Linking in vitro lipolysis and microsomal metabolism for the quantitative prediction of oral bioavailability of BCS II drugs administered in lipidic formulations

Lipidic formulations (LFs) are increasingly utilized for the delivery of drugs that belong to class II of the Biopharmaceutics Classification System (BCS). The current work proposes, for the first time, the combination of in vitro lipolysis and microsomal metabolism studies for the quantitative prediction of human oral bioavailability of BCS II drugs administered in LFs. Marinol® and Neoral® were selected as model LFs and their observed oral bioavailabilities (Fobserved) obtained from published clinical studies in humans. Two separate lipolysis buffers, differing in the level of surfactant concentrations, were used for digestion of the LFs. The predicted fraction absorbed (Fabs) was calculated by measuring the drug concentration in the micellar phase after completion of the lipolysis process. To determine first-pass metabolism (Fg∙Fh), drug depletion studies with human microsomes were performed. Clearance values were determined by applying the “in vitro half-life approach”. The estimated Fabs and Fg∙Fh values were combined for the calculation of the predicted oral bioavailability (Fpredicted). Results showed that there was a strong correlation between Fobserved and Fpredicted values only when Fabs was calculated using a buffer with surfactant concentrations closer to physiological conditions. The general accuracy of the predicted values suggests that the novel in vitro lipolysis/metabolism approach could quantitatively predict the oral bioavailability of lipophilic drugs administered in LFs

Marijuana Use in Potential Liver Transplant Candidates

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73843/1/j.1600-6143.2008.02468.x.pd

Comparing Trial and Real-world Adjuvant Oxaliplatin Delivery in Patients With Stage III Colon Cancer Using a Longitudinal Cumulative Dose

Importance: Delivery of adjuvant chemotherapy can differ substantially between trial and real-world populations. Adherence metrics like relative dose intensity (RDI) cannot capture the timing of modifications and mask differences in the total amount of chemotherapy received. Objective: To compare oxaliplatin delivery between MOSAIC trial participants and patients treated in the US Oncology Network with stage III colon cancer using a longitudinal cumulative dose (LCD). Design, Setting, and Participants: This cohort study used secondary data from the MOSAIC trial, an international randomized clinical trial (concluded in 2004), and electronic health records from US Oncology (2009-2018), a network of community oncology practices in the US. It included participants in MOSAIC with stage III colon cancer who were randomized to receive treatment with oxaliplatin and fluorouracil/leucovorin (n = 663) and US Oncology patients with stage III colon cancer who were treated with a modified FOLFOX-6 regimen (n = 2523). Exposures: Oxaliplatin and fluorouracil/leucovorin. Outcomes and Measures: We evaluated RDI and LCD over time and at the end of treatment in the MOSAIC and US Oncology populations. We used bootstrapping to estimate 95% confidence bands for LCD differences between the populations. Results: The 663 MOSAIC participants (296 women [44.7%]) and 2523 US Oncology patients (1245 women [49.4%]) were generally similar with respect to demographic characteristics. Median RDI was lower in US Oncology (80% in MOSAIC vs 70% in US Oncology). The LCD also suggested differences in the total amount of oxaliplatin received between populations; the final median LCD in US Oncology was 10.2% lower than in MOSAIC, equivalent to receiving 1.2 fewer treatment cycles less of oxaliplatin. This difference only began 133 days into treatment and persisted after accounting for covariates, likely in terms of more frequent oxaliplatin treatment discontinuation in US Oncology patients than their MOSAIC counterparts. Conclusions and Relevance: The study results suggest that real-world patients in community practice in the US treated with modified FOLFOX 6 received less oxaliplatin than their historical counterparts in the MOSAIC trial, with differences manifesting late in the treatment course. The LCD allowed us to identify the amount and extent of these differences, the timing of which was unclear when using RDI alone. Trial Registration: ClinicalTrials.gov identifier: NCT00275210

Measure of quality of life for Taiwanese persons with early to moderate dementia and related factors

