Pressurized IntraPeritoneal Aerosol Chemotherapy with one minute of electrostatic precipitation (ePIPAC) is feasible,but the histological tumor response in peritoneal metastasis is insufficient

IntroductionElectrostatic precipitation Pressurized IntraPeritoneal Aerosol Chemotherapy (ePIPAC) has shown superior penetration depth and tissue uptake compared to standard PIPAC. We investigated the feasibility and objective tumor response to ePIPAC with 1 min of precipitation in patients with peritoneal metastasis (PM).Materials and methodsPatients with PM from various abdominal cancers were included in an amendment to the ongoing prospective PIPAC-OPC2 trial. Colorectal and appendiceal PM were treated with oxaliplatin, patients with PM from other primaries were treated with a combination of cisplatin and doxorubicin. Three ePIPAC procedures were planned in each patient including repeated peritoneal biopsies for response evaluation. After emission to the peritoneal cavity, the aerosolized chemotherapeutics were precipitated for 1 min followed by immediate exsufflation and abdominal closure. Histological regression from the first to the third ePIPAC was evaluated according to the Peritoneal Regression Grading Score (PRGS) and compared to data from the PIPAC-OPC1 trial. Complications and toxicities were recorded according to Dindo-Clavien and CTCAE.ResultsSixty-five ePIPAC procedures were performed in 33 patients (median 2, range 1–6). Ten patients were eligible for response evaluation based on biopsies from the first and third ePIPAC procedure. Four patients had disease progression, four patients had regressive disease, and two patients had stable disease according to PRGS. No life threatening adverse reactions and no mortality was observed following ePIPAC.ConclusionOne minute ePIPAC was feasible and safe, but the histological tumor response was insufficient compared to standard PIPAC directed therapy with 30 min passive diffusion time.     

Population Balance Model for Simulation of the Supersaturation–Precipitation Behavior of Drugs in Supersaturable Solid Forms

We developed a simulation method to describe in vitro drug concentration?time profiles under supersaturated conditions. In a nonsink dissolution test of carbamazepine polymorphic form III (CBZ_III), a model supersaturable solid, the concentration of carbamazepine reached a supersaturated state against its dihydrate form (CBZ_DH). After a certain period, de-supersaturation due to the precipitation of CBZ_DH was observed. In the simulation of this typical dissolution?precipitation profile, the precipitation process of CBZ_DH was simulated by a population balance model in which the rates of primary/secondary nucleation and growth of CBZ_DH were considered. Six rate constants in the precipitation model were determined from de-supersaturation profiles in unseeded isothermal crystallization experiments of CBZ_DH. The dissolution process of CBZ_III was modeled on the basis of its dissolution profile under a sink condition. The simulated concentration versus time curves satisfactorily reproduced the characteristics of dissolution, supersaturation, and precipitation behavior of the model drug. The presented method will enable rational design of formulations and accurate prediction of the oral absorbability of drugs in supersaturable solid forms.     

Fluconazole nanoparticles prepared by antisolvent precipitation technique: Physicochemical,in vitro,ex vivo and in vivo ocular evaluation

The goal of this research was to prepare and characterize nanonized particles of the antifungal drug, fluconazole (FLZ) using antisolvent precipitation nanonization technique to improve its ocular permeation. The impact of various concentrations of different stabilizers, namely Pluronic F-127 (PL F 127), Kollicoat IR (KL), hydroxypropyl methylcellulose E3 (HPMC), xanthan gum (XG), polyvinyl pyrrolidone K30 (PVP), and sodium lauryl sulfate (SLS) upon the resulting nanoparticles was investigated. Additionally, the ex vivo release of the FLZ nanonized particles from ophthalmic gel bases was studied by using goat cornea, and the ocular pharmacokinetics of appropriate ophthalmic gel base containing optimized drug nanoparticle formula compared to the untreated drug were studied in rabbits. FLZ nanoparticles were successfully prepared with different concentrations of stabilizers. However, the effects of these stabilizers on nanoparticle size and zeta potential values varied according to the concentration and type of stabilizer used. Based on differential scanning calorimetry, the drug was in its amorphous state in the tested nanoparticle formulations. The results of ex vivo ocular diffusion of the FLZ nanoparticle gel formulations revealed an improvement compared to that with the FLZ untreated gel. Nanoparticle formula (F3) prepared by using 5% PL F127 showed small particle size (352 ± 6.1 nm) with zeta potential value of −18.3 mV with highest ex vivo release rate from goat cornea (100% after 6 h). Moreover, the AUC_0-8h from ocular application of FLZ from sodium alginate gel containing nanoparticle formula F3 was 1.4-fold higher than that after its administration in the untreated formula. Based on our findings, the ophthalmic gel formulations containing FLZ nanoparticles enhanced drug corneal permeation and improved the ocular pharmacokinetic parameters.     

