Extractable substances from plastic materials used in solution contact applications: an updated review

This is an updated review related to the identification and/or accumulation of organic and inorganic extractable substances from di(2-ethylhexyl) phthalate (DEHP)-plasticized polyvinyl chloride (PVC), polyolefin, and various other plastic materials. The review considers the identification of such extractables, their reported levels in material extracts, and the strategic issues associated with investigations of extractables/leachables.     

A comparison of two contact angle measurement methods and inverse gas chromatography to assess the surface energies of theophylline and caffeine

The wettability of two powders has been assessed by three methods and values for surface energies have been determined. Two contact angle methods have been used, both of which are variations of the Wilhelmy plate approach. One method was to use compressed plates of powder, the other to stick uncompacted powder to a glass plate (as a support). It was found that the method using adhesion to the glass plate gave more realistic values for the surface energy of the powders than did the compacted plate approach. It can be concluded that the use of plates with powder adhered to the surface offers a significant advantage for contact angle assessment. The third method used was inverse gas chromatography, which has seen little application to date in the pharmaceutical sciences. It was found that the dispersion component of surface energy obtained by inverse gas chromatography (IGC) was almost identical to the equivalent (Lifshitz-van der Waals) term obtained by use of the contact angle data from the glass side method. The acid-base (polar) contributions to surface energy were not directly comparable, due to the different data manipulation methods associated with contact angle and IGC data. It can be concluded that the little used methods of adhering powder to an inert support for contact angle measurement and IGC have great promise as means of assessing the surface properties of powders. Both these techniques have the advantage of not requiring powder compaction (or any other surface damaging treatment) prior to use.     

皮内注射用卡介苗与直接接触的包装容器的相容性

目的 考察皮内注射用卡介苗与其直接接触的包装容器的相容性,评估疫苗现用包装容器低硼硅玻璃安瓿的适宜性。方法 分别检测已包装的皮内注射用卡介苗在加速条件及长期规定储存条件下,疫苗及低硼硅玻璃安瓿的外观、安瓿中有毒有害金属离子（As、Sb、Pb、Cd） 迁移量、安瓿内表面脱片风险等,同时分析安瓿对疫苗质量的影响程度及安瓿是否被疫苗腐蚀受损。结果 3 批皮内注射用卡介苗在23~27 ℃放置 6个月,2～8 ℃放置30个月,安瓿中有毒有害金属离子迁移至疫苗中的量远低于安全限值,As迁移量为0.001~0.006 μg/支、Sb迁移量≤0.005 μg/支、Pb迁移量为0.028~0.080 μg/支、Cd迁移量为0.007~0.018 μg/支,低硼硅玻璃安瓿内表面被疫苗腐蚀脱片的风险较低。3批皮内注射用卡介苗在23~27 ℃放置6个月和2~8 ℃放置27个月,疫苗及低硼硅玻璃安瓿外观与0个月一致;关键质量检定结果水分为1.5%~-2.4%、渗透压摩尔浓度为342~378 mOsmol/kg、活菌数为（3.61~7.75）×10⁶  CFU/mg、效力为15~20 mm,均合格。结论 皮内注射用卡介苗与低硼硅玻璃安瓿发生相互作用的风险可接受,相容性良好,表明现用低硼硅玻璃安瓿是适宜的。     

Eosinophilia as a presenting symptom of the metastatic lung adenocarcinoma with an unknown primary localization

Apparent hematological symptoms rarely dominate the clinical picture of an underlying non-hematological malignancy. Malignancy-associated eosinophilia can result from clonal or non-clonal proliferation of eosinophils. Here, we report the case of a 59-year-old man with metastatic adenocarcinoma of the lung with an unknown primary tumor site, which presented as hypereosinophilia, anemia, lymphadenopathy, weight loss, and malaise. Bone marrow biopsy disclosed metastatic adenocarcinoma positive in immunohistochemistry for cytokeratin 7. Further assessment of specimens obtained from the bronchoalveolar lavage and biopsy of the mediastinal lymph nodes confirmed the diagnosis of the metastatic lung cancer, although the primary tumor site remained undiscovered. This case underlines that eosinophilia may represent a rare primary manifestation of an undetected malignancy, and it is thus important to consider this as part of the differential diagnosis in patients presenting with unexplained eosinophilia.     