Background This study validates the Chinese Dementia-Quality of Life instrument (DQoL) in patients with early to moderate stages of Alzheimer's disease (AD) (Clinical Dementia Rating Scale, CDR = 0.5, 1, and 2; MMSE > = 12). Methods A cross-sectional design was used involving 98 participants (27 controls, 35 patients with questionable dementia (QD), and 36 patients with mild to moderate AD) and 51 paired family caregivers (FCs) (20 FCs of QD patients, 31 FCs of AD patients). FCs were recruited to evaluate patients' DQoL using the parallel form. Internal consistency, construct validity and concurrent validity of the DQoL were examined. Results The findings indicated that the Chinese DQoL instrument has stable internal consistency but only moderate validity when used in early to moderate AD participants with MMSE greater than, or equal to 12. The DQoL and Self-esteem subscales were significantly different across the three dementia severity groups. The values of internal consistency of the DQoL and its five subscales were high for the ratings of both the patients and the FCs. The interscale correlations for the DQoL were almost all significant for patients' and FCs' ratings. Agreement of the DQoL and its subscales for patients and FCs was significant. However, two inconsistencies were found in the results of the factor analysis and the prior conceptualization of patients' DQoL, the subscales of Self-esteem and Negative Affect. Global cognitive impairment and self-care problems significantly correlated with the patients' DQoL, while the patients' depressive symptoms and self-care problems significantly correlated with the FCs' DQoL. Conclusions The Chinese DQoL reported by early to moderate AD patients has good reliability, but moderate validity because the patients' depressive symptoms did not correlate with their DQoL and the major subscales. Both patients' and FCs' ratings on DQoL are important in research and treatment decision making. Copyright © 2007 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58642/1/1938_ftp.pd

Depression diagnoses following the identification of bipolar disorder: costly incongruent diagnoses

<p>Abstract</p> <p>Background</p> <p>Previous research has documented that the symptoms of bipolar disorder are often mistaken for unipolar depression prior to a patient's first bipolar diagnosis. The assumption has been that once a patient receives a bipolar diagnosis they will no longer be given a misdiagnosis of depression. The objectives of this study were 1) to assess the rate of subsequent unipolar depression diagnosis in individuals with a history of bipolar disorder and 2) to assess the increased cost associated with this potential misdiagnosis.</p> <p>Methods</p> <p>This study utilized a retrospective cohort design using administrative claims data from 2002 and 2003. Patient inclusion criteria for the study were 1) at least 2 bipolar diagnoses in 2002, 2) continuous enrollment during 2002 and 2003, 3) a pharmacy benefit, and 4) age 18 to 64. Patients with at least 2 unipolar depression diagnoses in 2003 were categorized as having an incongruent diagnosis of unipolar depression. We used propensity scoring to control for selection bias. Utilization was evaluated using negative binomial models. We evaluated cost differences between patient cohorts using generalized linear models.</p> <p>Results</p> <p>Of the 7981 patients who met all inclusion criteria for the analysis, 17.5% (1400) had an incongruent depression diagnosis (IDD). After controlling for background differences, individuals who received an IDD had higher rates of inpatient and outpatient psychiatric utilization and cost, on average, an additional $1641 per year compared to individuals without an IDD.</p> <p>Conclusions</p> <p>A strikingly high proportion of bipolar patients are given the differential diagnosis of unipolar depression <it>after </it>being identified as having bipolar disorder. Individuals with an IDD had increased acute psychiatric care services, suggesting higher levels of relapses, and were at risk for inappropriate treatment, as antidepressant therapy without a concomitant mood-stabilizing medication is contraindicated in bipolar disorder. Further prospective research is needed to validate the findings from this retrospective administrative claims-based analysis.</p

Reviews: Quality of Life Measures for Residents of Aged Care Facilities: A Literature Review

With increases in life expectancy and increasing numbers of older people utilising residential aged care, there is a widely felt need to improve the quality of long term care for older people. One facet of quality of care being strongly advocated is the consumer perspective, in particular, the attainment of an optimum quality of life. Yet, despite the proliferation of quality of life measures, those with utility in the residential aged care setting are quite limited. This paper explores issues of quality of life measurement with particular emphasis on the availability and appropriateness of tools for use in the residential aged care setting. Residents of aged care facilities tend to be significantly frailer than the general population and are living in a distinctly different environment. The majority of quality of life measures available either do not measure issues relevant to residents of aged care facilities, such as control and autonomy, or they measure areas that are not appropriate, such as work status. Further, an over-emphasis on health and physical function and a lack of resident-centred measures may produce a more negative picture of quality of life, than actually experienced by this group of people. This paper argues for the utilisation of a standard quality of life research instrument that is resident-focused and includes the many facets and domains that comprise quality of life for the residential aged care recipient. Data from such a tool may assist policy makers in their decision-making, if used on a national basis