Antigenic diversity of the circumsporozoite proteins in the Plasmodium cynomolgi complex

Antigenic diversity was observed in the circumsporozoite (CS) proteins of five of the six Plasmodium cynomolgi isolates (NIH, Mulligan, London, Gombak, Ceylon, RO) that we examined. Monoclonal antibodies were produced against salivary gland sporozoites of three of the isolates. Interaction of these monoclonal antibodies with the sporozoites was isolate specific, the exception being the anti-NIH monoclonals which also reacted with Mulligan strain sporozoites. Inhibition of binding between the different monoclonal antibodies indicated that for each of the NIH, London, and Gombak strains, the homologous monoclonals were recognizing the same or a topographically close immunodominant epitope on the respective CS protein. Also the binding of a polyvalent anti-NIH rhesus serum to the homologous antigen could only be inhibited by anti-NIH monoclonal antibody. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis of sporozoite extracts demonstrated clear differences in the apparent molecular weights of the CS proteins of four of the six isolates. This is the first study which provides evidence of antigenic diversity in the CS proteins of different isolates of a primate plasmodial species.     

Decrease in bovine in vitro embryo production efficiency during winter season in a warm‐summer Mediterranean climate

Retrospective analysis of monthly embryo production from December 2011 to May 2015 and its correlation with meteorological data in our geographic zone was made. We had observed that in certain time of the year, in vitro blastocyst production decreases. Accordingly, was examined the association between blastocyst production and climatological parameters. Cleavage rates correlate positively with blastocyst rates (p < .05). Significant differences in cleavage rates between autumn and summer (79.8%; 71.5%), and between winter and autumn (71.8%; 79.8%), were found. Blastocyst production had lower efficiency in June (9 ± 12%) and July (4.9 ± 5.7%), which coincides with winter season. In contrast, higher embryo production was obtained in February (22.2 ± 9.7%), March (22.9 ± 14%) and September (25.2 ± 6.6%), which coincides with autumn and spring season. Similarly, embryo production correlates with meteorological parameters: blastocyst production positively correlates with sunshine hours, maximum temperature and average temperature. Similarly, blastocyst production inversely correlates with total precipitation and days >1 mm precipitation (p < .05). There is a significant decrease in bovine in vitro embryo production efficiency during winter season in our warm‐summer Mediterranean climate zone. It remains to be investigated the direct effect of environmental factors on oocyte quality and its impact on in vitro production efficiency.     

2种根类药材醇沉絮体的分形维数测定方法建立

目的:建立黄芪与板蓝根2种根类药材醇沉絮体的分形维数测定方法。方法:分别以黄芪、板蓝根的水提醇沉絮体为研究对象,采用大津算法对醇沉絮体原始显微图像进行二值化处理,运用周长-面积法分别考察沉淀絮体取样体积、稀释倍数、图像放大倍数及图像采集位点数对分形维数的影响。结果:黄芪与板蓝根醇沉絮体均具有分形特征;确定这2个醇沉絮体取样体积在600～800μL,样品稀释至5～20倍,显微图像放大200倍或400倍,选取4个图像采集位点时,能够得到稳定可靠的醇沉絮体分形维数。结论:建立的测定方法稳定可行,可为根类药材醇沉絮体的分形理论研究提供参考。     

