具有两阶段结构的自治SI传染病模型

就一类具有两阶段结构和非时滞的自治 SI传染病模型进行了研究 ,讨论了疾病消除平衡点与地方病平衡点的局部渐近稳定性及全局渐近稳定性 ,得到了传染病最终消除的结论     

一种非线性传染病模型的定性分析

探讨了一类具有非线性传染率的传染病模型平衡点的稳定性及周期解存在唯一性的条件。     

预防传染病mRNA疫苗成品质量控制要点分析

mRNA疫苗已经开发近30年,但由于生产环节、稳定性和反应原性存在一定的技术瓶颈,导致mRNA疫苗发展较为缓慢。如今,基于预防COVID-19的mRNA疫苗的应用,充分验证了预防传染病mRNA疫苗的有效性和安全性。本文通过梳理WHO及药品监管和标准化机构关于预防传染病mRNA疫苗成品质控的指导文件,总结归纳预防传染病mRNA疫苗成品关键质量控制属性及相关要求,旨在为中国预防传染病mRNA疫苗质量控制提供参考。     

具超音速边界可压Navier-Stokes方程解的指数衰减

考虑了二维空间上具超音速物理边界的可压Navier-Stokes方程的初边值问题.给定常数平衡态$(\rho^{\ast},0)$,得到了所考虑问题解的整体存在性. 在平衡态附近的小扰动下, 利用加权能量估计方法得到解的指数衰减性.     

传染病体外诊断试剂标准物质研制技术要求的介绍

传染病体外诊断试剂标准物质是指用于与致病性病原体抗原、抗体以及核酸等检测相关的试剂质量评价的标准物质。为进一步规范该类标准物质的研制工作,中检院制定了相关的研制技术规范。本文详细介绍该规范中对传染病体外诊断试剂标准物质的原材料、制备、标定、稳定性研究、包装、储存及供应方面的要求。     

Hopfield型连续神经网络模型的稳定性

利用单调流方法得到一类 Hopfield型连续神经网络模型存在唯一全局渐近稳定正平衡态的充分条件     

药物经离体角质层渗透的非平衡态特性药物经离体角质层渗透的非平衡态特性

目的阐述药物在经角质层渗透过程中的非平衡态特性,为经皮给药技术提供理论和方法。方法把离体扩散池系统设定为孤立系统,建立系统达到平衡态的条件和网络热力学模型。以替硝唑为模式药物,进行非平衡态实验和漏糟实验。结果非平衡态包括:达到平衡态的长时程性;渗透启动的延迟性;初始通量的不确定性。漏糟包括:渗透通量递减性;渗透时间常数的可变性。结论扩散池药物经角质层渗透系统是一个非线性时变系统。     

一类含有潜伏期的传染病动力学模型

在不考虑人群具有迁移和人群具有出生与死亡的情形下 ,应用动力学方法建立了含有潜伏期且在潜伏期和发病期内均具有传染性的传染病模型 ,并利用 Liapunov-Lasalle定理和 Routh-Hurwits判据证明了疾病消除平衡点和地方病平衡点的稳定性。     

纳米疫苗的发展与应用

传统疫苗在传染病防治领域发挥了重要作用,但其仍不同程度地存在安全性差、免疫原性低、稳定性差、难以诱导持久免疫反应等问题。纳米递送系统可提高抗原稳定性并靶向抗原提呈细胞,促进抗原提呈细胞成熟并激活特异性免疫反应。目前已有大量研究利用纳米递送载体制备高效疫苗。该文简要阐述纳米递送载体在增强疫苗免疫效应中的应用。     

一类多传染阶段的艾滋病模型

当前国内外对艾滋病传染模型的研究引起了广泛的重视，在各种不同的假设下，建立了各种不同的模型。随着研究的深入，所建立的模型正在逐步接近实际。本文在文〔１〕、〔２〕和〔３〕的基础上作进一步的讨论，除了考虑将ＨＩＶ感染者分成ｎ个不同感染阶段外，还对性接触数不为常数而是性活动积极者总数Ｎ的函数的情况，来建立模型和进行分析，以得出复发数与疾病消除平衡态及流行平衡态之关系的阈值定理。     

