Statistical Methods for Conditional Survival Analysis

We investigate the survival distribution of the patients who have survived over a certain time period. This is called a conditional survival distribution. In this paper, we show that one-sample estimation, two-sample comparison and regression analysis of conditional survival distributions can be conducted using the regular methods for unconditional survival distributions that are provided by the standard statistical software, such as SAS and SPSS. We conduct extensive simulations to evaluate the finite sample property of these conditional survival analysis methods. We illustrate these methods with real clinical data.     

Modified translationally controlled tumor protein-derived protein transduction domain enhances nasal delivery of exendin-4 as shown with insulin

Protein transduction domains (PTDs) have been shown to promote the delivery of therapeutic proteins or peptides into the living cells. In a previous study, we showed that the double mutant of TCTP-PTD 13, TCTP-PTD 13M2, was more effective in the delivery of insulin than the wild-type TCTP-PTD 13. In this study, we applied this approach to the nasal delivery of a different peptide, exendin-4, using as carriers, several modified TCTP-PTDs, such as TCTP-PTD 13M1, 13M2, and 13M3. Nasal co-administration of TCTP-PTD 13M2 with exendin-4 showed the highest exendin-4 uptake among the three analogs in normal rats, and also decreased blood glucose levels by 43.3% compared with that of exendin-4 alone and by 18.6% compared with that of exendin-4 plus TCTP-PTD 13 in diabetic mice. We also designed an additional covalently linked conjugate of TCTP-PTD 13M2 and exendin-4 and evaluated its hypoglycemic effect after subcutaneous or intranasal delivery. Subcutaneous administration of exendin-4 that its C-terminus is covalently linked to TCTP-PTD 13M2 showed hypoglycemic effect of 42.2% compared to that in untreated group, whereas intranasal delivery was not successful in diabetic mice. We conclude that a simple mixing TCTP-PTD 13M2 with peptide/protein drugs can be potentially a generally applicable approach for intranasal delivery into animals.     

Two flavonol glycosides from <Emphasis Type="Italic">Liparis bootanensis</Emphasis>

Two new flavonol glycosides, bootanenside I and II (1 and 2), along with ten known compounds (3–12), were isolated from whole plant of Liparis bootanensis Griff. Their structures were elucidated on the basis of extensive spectroscopic analyses, including high-resolution electrospray-ionization mass spectrometry (HR–ESIMS) and one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR). The cytotoxicity of the compounds was investigated against HCT116 human cancer cell line, revealing that none of them possessed considerable cytotoxic activity. Bioassays of the new metabolites showed that compounds 1 and 2 displayed moderate in vitro antiinflammatory activity by inhibiting expression of inducible nitric oxide synthase (iNOS) protein in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells.     

Enzyme linked immunosorbent assay for total potent estrogenic miroestrol and deoxymiroestrol of <Emphasis Type="Italic">Pueraria candollei</Emphasis>, a Thai herb for menopause remedy

Miroestrol and deoxymiroestrol are the most potent phytoestrogens of Pueraria candollei var. mirifica, having been proved as an effective herb for menopausal symptoms in folk medicines and clinical trials. To ensure efficacy and safety of P. candollei var. mirifica involved in nutraceutical products being available worldwide, the content of potent phytoestrogens as active ingredients should be specified. Therefore, in this study, we produced a monoclonal antibody for total analysis of potent estrogenic miroestrol and deoxymiroestrol, for which an analytical method was developed using a procedure for an indirect competitive enzyme-linked immunosorbent assay. The antibody exhibited equal reactivity against miroestrol and deoxymiroestrol. The sensitivity of determination was in the range of 31.3–500 ng/ml with high precision. The analytical parameters, such as accuracy (99.6–106% recovery) and high correlation with a HPLC–UV method, indicated the reliability of analysis. This method is of high performance, and it is cheap to control optimal miroestrol and deoxymiroestrol doses of P. candollei var. mirifica nutraceutical products.     

Total syntheses of schizandriside,saracoside and (±)-isolariciresinol with antioxidant activities

Lignans are widely distributed in plants and exhibit significant pharmacological effects, including anti-tumor and antioxidative activities. Here, we describe the total synthesis of schizandriside (1), a compound we previously isolated from Saraca asoca by monitoring antioxidative activity using the 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay. Starting from a tandem Michael-aldol reaction, the lignan skeleton was synthesized in 6 steps, including a cyclization step. To determine the stereochemistry of 1, we synthesized the natural product (±)-isolariciresinol (18) from alcohol 17. Comparison of the spectral data showed good agreement. Glycosylation was investigated using four different glycosyl donors. Only the Koenigs–Knorr condition using silver trifluoromethanesulfonate with 1,1,3,3-tetramethylurea provided the glycosylated product. Deprotection and purification using reverse-phase high-performance liquid chromatography gave schizandriside (1) and its diastereomer saracoside (2). Synthesized 1, 2 and 18 showed antioxidant activity with IC₅₀?=?34.4, 28.8, 53.0 μM, respectively.     

Pharmacists' interventions to reduce sedative/hypnotic use for insomnia in hospitalized patients

Background

Hospitalization can contribute to insomnia in many patients and is usually treated symptomatically. However, sedative/hypnotic misuse is associated with complications in this population, especially in the elderly. Such complications include dizziness, falls and over-sedation. Due to the implicit dangers, widespread use of these drugs for insomnia, particularly in older patients, has been discouraged by many hospitals. The aim of this study was to review and evaluate prescribing patterns and to optimize the use of the sedative/hypnotic agents through daily pharmacy interventions at a community hospital.

The anti-tumor effect of pachymic acid on osteosarcoma cells by inducing PTEN and Caspase 3/7-dependent apoptosis

Pachymic acid (PA) is a lanostane type triterpenoid isolated from Poria cocos, which possesses an anti-tumor effect in breast cancer, prostate cancer, lung cancer, and bladder cancer cells. In this study, we investigated the effect of PA on the growth and apoptosis of human immortalized cell line (HOS) and primary osteosarcoma cells by a Cell Counting Kit-8 (CCK-8) and Annexin V and propidium iodide (PI) staining, respectively. Western blot was used to measure the expression of cleaved Caspase 3, PTEN, and AKT, as well as the AKT phosphorylation. The Caspase 3 activity was determined using the Caspase-3 Colorimetric Assay Kit. From the results, PA significantly reduced cell proliferation in a concentration- and time-dependent manner. PA also induced cell apoptosis in a dose-dependent fashion. PA treatment led to increased Caspase 3 activation and PTEN expression, as well as reduced AKT phosphorylation. Moreover, Ac-DEVD-CHO (a Caspase 3/7 inhibitor) pre-treatment or PTEN knockdown partially blocked the effects of PA on cell proliferation and apoptosis. Caspase 3/7 inhibitor had an additive effect with PTEN knockdown. Collectively, our results suggested that induction of apoptosis by PA was mediated in part by PTEN/AKT signaling and Caspase 3/7 activity. This study provides evidence that PA might be useful in the treatment of human osteosarcoma.     

Two new secoiridoid glucosides and a new lignan from the roots of <Emphasis Type="Italic">Ilex pubescens</Emphasis>

Two new secoiridoid glucosides, ilexpublignoside (1), pubzenoside (2), and a new lignan, ilexlignan B (3), along with seven known compounds (4–10) were isolated from the roots of Ilex pubescens for the first time. Their chemical structures were elucidated on the basis of extensive spectroscopic methods, including IR, UV, HR-ESI–MS, CD, NMR experiments, as well as comparison with the reported data.