运用AHP结合熵权法优化疏风定喘颗粒炙麻黄组的醇沉工艺

目的:运用层次分析法(AHP)结合信息熵权法对多评价指标进行综合评分,优化疏风定喘颗粒炙麻黄组的醇沉工艺,为该药物的制剂工艺研究提供参考。方法:以盐酸麻黄碱、盐酸伪麻黄碱、苦杏仁苷和含固量转移率为综合考察指标,选取醇沉后乙醇体积分数、浓缩液相对密度、静置温度为影响因素进行响应面试验设计,采用AHP结合熵权法确定各指标的权重,实现醇沉工艺的优化。结果:最佳醇沉工艺为醇沉后乙醇体积分数75%,浓缩液相对密度1.10 g·m L~(-1)(25℃),静置温度25℃;在此条件下,盐酸麻黄碱、盐酸伪麻黄碱、苦杏仁苷和含固量转移率依次分别为95.31%,94.91%,96.02%,50.29%。结论:AHP结合信息熵权法的综合评分既能反映中药的君臣佐使,又能体现客观试验数据,适用于疏风定喘颗粒的醇沉工艺优化。     

Production of Ultrafine Sumatriptan Succinate Particles for Pulmonary Delivery

PURPOSE: Drug particle physical properties are critical for the efficiency of a drug delivered to the lung. The purpose of this study was to produce ultrafine sumatriptan succinate particles for inhalation. METHODS: Sumatriptan succinate particles were produced via reactive precipitation without any surfactants. Several low toxic organic solvents such as acetone, isopropanol, and tetrahydrofuran were investigated as the reaction medium. And the dry powder was obtained via spray drying. FT-IR, HPLC, SEM and XRD were exploited to characterize the physicochemical properties of the ultrafine sumatriptan succinate dry powder. The aerosol performance of the powder was evaluated using an Aeroliser connected to a multi stage liquid impinger operating at 60 l/min. RESULTS: The mean particle size of the ultrafine sumatriptan succinate particles obtained under optimum conditions was in the range of 630-679 nm and consequently they were in the respirable range. The spray-dried powder whose fine particle fraction was increased up to 50.6 +/- 8.2% showed good aerosol performance whereas the vacuum-dried powder was approximate 18.2 +/- 3.0%. CONCLUSIONS: Good aerosol performance ultrafine sumatriptan succinate particles could be produced by reactive precipitation without any additives followed by spray drying at the optimum parameters.     

注射用三七提取物的纯化方法优选

目的优选注射用三七提取物的纯化方法。方法以三七总皂苷的转移率、质量分数、杂质的清除效果和复溶性作为考察指标,采用明胶沉淀法、澄清剂法、石硫醇法、碱性醇沉法和大孔吸附树脂法对三七进行纯化,优选纯化条件,并对纯化结果进行比较。结果5种纯化方法单独使用均不能达到注射用要求,将碱性醇沉法和大孔吸附树脂法联用纯化三七药材,三七总皂苷的转移率和质量分数较高,杂质清除效果较好,复溶性较好。结论通过对不同纯化方法的比较,碱性醇沉法和大孔吸附树脂法联用可提高三七的纯化效果,并能达到注射用要求。     