生物标志物免疫分析方法学验证难点：稳定性

在生物标志物分析方法学验证项中,稳定性验证是难点。与药动学分析不同的是,生物标志物分析待测物为内源性物质,其稳定性与标准品（一般为重组蛋白）有很大不同。所以,生物标志物稳定性验证样品应采用内源性真实样本。但是受分析方法变异影响,内源性真实样本的准确浓度无法得知,而且难以获取新鲜的未冻存过的样本,最终导致稳定性的接受标准难以界定。运用趋势控制图和计算机分析等手段可以更准确地判断生物标志物的稳定性。     

Renin inhibitors based on dipeptide analogues. Incorporation of the hydroxyethylene isostere at the P2/P3 sites

The synthesis of a series of renin inhibitors in which the P2 and P3 amino acids are replaced with the hydroxyethylene dipeptide isostere is reported. In vitro evaluation of the inhibitors has revealed that this isostere is an acceptable amide-bond replacement in which activity is maintained and stability is enhanced. Structure-activity relationships of this series resemble but do not parallel those of the corresponding dipeptide-containing inhibitors.     

A Fast Method for Testing Covariates in Population PK/PD Models

The development of covariate models within the population modeling program like NONMEM is generally a time-consuming and non-trivial task. In this study, a fast procedure to approximate the change in objective function values of covariate-parameter models is presented and evaluated. The proposed method is a first-order conditional estimation (FOCE)-based linear approximation of the influence of covariates on the model predictions. Simulated and real datasets were used to compare this method with the conventional nonlinear mixed effect model using both first-order (FO) and FOCE approximations. The methods were mainly assessed in terms of difference in objective function values (ΔOFV) between base and covariate models. The FOCE linearization was superior to the FO linearization and showed a high degree of concordance with corresponding nonlinear models in ΔOFV. The linear and nonlinear FOCE models provided similar coefficient estimates and identified the same covariate-parameter relations as statistically significant or non-significant for the real and simulated datasets. The time required to fit tesaglitazar and docetaxel datasets with 4 and 15 parameter-covariate relations using the linearization method was 5.1 and 0.5 min compared with 152 and 34 h, respectively, with the nonlinear models. The FOCE linearization method allows for a fast estimation of covariate-parameter relations models with good concordance with the nonlinear models. This allows a more efficient model building and may allow the utilization of model building techniques that would otherwise be too time-consuming.     

Ligand-induced stabilization and activation of peroxisome proliferator-activated receptor gamma

Peroxisome proliferator-activated receptor gamma belongs to the nuclear receptor superfamily and is activated by the antidiabetic drugs rosiglitazone and pioglitazone. Ligand-independent constitutive activity of peroxisome proliferator-activated receptor gamma is also demonstrated. X-ray crystallographic structures show that the active or inactive conformations of the receptor are determined by the position of helix 12 in the C-terminal end. In this study, molecular dynamics simulations were used to gain molecular insight into the activation process and the structural stability of inactive and active peroxisome proliferator-activated receptor gamma receptor structure. The simulations showed: (i) during molecular dynamics simulations without agonist at the active site, the receptor structure with helix 12 in a position corresponding to activated receptor structure was structurally more stable than with helix 12 in a position corresponding to inactive receptor structure, which may contribute to the constitutive activity of the receptor; (ii) docosahexenoic acid stabilized the active receptor conformation more efficiently than the glitazones; (iii) docosahexenoic acid, but not glitazones, induced structural changes into the inactive receptor structure such that helix 12 was shifted into a position more similar to that of an active receptor structure, which indicate that docosahexenoic acid is a more effective peroxisome proliferator-activated receptor gamma agonist than the glitazones.     

