problems due to sticking may only become apparent towards the end of the development process when a prolonged run on the tablet press is attempted for the first time. It would be beneficial to predict in a relative sense if a formulation or new chemical entity has the potential for adhesion problems early in the development process. It was hypothesized that favorable intermolecular interaction between the drug molecules and the punch face is the first step or criterion in the adhesion process. Therefore, the rank order of adhesion during tablet compression should follow the rank order of these energies of interaction. The adhesion phenomenon was investigated using molecular simulations and contact mode atomic force microscopy (AFM). Three model compounds were chosen from a family of "profen" compounds. Silicon nitride AFM tips were modified by coating a 20-nm iron layer on the surfaces by sputter coating. Profen flat surfaces were made by melting and recrystallization. The modified AFM probe and each profen surface were immersed in the corresponding profen saturated water during force measurements using AFM. The work of adhesion between iron and ibuprofen, ketoprofen, and flurbiprofen in vacuum were determined to be -184.1, -2469.3, -17.3 mJ. m(-2), respectively. The rank order of the work of adhesion between iron and profen compounds decreased in the order: ketoprofen > ibuprofen > flurbiprofen. The rank order of interaction between the drug molecules and the iron superlattice as predicted by molecular simulation using Cerius(2) is in agreement with the AFM measurements. It has been demonstrated that Atomic Force Microscopy is a powerful tool in studying the adhesion phenomena between organic drug compounds and metal surface. The study has provided insight into the adhesion problems occurring during tablet compression and a direction for continued study.