脂质蓄积指数和内脏脂肪指数对成年人代谢综合征的预测价值研究

背景　脂质蓄积指数（LAP）和内脏脂肪指数（VAI）是反映个体脂肪分布及内脏脂肪蓄积程度的重要指标，与肥胖相关的慢性代谢性疾病关系密切。目的　探讨LAP和VAI与成年人代谢综合征（MS）的相关性，并评估LAP、VAI对MS的预测价值。方法　纳入2018年9月至2019年5月在中日友好医院体检中心进行体检的708例受试者，其中MS患者249例（MS组），非MS患者459例（非MS组），比较两组患者LAP、VAI及相关生化指标。根据LAP、VAI四分位数将受试者进行分组（L1组、L2组、L3组、L4组各177例；V1组、V2组、V3组、V4组各177例），比较各组MS及其组分发生率。采用多因素Logistic回归分析计算不同LAP、VAI受试者MS的发生风险，并分别绘制不同性别LAP、VAI、腰围（WC）、体质指数（BMI）预测MS发生风险的受试者工作特征（ROC）曲线。结果　LAP和VAI与成年人MS发生率呈高强度正相关（Cramer's V=0.585、0.577）。多因素Logistic回归分析结果显示，在调整各危险因素后，L3组、L4组MS发生风险仍高于L1组，V3组、V4组MS发生风险仍高于V1组（P<0.001）。ROC曲线分析结果显示，男性LAP、VAI预测MS发生风险的ROC曲线下面积（AUC）分别为0.831〔95%CI（0.795，0.867）〕、0.825〔95%CI（0.788，0.863）〕，临界值分别为52.03、1.99；女性LAP、VAI预测MS发生风险的AUC分别为0.887〔95%CI（0.834，0.940）〕、0.886〔95%CI（0.827，0.945）〕，临界值分别为54.84、2.54。结论　LAP、VAI与成年人MS发生率呈高强度正相关，随着LAP、VAI增高，MS发生风险亦增高；LAP、VAI对MS有良好的预测价值，联合WC和BMI能有效预测MS。     

Solving the Faddeev-Merkuriev Equations in Total Orbital Momentum Representation via Spline Collocation and Tensor Product Preconditioning

The computational approach for solving the Faddeev-Merkuriev equations in total orbital momentum representation is presented. These equations describe a system of three quantum charged particles and are widely used in bound state and scattering calculations. The approach is based on the spline collocation method and exploits intensively the tensor product form of discretized operators and preconditioner, which leads to a drastic economy in both computer resources and time.     

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.     

Insights into the Progression of Labile Hb A1c to Stable Hb A1c via a Mechanistic Assessment of 2,3-Bisphosphoglycerate Facilitation of the Slow Nonenzymatic Glycation Process

Nonenzymatic glycation (NEG) of human hemoglobin (Hb A) consists of initial non covalent, reversible steps involving glucose and amino acid residues, which may also involve effector reagent(s) in the formation of labile Hb A_1c (the conjugate acid of the Schiff base). Labile Hb A_1c can then undergo slow, largely irreversible, formation of stable Hb A_1c (the Amadori product). Stable Hb A_1c is measured to assess diabetic progression after labile Hb A_1c removal. This study aimed to increase the understanding of the distinctions between labile and stable Hb A_1c from a mechanistic perspective in the presence of 2,3-bisphosphoglycerate (2,3-BPG). 2,3-Bisphosphoglycerate is an effector reagent that reversibly binds in the Hb A_1c pocket and modestly enhances overall NEG rate. The deprotonation of C2 on labile Hb A_1c in the formation of the Amadori product was previously proposed to be rate-limiting. Computational chemistry was used here to identify the mechanism(s) by which 2,3-BPG facilitates the deprotonation of C2 on labile Hb A_1c. 2,3-Bisphosphoglycerate is capable of abstracting protons on C2 and the α-nitrogen of labile Hb A_1c and can also deprotonate water and/or amino acid residues, therefore preparing these secondary reagents to deprotonate labile Hb A_1c. Parallel reactions not leading to an Amadori product were found that include formation of the neutral Schiff base, dissociation of glucose from the protein, and cyclic glycosylamine formation. These heretofore under appreciated parallel reactions may help explain both the selective removal of labile from stable Hb A_1c and the slow rate of NEG.     

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.     

How to Tailor Structural Colors for Extended Visibility and White Light Generation Employing Direct Laser Interference Patterning

The appearance of a surface can be controlled by creating periodic microstructures designed to diffract light and produce structural colors. Nevertheless, since structural coloration is based on diffraction, the produced colors have a strong dependence on the viewing angle and absence of coloration takes place while tilting the samples. In this work direct laser interference patterning is used to firstly provide transparent polymer sheets a structural coloration with a high‐range observation angle, and secondly to demonstrate the combination of structural colors, producing a white coloring effect. The employed approaches are based on the fabrication of micro‐gratings with multiple periods in the same structured area and on the engineering of the diffraction orders of the diffraction spectrum. The patterned surfaces are characterized by confocal microscopy and angular spectrometry in reflection mode. The morphological characterization shows homogeneous surface patterns, while the spectral results demonstrate that combining four spatial periods on a single patterned surface, a white appearance is obtained over an angular observation range higher than 30°. The experimental results are supported by theoretical predictions by means of generalized formulas based on the diffraction of light.     

Innovation in Chemistry,Manufacturing, and Controls—A Regulatory Perspective From Industry

This review describes the landscape of novel modalities such as cell and gene therapies, viruses, other novel biologics, oligomers, and emerging technologies, including modern analytics. We summarize the regulatory history and recent landmark developments in some major markets and examine specific chemistry, manufacturing, and controls (CMC) challenges, including suggestions for exploration of potential science-based approaches in support of regulatory strategy development from an industry perspective. In addition, we evaluate the economic factors contributing to patient access to innovation and discuss the impact of regulation. There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools. Although these tools are well described in current guidance documents, the specifics of applicability to complex novel modalities can still result in differing regulatory advice and outcomes. The future goals for efficiently regulating innovative modalities and technologies could be aided by more regulatory harmonization, regulatory education, and industry cooperation through consortia, enabling industry to supply key information to regulators in a transparent yet well-defined manner, and utilizing mutually understood risk-benefit analyses to produce drugs with appropriate safety, efficacy, and quality characteristics.     

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。