Influence of sea ice on Arctic precipitation

Global climate is influenced by the Arctic hydrologic cycle, which is, in part, regulated by sea ice through its control on evaporation and precipitation. However, the quantitative link between precipitation and sea ice extent is poorly constrained. Here we present observational evidence for the response of precipitation to sea ice reduction and assess the sensitivity of the response. Changes in the proportion of moisture sourced from the Arctic with sea ice change in the Canadian Arctic and Greenland Sea regions over the past two decades are inferred from annually averaged deuterium excess (d-excess) measurements from six sites. Other influences on the Arctic hydrologic cycle, such as the strength of meridional transport, are assessed using the North Atlantic Oscillation index. We find that the independent, direct effect of sea ice on the increase of the percentage of Arctic sourced moisture (or Arctic moisture proportion, AMP) is 18.2 ± 4.6% and 10.8 ± 3.6%/100,000 km² sea ice lost for each region, respectively, corresponding to increases of 10.9 ± 2.8% and 2.7 ± 1.1%/1 °C of warming in the vapor source regions. The moisture source changes likely result in increases of precipitation and changes in energy balance, creating significant uncertainty for climate predictions.There is increasing interest in the response of the Arctic hydrologic cycle to changing climate because of its potential to influence, or feedback to, future climate change. Modeling studies have identified enhanced transport of subtropical moisture to the Arctic as well as increased Arctic evaporation as potential mechanisms of augmentation of the water cycle (1–3). The enhanced hydrologic cycle may feedback to climate change either positively or negatively; both the sign and the magnitude are yet to be determined.Observational evidence for hydrological acceleration during the past few decades is limited. Direct measurement of precipitation is difficult in the Arctic because of its cold, windy environments (4). Despite these difficulties, increasing precipitation has been reported for some Arctic locations (5, 6), and it has been hypothesized that changes in sea ice extent may have significantly influenced precipitation both in the past (7) and today (8–10). We report a study of changes in the isotopic composition of precipitation to understand the larger-scale changes of the hydrologic cycle, focusing on moisture source changes. The objective of this work is to assess observationally the effect of sea ice and the moisture transport regime on Arctic precipitation from 1990 to 2012, using the isotopic composition of precipitation from six Arctic stations. In particular, we quantify how the fraction of the total Arctic precipitation that is sourced in the Arctic responds to the sea ice extent. We then use these empirically established sensitivities of precipitation isotope ratios to sea ice change to project potential future precipitation changes and to evaluate impacts of these changes on the energy balance.Our approach is based on the premise that Arctic precipitation is composed mostly of water from two marine evaporation regions or “moisture sources”—one subtropical and one local—and that the relative contributions of the two sources to the precipitation can be determined from the stable isotopic ratios of the precipitation. We partition the two proportions, using the precipitation deuterium excess (d-excess, defined as d = δD − 8δ¹⁸O, where δD and δ¹⁸O are the parts per thousand deviation of deuterium/hydrogen and ¹⁸O/¹⁶O atomic ratios, respectively, from those of the standard mean ocean water), which is an indicator of moisture source conditions, principally the sea surface temperature (SST) and relative humidity (RH) (11–13). Moisture from subtropical regions has high d-excess values, indicative of relatively high SST and low RH at the source, whereas locally evaporated Arctic moisture has low d-excess values (14), indicating low SST and high RH. We hypothesize that precipitation d-excess is positively associated with sea ice area as a consequence of increasing local evaporation and thus increasing proportion of Arctic-sourced moisture with reduction of sea ice.We use the North Atlantic Oscillation (NAO) index as a proxy for general climate conditions to quantify effects that are independent of the sea ice influence on precipitation. Most importantly, the NAO is associated with the strength of meridional transport (15), which in turn affects precipitation d-excess by changing the proportion of subtropical moisture in the total precipitation. For example, if winds from the south strengthen, the proportion of moisture transported from the subtropics would increase, thus increasing the d-excess. In addition to meridional transport, the NAO also influences other variables, such as location of the subtropical moisture source region, temperature and humidity along the storm track, etc., all of which may affect the d-excess of precipitation. When holding the NAO constant (statistically), we also effectively remove the influences of these variables, achieving limited contamination to the signal of the direct precipitation–sea ice relationship.The six sites included in this work were from two regions, the Canadian Arctic (Alert, Eureka, and Cambridge Bay, Canada) and Greenland Sea (Reykjavìk, Iceland, Ny-Ålesend, Norway, and Danmarkshavn, Greenland) (Fig. 1). We consider all sites within a region to share similar local moisture sources. The Canadian Arctic sites receive most of their local moisture from Baffin Bay (16) and the Greenland Sea sites receive it from the Greenland Sea (17).Open in a separate windowFig. 1.Location of sites for monthly precipitation isotope ratio measurements. Shown are Canadian Arctic sites Alert, Eureka, and Cambridge Bay, Canada and Greenland Sea sites Reykjavìk, Iceland; Ny-Ålesend, Norway; and Danmarkshavn, Greenland. Local moisture sources Baffin Bay (BB) and Greenland Sea (GS) are labeled as well.