Anti-glycative and anti-inflammatory effects of protocatechuic acid in brain of mice treated by d-galactose

Protocatechuic acid (PCA) at 0.5%, 1% or 2% was supplied to d-galactose (DG) treated mice for 8 week. PCA intake at 2% increased its deposit in brain. DG treatment increased brain level of reactive oxygen species, protein carbonyl, carboxymethyllysine, pentosidine, sorbitol, fructose and methylglyoxal (P < 0.05). PCA intake, at 1% and 2%, lowered brain level of these parameters (P < 0.05). DG treatments enhanced activity and protein expression of aldose reductase (AR) and sorbitol dehydrogenase, as well as declined glyoxalase I (GLI) activity and protein expression (P < 0.05). PCA intake at 1% and 2% reduced activity and protein expression of AR (P < 0.05), and at 2% restored GLI activity and expression (P < 0.05). DG injection also elevated cyclooxygenase (COX)-2 activity and expression, and increased the release of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and prostaglandin E₂ in brain (P < 0.05). PCA intake decreased these cytokines (P < 0.05), and at 1% and 2% suppressed COX-2 activity and expression (P < 0.05). PCA intake at 1% and 2% also lowered DG-induced elevation in activity, mRNA expression and protein production of nuclear factor kappa B p65 (P < 0.05). These findings suggest that the supplement of protocatechuic acid might be helpful for the prevention or alleviation of aging.     

Conversion factors for determining organ doses received by paediatric patients in high-resolution single slice computed tomography with narrow collimation

Estimations of organ doses D_T received during computed tomographic examinations are usually performed by applying conversion factors to basic dose indicators like the computed tomography dose index (CTDI) or the dose-length-product (DLP). In addition to the existing conversion factors for beam apertures of 5 mm or 10 mm, we present new DLP-D_T conversion factors adapted to high-resolution CT (HRCT) examinations of infants and young children with beam apertures of the order of 1 mm and under consideration of bow tie filtration. Calculations are performed on mathematical MIRD phantoms for an age range from 0, 1, 5, 10, 15 up to (for comparison) 30 years by adapting PCXMC, a Monte Carlo algorithm originally developed by STUK (Helsinki, Finland) for dose reconstructions in projection radiography. For this purpose, each single slice CT examination is approximated by a series of corresponding virtual planar radiographies comprising all focus positions. The transformation of CT exposure parameters into exposure parameters of the series of corresponding planar radiographies is performed by a specially developed algorithm called XCT. The DLP values are evaluated using the EGSRay code. The new method is verified at a beam aperture of 10 mm by comparison with formerly published conversion factors. We show that the higher spatial resolution leads to an enhanced DLP-D_T conversion factor if a small organ (e. g. thyroid gland, mammae, uterus, ovaries, testes) is exactly met by the chosen CT slice, while the conversion factor is drastically reduced if the chosen CT slice is positioned above or below the organ. This effect is utilized for dose-saving examinations with only a few single slices instead a full scan, which technique is applied in about 10% of all paediatric chest CT examinations.     

Bioequivalence and Food Effect of Dapagliflozin/Saxagliptin/Metformin Extended-release Fixed-combination Drug Products Compared With Coadministration of the Individual Components in Healthy Subjects

PurposeFixed-combination drug products (FCDPs) for patients with type 2 diabetes mellitus (T2DM) may show efficacy comparable to their individual components (ICs) while improving adherence to treatment. This study evaluated the bioequivalence and safety of 2 dapagliflozin/saxagliptin/metformin extended-release (XR) FCDPs relative to their ICs: saxagliptin and dapagliflozin/metformin XR.MethodsThis randomized, open-label, single-dose, single-center crossover study was conducted in 84 healthy subjects aged 18–55 years. The primary objective was to evaluate the fed-state bioequivalence of a dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP and a dapagliflozin 10-mg/saxagliptin 5-mg/metformin 1000-mg XR FCDP relative to the ICs. Secondary objectives included the evaluation of the effect of food on the pharmacokinetic (PK) parameters of saxagliptin, dapagliflozin, and metformin in both FCDPs and characterization of the PK parameters of the active metabolite of saxagliptin, 5-hydroxy saxagliptin, in healthy subjects. PK parameters (AUC_0–∞, AUC_0–t, and C_max) were used to assess the bioequivalence of the 2 FCDPs with their ICs. The C_max and AUC_0–t of the study drugs were compared between female and male subjects to assess sex differences in exposure. Safety and tolerability of both FCDPs and ICs were also assessed with adverse events, vital signs (systolic and diastolic blood pressures and pulse rate), 12-lead ECG, physical examinations, and laboratory assessments.FindingsBoth dapagliflozin/saxagliptin/metformin XR FCDPs were bioequivalent to their ICs. For the dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP, the 90% CI for the geometric mean ratio of dapagliflozin C_max was slightly above the 80%–125% bioequivalence limit, which is unlikely to be clinically relevant. Food delayed the absorption of the study drugs in both FCDPs, which is unlikely to have a clinically relevant impact on efficacy. In both cohorts, exposure was higher in female subjects compared with male subjects, potentially due to the lower body weight of the female subjects. The safety profile and tolerability of the FCDPs were similar to those of their ICs, and no deaths or serious adverse events were reported.ImplicationsThese data support the use of the dapagliflozin/saxagliptin/metformin XR FCDP in patients with T2DM. ClinicalTrials.gov identifier: NCT03169959.     