Estimation of parameters for the elimination of an orally administered test substance with unknown absorption

Assessment of the elimination of an oral test dose based on plasma concentration values requires correction for the effect of gastric release and absorption. Irregular uptake processes should be described ‘model independently’, which requires estimation of a large number of absorption parameters. To limit the associated computational effort a new approach is developed with a reduced number of unknown parameters. A marginalized and regularized absorption approach (MRA) is defined, which uses for the uptake just one parameter to control rigidity of the uptake curve. For validation, elimination and absorption were reproduced using published IVIVC data and a synthetic data set for comparison with approaches using a ‘model-free’—staircase function or mechanistic models to describe absorption. MRA performed almost as accurate as well specified mechanistic models, which gave the best reproduction. MRA demonstrated a 50fold increase in computational efficiency compared to other approaches. The absorption estimated for the IVIVC study demonstrated an in vivo–in vitro correlation comparable to published values. The newly developed MRA approach can be used to efficiently and accurately estimate elimination and absorption with a restricted number of adaptive parameters and with automatic adjustment of the complexity of the uptake.     

彩超引导下不同路径进针自动肾活检的临床研究

目的:探讨彩超引导下自动肾活检斜角进针与垂直进针取材和并发症的发生情况。方法:714例肾脏疾病住院患者,随机分为两组,A组368例采用斜角进针法穿刺(穿刺针自探头头端进针),B组346例采用垂直进针法穿刺(穿刺针自探头尾端进针),对两组穿刺取材情况和并发症作对比分析。结果:两组穿刺成功率、平均穿刺次数和取材长度无明显差异;两组取得的肾小球数、肾组织的构成和并发症差异有显著性(P<0.05)。结论:超声引导自动肾活检,斜角进针比垂直进针取材更满意,并发症更少,值得推广。     

Enhanced physical stabilization of fenofibrate nanosuspensions via wet co-milling with a superdisintegrant and an adsorbing polymer

Drug nanoparticles in suspensions can form aggregates leading to physical instability, which is traditionally mitigated using soluble polymers and surfactants. The aim of this paper was to explore common superdisintegrants, i.e., sodium starch glycolate (SSG), croscarmellose sodium (CCS), and crospovidone (CP), as novel class of dispersants for enhanced stabilization of fenofibrate (FNB), a model BCS Class II drug, suspensions. FNB was wet-milled with superdisintegrants along with hydroxypropyl methylcellulose (HPMC), a soluble adsorbing polymer, in a stirred media mill. For comparison, FNB was also milled in the presence of HPMC and/or SDS (sodium dodecyl sulfate) without superdisintegrants. Laser diffraction, scanning electron microscopy, viscometry, differential scanning calorimetry, and powder X-ray diffraction were used to characterize the suspensions. The results show that 2% HPMC along with 1% SSG or 1% CCS mitigated the aggregation of FNB nanoparticles significantly similar to the use of either 5% HPMC or 1% HPMC–0.075% SDS, whereas CP was not effective due to its low swelling capacity. CCS/SSG enhanced steric–kinetic stabilization of the FNB suspensions owing to their high swelling capacity, viscosity enhancement, and physical barrier action. Overall, this study provides a mechanistic basis for a novel method of formulating surfactant-free drug nanosuspensions with co-milled superdisintegrants.     

直接法和浸提液法两种不同方法对药包材溶血率影响的研究

目的采用直接法和浸提液法两种检查方法对药品包装材料进行评价,比较两种方法对药包材检测灵敏性的差异。方法选择11种具有代表性的药包材,分别采用直接法和浸提液法进行溶血性能检测,并对两种方法测得的溶血结果进行比对。结果浸提液法溶血率大于直接法,均符合规定但不存在显著性差异(P>0.05)。结论直接法和浸提液法均可用于药包材的溶血性能检测,浸提液法作为药包材溶血性能的一个探索,更符合临床使用特点,建议全面考察药包材溶血性能,增加浸提液评价方法。     