Replacing succinate with glycolate buffer improves the stability of lyophilized interferon-γ

Lyophilization is commonly used to dry protein pharmaceuticals to enhance their shelf life. During the freezing step of this process, significant events (e.g. pH shifting) can occur in the uncrystallized, liquid portion which influence the stability of the product. Herein, we present evidence of such an effect and the impact on the quality of recombinant human interferon-γ (IFN-γ) lyophilized from mannitol-containing succinate buffer at pH 5. In the frozen matrix, we hypothesize that the monosodium form of succinic acid crystallized, as evidenced by electrical resistance data, affecting the buffer system's ability to maintain pH, as probed by Fourier-transform infrared (FT-IR) spectroscopy. The latter indicated that the succinate buffer lyophilized from aqueous solution at pH 5 exhibited an ionization state corresponding to that of some 1–2 pH units lower. In exploring the implications for stability, we found that IFN-γ exhibited a marked bioactivity loss during aqueous incubation at pH 3 compared with pH 5. This loss correlated with (reversible) unfolding of the IFN-γ molecule at low pH, as determined by both FT-IR spectroscopy and circular dichroism. We also examined the stability of IFN-γ following lyophilization from pH 5 in two different buffer systems, succinate and glycolate. The latter, which appeared to minimize the freeze-induced pH shifting, exhibited superior solid-state stability upon 4-week incubation at 25°C. Both samples had a similar cake structure (based on X-ray diffraction and differential scanning calorimetry) and had the same residual moisture content. The data suggest that the difference in stability was a consequence of the freeze-induced pH shifting in the succinate buffer system, resulting in a more perturbed (solid-state) structure for IFN-γ. This is consistent with our FT-IR spectroscopic analysis of the lyophilized protein.     

Mechanism and Impact of Excipient Incompatibility: Cross-Linking of Xanthan Gum in Pediatric Powder-for-Suspension Formulations

Research on pharmaceutical pediatric powder-for-suspension formulations mainly focuses on chemical and physical stability of the active pharmaceutical ingredient. However, the chemical stability of excipients could also play a key role in governing the quality and performance of the product. The suspending agents that are added into formulations to suspend the active pharmaceutical ingredient particles are critical to ensure the suspension dose accuracy. In this article, we investigate the chemical stability of the suspending agent—xanthan gum—in the presence of other excipients, particularly commonly used acid modifiers (i.e., citric acid, malic acid, succinic acid, and fumaric acid) in pediatric powder-for-suspension formulations. We observed that some of the acid modifiers catalyze cross-linking of xanthan gum during accelerated stability studies in powder blends, which significantly decreases the viscosity of the corresponding constituted suspension, resulting in poor suspendability and dose inaccuracy. Furthermore, we found that the cross-linking of xanthan gum is acid-dependent and that a careful selection of acid modifiers can mitigate the degradation issues of xanthan gum. Finally, we characterized the cross-linked xanthan gum using Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance and discussed the possible degradation mechanisms.     

Guidelines for the practical stability studies of anticancer drugs: a European consensus conference

Stability studies performed by the pharmaceutical industry are only designed to fulfill licensing requirements. Thus, post-dilution or -reconstitution stability data are frequently limited to 24 h only for bacteriological reasons regardless of the true chemical stability which could, in many cases, be longer. In practice, the pharmacy-based centralized preparation may require infusions to be made several days in advance to provide, for example, the filling of ambulatory devices for continuous infusions or batch preparations for dose banding. Furthermore, a non-justified limited stability for expensive products is obviously very costly. Thus, there is a compelling need for additional stability data covering practical uses of anticancer drugs. A European conference consensus was held in France, May 2010, under the auspices of the French Society of Oncology Pharmacy (SFPO) to propose adapted rules on stability in practical situations and guidelines to perform corresponding stability studies. For each anticancer drug, considering their therapeutic index, the pharmacokinetics/pharmacodynamics (PK/PD) variability, specific clinical use and risks related to degradation products, the classical limit of 10% of degradation can be inappropriate. Therefore, acceptance limits must be clinically relevant and should be defined for each drug individually. Design of stability studies has to reflect the different needs of the clinical practice (preparation for the week-ends, outpatient transportations, implantable devices, dose banding…). It is essential to use validated stability-indicating methods, separating degradation products being formed in the practical use of the drug. Sequential temperature designs should be encouraged to replicate problems seen in daily practice such as rupture of the cold-chain or temperature-cycling between refrigerated storage and ambient in-use conditions. Stressed conditions are recommended to evaluate not only the role of classical variables (pH, temperature, light) but also the mechanical stress. Physical stability such as particles’ formation should be systematically evaluated. The consensus conference focused on the need to perform more studies on the stability of biotherapies, including a minimum of three complementary separating methods and a careful evaluation of submicron aggregates. The determination of the biological activity of proteins could be also useful. A guideline on the practical stability of anticancer drugs is proposed to cover current clinical and pharmaceutical practice. It should contribute to improved security of use, optimization of centralized handling and reduced costs. Finally, we have attempted to establish a new drug stability paradigm based on practical clinical needs, to complement regulatory guidelines which are essentially orientated to the stability of manufactured drugs.     