A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms

Abstract

This paper proposes the development of a drug product Manufacturing Classification System (MCS) based on processing route. It summarizes conclusions from a dedicated APS conference and subsequent discussion within APS focus groups and the MCS working party. The MCS is intended as a tool for pharmaceutical scientists to rank the feasibility of different processing routes for the manufacture of oral solid dosage forms, based on selected properties of the API and the needs of the formulation. It has many applications in pharmaceutical development, in particular, it will provide a common understanding of risk by defining what the “right particles” are, enable the selection of the best process, and aid subsequent transfer to manufacturing. The ultimate aim is one of prediction of product developability and processability based upon previous experience.

This paper is intended to stimulate contribution from a broad range of stakeholders to develop the MCS concept further and apply it to practice. In particular, opinions are sought on what API properties are important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. Feedback can be given by replying to our dedicated e-mail address (mcs@apsgb.org); completing the survey on our LinkedIn site; or by attending one of our planned conference roundtable sessions.     

从结构相似模型化合物进行天然产物结构鉴定-以番石榴叶黄酮苷类化合物鉴定为例

天然产物的结构鉴定主流手段是核磁共振波谱法,与结构相似模型化合物的核磁数据进行比较,确定未知化合物结构是一种重要的方式。论文从结构鉴定过程中有机分子可分拆解析,如何寻找相似模型化合物和实例例举3个方面,探讨相似模型化合物对于未知图谱结构鉴定的作用和意义,并建议在平时的结构分析过程中注重模型化合物数据的收集和积累。     

2014年上半年国内22城市（地区）样本医院用药分析

本文分析了国内22城市（地区）样本医院用药数据，发现，近三年样本医院购入药品总金额增幅继续保持在12％左右，整个医院市场趋于平稳；抗感染药物目前己进入常态化管理，已从负增长的困境中走出，该大类药物在样本医院中所占份额不容忽视；供应医院领先厂商中进口、合资企业较本土企业稍占优势，提示，二三级医院对药品的临床使用效果或药品的来源及质量相当重视。     

Survival after transfusion in the Netherlands

Background Cost‐effectiveness analyses of blood safety interventions require estimates of the life expectancy after blood product transfusion. These are best derived from survival after blood transfusion, per age group and blood component type. Study design and methods In the PROTON (PROfiles of TransfusiON recipients) study transfusion recipient data was collected from a hospital sample covering 28% of the total blood use between 1996 and 2006 in the Netherlands. The dataset includes date of transfusion, blood component type transfused and recipient identification details. PROTON data were individually matched to mortality data of the Netherlands. Survival after first transfusion and after any transfusion was calculated, per blood component type and age group. PROTON mortality rates were compared to mortality rates in the general population. The results were used to estimate survival beyond the study period and to estimate life expectancy after transfusion. Results Of all 2 405 012 blood product transfusions in the PROTON dataset, 92% was matched to the national Dutch Municipal Population Register, which registers all deaths. After 1 year, survival after any transfusion was 65·4%, 70·4% and 53·9% for RBC, FFP and PLT respectively. After 5 years, this was 46·6%, 58·8% and 39·3% for RBC, FFP and PLT, respectively. Ten years after transfusion, mortality rates of recipients are still elevated in comparison with the general population. Conclusion Mortality rates of transfusion recipients are higher than those of the general population, but the increase diminishes over time. The mortality rates found for the Netherlands are lower than those found in comparable studies for other countries.     

Investigation of Solid Dosage Form Components Interaction Using Orthogonal Techniques- Discovery of New Forms of Sodium Stearyl Fumarate

Physical or chemical interactions between drug product (DP) components can occur during manufacturing and/or upon storage; and may alter DP shelf life and performance. In this work a new Powder X-ray Diffraction (PXRD) peak was observed in DP under accelerated storage conditions. Due to the complex drug product matrix (including API, polymer, fillers, super disintegrant and lubricant), it was challenging to pinpoint the component(s) responsible for the new peak. In addition to PXRD, other orthogonal techniques including Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), Solid State Nuclear Magnetic Resonance (SSNMR) and Infrared (IR) spectroscopy were employed in this investigation to understand the root cause mechanistically. Specifically, multi nuclei SSNMR (¹H, ²³Na, ¹³C) was instrumental in delineating the components of the matrix. We identified the root cause to be an acid base reaction occurring in the DP, whereby sodium ion in sodium stearyl fumarate (SSF) is replaced by proton leading to SSF form conversion. We also identified commercially available SSF to be a hydrate that can dehydrate to an anhydrous form upon heating. In general, the same techniques can be used to investigate interactions of any multi component solid dosage forms.