Biological impact of contact with metals on cells

In order to investigate the in vivo effect of metals used in dentistry, we investigated the effect of direct contact with metal plates (20 x 20 x 0.5 mm3) made of gold (Au), silver (Ag), copper (Cu) or palladium (Pd) on human promyelocytic leukemic HL-60 cells grown in RPMI1640 medium supplemented with 10% fetal bovine serum. When 0.5 mL of cell suspension was applied to the metal plates, cells were precipitated on the surface of the metal plate within 10 min. Contact with Cu induced a rapid decline of cell viability, the smear pattern of DNA fragmentation, and only minor activation of caspase-3. These effects were accompanied by a progressive decrease in the extracellular concentration of methionine, cysteine and histidine, with a corresponding increase in the concentration of methionine sulfoxide. Electron microscopy showed that contact with Cu induced vacuolization and cytoplasmic damage, prior to nuclear damage, without affecting the cell surface microvilli or mitochondrial integrity. Contact with the other metals did not induce such changes during the 3 h incubation, nor was any hormetic response (beneficial action at lower concentration) observed in the cells with any metals. Addition of N-acetyl-L-cysteine (4-5 mM) almost completely abrogated the Cu-induced cytotoxicity, whereas sodium ascorbate (0.1-0.5 mM) and catalase (6,000(1)-30,000 units/mL) were ineffective. Numerous serum proteins were adsorbed to the Ag plate, while bovine serum albumin was the major protein adsorbed to other metal plates. The present study suggests that direct contact with Cu induced non-apoptotic cell death by an oxidation-involved mechanism. The present model system may be applicable to the study of the interaction between cells and dental restorative materials.     

胰岛素加利福平湿敷法对糖尿病足的疗效研究

目的：探讨胰岛素加利福平对糖尿病足治疗效果的影响。方法：选取需要接受治疗的糖尿病足患者40例,将患者随机分为两组．试验组采用4U胰岛素加0．15g利福平和10ml生理盐水稀释进行湿敷,对照组无干预,用4U胰岛素加10ml生理盐水稀释湿敷。两组患者均接受每日2次湿敷治疗,连续治疗30天。判断并比较两组患者湿敷治疗效果。结果：试验组糖尿病足康复率为75％,对照组康复率为30％,两组差异有显著性（P〈0．05）。结论：用胰岛素加利福平可以显著改善糖尿病足的治疗效果。     

Identification of an unknown trace-level impurity in bulk drug of Seroquel by high-performance liquid chromatography combined with mass spectrometry

An impurity was detected in bulk drug Seroquel at about 0.4% level by the reversed-phase high-performance liquid chromatography with UV detection. The accurate mass of impurity was measured by FTICR equipped with electrospray ionization interface, and the structure of impurity was characterized on the basis of the on-line multi-stage mass spectrometric evidences. The proposed structure was further confirmed by multi-stage mass spectrometry of Seroquel and four related compounds.     

Influence of the surface properties of low contact angle surfactants on the body distribution of 14C-poly(methyl methacrylate) nanoparticles.

The body distribution of surfactant-coated and non-coated poly(methyl methacrylate) nanoparticles with a size of 131 +/- 30 nm after intravenous injection into rats was investigated. The coating materials were poloxamine 904, poloxamine 908, poloxamine 1508, poloxamer 338, and Brij 35. These materials were preselected by the method of contact angle measurement. No overall valid relation between contact angles and the modification of body distribution could be found. However, the classification of surfactants by determination of the contact angles of the surfactant solution on the polymer material seems to be a very helpful method for preselection of poloxamers and poloxamines. Another parameter for preselection could be molecular weights of the poloxamines. Poloxamine 1508 was the most efficient coating material in reducing the liver uptake and increasing the blood levels of poly(methyl methacrylate) nanoparticles.     

Effects of two organomodified clays intended to food contact materials on the genomic instability and gene expression of hepatoma cells

Globally, food industries have made significant progress in order to increase the shelf-life of food products and have fewer economic losses. In this sense, the use of organomodified clays destined to be incorporated in polymer matrices play a novel role, leading to improved materials named nanocomposites with enhanced technological profiles. Due to the presence of these clays into the package, the safety of the consumers is a main concern. Cloisite^®30B and Clay1 are two organomodified clays containing quaternary ammonium salts as modifiers, that can be potentially used to reinforce packaging polymers. Available toxicity data about these clays, specifically genotoxicity, is still limited and inconclusive in some aspects. Thus, the purpose of this work was to evaluate both clays ability to induce genomic instability through the cytokinesis block micronucleus cytome assay (CBMN) and for the first time, their influence in the modulation of several genes involved in genotoxicity and cell death mechanisms. Overall, no genotoxicity response was obtained in any case at the conditions tested. On the other hand, significant expression changes were observed on the genes selected. Nevertheless, further studies are highly needed to elucidate and increase the knowledge about the molecular mechanisms of clays toxicity.     