热熔挤出技术制备固体分散体的辅料研究进展

热熔挤出技术(HME)是一种制备固体分散体的新技术。固体分散体的制备和性质主要依赖于辅料的选择。HME的辅料应具有较强的热塑性、较高的热稳定性、适宜的熔融黏度和原辅料的相容性。依据辅料的用途,HME的辅料主要分为载体、塑化剂和功能性辅料。依据载体溶解能力的不同,载体又分为水溶性、难溶性和肠溶性3类,对应制备出速释、缓控释功能的固体分散体。通过塑化剂和功能性辅料的修饰和辅助,进一步优化固体分散体的稳定性和释放特性。主要从载体、塑化剂和功能性辅料等方面对HME的辅料进行综述,旨在为固体分散体载体的选择、固体分散体的制备提供参考和依据。     

In vivo comparative study of lipid/DNA complexes with different in vitro serum stability: effects on biodistribution and tumor accumulation

To evaluate the in vivo biodistribution and expression of DOTAP-Chol/DNA complexes (lipoplexes) with different in vitro serum stability, quantitative real-time PCR, in vitro luciferase expression and whole body luminescence imaging were used. In general, less tissue biodistribution, lower luciferase expression and whole body luminescence were observed for DOTAP:Chol (mol/mol 1:4)/DNA lipoplexes which had higher in vitro serum stability as compared to DOTAP:Chol (mol/mol 1:1)/DNA lipoplexes. Plasmid DNA biodistribution and expression were mainly confined to the lungs, and the results suggest that in vitro serum stability may serve as a predictor of transfection in the lung. No correlation between plasmid DNA tissue biodistribution and gene expression was observed by simultaneous determination of the level of plasmid DNA tissue biodistribution and gene expression. While high doses of the formulation possessing increased in vitro serum stability did exhibit reduced entrapment in the lung, no corresponding increase in the plasmid levels of other tissues was observed. However, this formulation did show increased accumulation in tumors that was not further enhanced by PEGylation.     

Improved anticonvulsant activity of phenytoin by a redox brain delivery system. II: Stability in buffers and biological materials

The stability of nine chemical delivery systems (CDSs) for phenytoin (DPH) was studied in aqueous buffers and in biological materials. The systems were based on a dihydropyridine in equilibrium quaternary pyridinium salt redox pair attached to 3-(hydroxymethyl)phenytoin via an ester linkage. The pyridinium derivatives released DPH in aqueous buffers and their hydrolytic reactivity was consistent with their chemical structure. Although in rat blood and plasma all pyridinium esters hydrolyzed rapidly, there was a wide range in the hydrolysis rates in rat brain homogenate. The sterically hindered 1-alkylcarboxynicotinamide was the least reactive ester (t1/2 = 98.2 min), while the trigonellylglycolate ester was the fastest to hydrolyze enzymatically (t1/2 = 2 min) in rat brain homogenate. In acidic media, the major products of all dihydropyridine esters were the corresponding water adducts, the 6-hydroxy- 1,4,5,6-tetrahydropyridines. These adducts were of no significance in biological materials. After comparison of the relative stability of the corresponding pairs of dihydropyridine and pyridinium ion in brain homogenate and the absolute stability of the various dihydropyridines, two CDSs were chosen for further in vivo evaluations. The CDSs chosen were the dihydrotrigonellinate ester and its 6-methyl derivative.