Classification of Inhibitors of Hepatic Organic Anion Transporting Polypeptides (OATPs): Influence of Protein Expression on Drug–Drug Interactions

ABSTRACT: The hepatic organic anion transporting poly-peptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug−drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors

Factors Associated with Functional Decline in Elderly Female Breast Cancer Patients in Appalachia

Background Functional status has been previously shown in the elderly cancer population to predict both mortality as well as treatment tolerance. The goal of this study was to determine if there are certain subsets of the elderly breast cancer population that are at higher risk of experiencing functional decline following treatment. Methods Patient charts from the Edwards Comprehensive Cancer Center in Huntington, West Virginia, from January 2006 - January 2016 were reviewed. Relevant inclusion criteria included patients of 65 years of age and older with a new diagnosis of Stage 0-III breast cancer. Functional decline was defined as an increase of at least one point in Eastern Cooperative Oncology Group (ECOG) scores within one year of diagnosis. ECOG performance status was subjectively determined by the physician. Fisher's exact test and Pearson's Chi-squared test were initially utilized to assess potential factors associated with functional decline such as pretreatment ECOG score, age at diagnosis, stage, hormone receptor status, type of surgery received, whether radiation therapy, chemotherapy, or hormonal therapy was received, medical comorbidities, body mass index (BMI), complaints of weakness at diagnosis, and ambulatory status. Factors that were found to be significant were further assessed via multivariate logistic regressions. Results Three-hundred and fourteen patients were identified as meeting inclusion criteria. At one-year follow-up, 45 patients (14.3% of the cohort) had documented functional decline. On initial analysis, factors associated with functional decline included Stage III disease (p=0.002) and complaints of weakness at diagnosis (p=0.004). Following multivariate analysis, Stage III disease (p = 0.02), complaints of weakness at diagnosis (p = 0.04), and bilateral mastectomy (p = 0.03) were significantly associated with functional decline. Conclusion Patients who were diagnosed with Stage III breast cancer, had complaints of weakness at time of diagnosis, or had bilateral mastectomies were more likely to have a decline in functional status at one-year follow-up. Awareness of factors associated with functional decline in the elderly Appalachian population with Stage 0-III breast cancer will be useful during discussions regarding patient expectations, treatment, and goals of care. Elderly breast cancer patients for whom bilateral prophylactic mastectomies are not indicated may be better served by lumpectomy alone (based on patient age, hormone receptor status, and tumor size), lumpectomy followed by radiation therapy, or unilateral mastectomy to maximize the likelihood of functional preservation following treatment.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Fyoozhun [Incorporated]: A business plan

Executive Summary. FYOOZHUN INCORPORATED is a corporation that is formed to answer the ever-changing needs of consumers. It is located at #7 Nottingham St. Hillsborugh Alabang Village, Cupang, Muntinlupa. Fashion is beginning to be expensive and the nine proponents took the challenge of designing, manufacturing, and selling their unique and innovative product, Futwurx sandals. These are sandals with interchangeable straps that can fit your mood and style. It\u27s innovation allows consumers to change the strap designs based on their preferences. This allows the consumer to buy less pairs and be practical, yet be fashionable at the same time. The primary market of this innovative, versatile and practical product is composed of schools and villages located in the Alabang, Parañaque, Muntinlupa and Makati. These are St. Francis of Assisi High School, De La Salle Santiago Zobel School, Assumption College and Merville Village. The total population of the primary market is 359 respondents. Three hundred fifty nine respondents from the above mentioned schools and village were selected through systematic random sampling and were surveyed by requesting them to answer a carefully formulated and pretested questionnaire. Upon completion of the survey, the data gathered were analyzed and interpreted. The market acceptability rate of Futwurx was determined to be 82.21% for the primary target market. Majority (84.1%) of the respondents found the product unique and innovative, with 85.2% willing to buy it. Monthly potential demand was computed to be 229 units. Market share of FYOOZHUN INCORPORATED for Futwurx was 62.88%. Using the time and motion study, the proponents determined that for Futwurx, the assembly line method would be the most effective method of production. The manufacturing process goes as follows: the patterns for the sole and straps are traced and cut on different materials the different cut materials of the insole are bonded by rugby and primer is applied to the rubber sole these are sent to the sub-contractor for buffing and pressing the different cut materials of the straps are swen together and Futwurx is packaged. Within one production day, an average of 36 units of the product can be produced. Maximum output is 57 units while minimum output is 15 units. Cycle time for the production of one unit of Futwurx sandals is approximately 13 minutes, with the percentage of efficiency at 83.62%. Production cost per unit was computed to be P 163.28, while selling price of the product was computed to be P300.00. Break-even analysis showed that FYOOZHUN INCORPORATED needs to sell approximately 12 units of Futwurx, or achieve gross sales of P 3,423.91 per month. to avoid incurring losses. Corporation is the type of business ownership that the proponents have chosen because of its advantages. The corporate name FYOOZHUN INCORPORATED was chosen because the proponents are a fusion of different talents and ideas. The corporation will exist for 10 months. The stockholders and the board of directors are the proponents themselves. Each one of them has duties and responsibilities to perform as well as rules and regulations to follow. The different pre-operation, operation, and post-operation activities are also to be underwent by the proponents during its term of existence. Financial assumptions are specified for the proponents to follow. The proponents will finance the business through the help of their parents. Borrowing from financial institutions is not allowed. The project cost required to finance the first month of operation is P 17,000.00. Budgets were prepared to estimate the amounts of expenses to be incurred by the company. Projected financial statements are also provided to show the expected income from the business and the assets of the corporation. The said business is said to generate an income of P 596,400.00 at the end of its existence. The return on investment is 1,606.79% while the return on equity is 94.41%. This means that the business is very profitable and the proponents are able to utilize their assets effectively. In conclusion, the project is found to be feasible based on the studies made. However, the proponents must still consider factors that might affect the operations of the business in the future such as inflation and economic recession. keeping an open mind and keeping the initiative and determination will surely make the business a successful one

Anticancer Activity of Region B Capsaicin Analogs

The heterocyclic vanilloid compound capsaicin is responsible for the spicy and pungent flavor of chili peppers. Several convergent studies have shown that capsaicin suppresses the growth of multiple human cancers. Apart from capsaicin, natural and synthetic capsaicin-like compounds display growth suppressive activity in human cancers. The pharmacophore of capsaicin is comprised of three regions, namely region A (the aromatic ring), region B (the amide bond), and region C (the side chain). The present manuscript describes the isolation and synthesis of capsaicin analogs which have structural modifications in region B of the molecule. Furthermore, the pharmacokinetic properties, anticancer activity of region B capsaicin analogs, as well as the signaling pathways (underlying the growth-inhibitory effects of region B capsaicin analogs) have also been described. The discovery of novel, second-generation region B capsaicin analogs may foster the hope of innovative nutrition-based combination therapies in human cancers