生肌玉红汤纱布湿敷对兔血汞浓度的影响

目的 观察生肌玉红汤纱布湿敷对血汞含量的影响,探讨含汞制剂中药的用药安全.方法 选择32只兔子,雌雄各半,在背部建立慢性溃疡模型,随机分为两组,每组16只,一组为阴性对照组,用生理盐水纱布湿敷,另一组用生肌玉红汤纱布湿敷;分别用酸性氯化亚锡还原-冷原子吸收光谱法测定其血液中不同时间的汞含量.结果 生肌玉红汤湿敷组中血汞的含量随着时间的延长不断增加,至第四周未时其浓度为（92.68±8.0）nmol/L,明显高于阴性对照组（83.05±8.8）nmol/L,两组比较差异有极显著性（P＜0.01）.结论 在创面使用含汞制剂的中药时应控制用药的时间,不宜超过1个月,以免发生汞中毒.     

湿性换药联合红外线理疗对会阴侧切口的临床效果观察

目的 探究女性在接受会阴侧切术后,使用湿性换药联合红外线理疗的效果.方法 113例行会阴侧切的产妇,根据治疗方式的不同分为观察组(59例)与对照组(54例).对照组仅进行简单基础的措施,观察组在对照组基础上采用湿性换药联合红外线理疗治疗.比较两组术后疼痛程度、切口愈合等级及愈合时间.结果 观察组轻度疼痛占比86.44％...     

Droplet size measurement: I. Effect of three independent variables on droplet size distribution and spray angle from a pneumatic nozzle

The effect of three independent variables (atomizing air pressure, flow rate of binder solution and polyvinylpyrrolidone concentration) on the droplet size distribution from a pneumatic nozzle was studied using a normal 3³ factorial design. The droplet sizes and size distributions were determined by laser diffractometry. The effect of the same variables on the spray angle and cross-sectional area of spray cone (describes the area of wetted bed in a fluidized bed granulator) was also evaluated. The dependence of these latter response variables on the independent variables was studied by a multilinear stepwise regression analysis. It was noted that increasing the amount of polyvinylpyrrolidone in binder solution decreased the number of bimodal distributions and increased the width of the distributions. A high pressure with water as a binder solution resulted in a pronounced bimodality and a narrow width of distribution. Increasing the flow rate had no clear effect on the shape of distributions (uni- or bimodal), but the width of distributions increased. The atomizing air pressure was the most significant factor affecting the spray angle and the cross-sectional area of the spray cone. Increasing the pressure led to a decline in the spray angle and to a decreased area. The effect of PVP concentration was opposite to that of pressure. The effect of flow rate was controversial because, according to the regression analyses, it affected inversely the spray angle and the area.     

Air pollution particles activate NF-kappaB on contact with airway epithelial cell surfaces

Air pollution particles (PM) are known to elicit an acute inflammatory response in vivo that is mediated in part through PM-induced activation of the NF-kappaB signaling pathway. Many of the details of this process and particularly where in the cell it occurs are unclear. To determine whether contact of PM particles with an epithelial cell surface activates NF-kappaB, rat tracheal explants were exposed to Ottawa Urban Air Particles or iron-loaded fine TiO2, a model PM particle, for up to 2 h. During this period, there was no evidence of particle entry into the tracheal epithelial cells by light or electron microscopy, but both types of particle activated NF-kappaB as assayed by gel shifts. NF-kappaB activation could be inhibited by the active oxygen species scavenger, tetramethylthiourea; the redox-inactive metal chelator, deferoxamine; the Src inhibitor, PP2; and the epidermal growth factor (EGF) receptor inhibitor AG1478. An iron-containing citrate extract of both dusts also produced NF-kappaB activation. Both dusts and a citrate extract caused phosphorylation of the EGF receptor on tyrosine 845, an indicator of Src activity. We conclude that iron-containing PM particles can activate NF-kappaB via a pathway involving Src and the EGF receptor. This process does not require entry of particles into the airway epithelial cells but is dependent on the presence of iron and generation of active oxygen species by the dusts. These findings imply that even brief contact of PM with a pulmonary epithelial cell surface may produce deleterious effects in vivo.