Prognostic Analysis of Liver Cirrhosis Patients with Cerebral Infarction and/or Gastrointestinal Hemorrhage: A Retrospective Cohort Study.

Background: To explore the risk factors of gastrointestinal hemorrhage and/or cerebral infarction complications in liver cirrhosis and provide evidence for early prevention, clinical diagnosis, and treatment of liver cirrhosis. Methods: 200 liver cirrhosis patients were analyzed: liver cirrhosis (n = 78), liver cirrhosis complicated with cerebral infarction (n = 43), liver cirrhosis complicated with gastrointestinal hemorrhage (n = 57), and liver cirrhosis complicated with gastrointestinal hemorrhage and cerebral infarction (n = 22). The incidence of disease in each group of patients at different times was calculated. Multivariate logistic regression was used to analyze the risk factors of liver cirrhosis patients with gastrointestinal hemorrhage and cerebral infarction. After 12 months of follow-up, the mortality rate of each group was calculated. Results: The incidences of gastrointestinal hemorrhage, cerebral infarction, and gastrointestinal hemorrhage combined with cerebral infarction in patients with liver cirrhosis were 21.5%, 28.5%, and 11%, respectively. The width of the portal vein, D-2 polymer, albumin (ALB), and hemoglobin (Hb) were predictors of gastrointestinal hemorrhage and cerebral infarction in patients with liver cirrhosis. Age, hypertension, bleeding history, infection, portal vein width, and D-2 polymer were confirmed as risk factors for gastrointestinal hemorrhage and cerebral infarction in patients with liver cirrhosis. ALB and Hb were independent protective factors. Patients with liver cirrhosis and gastrointestinal hemorrhage with cerebral infarction had the worst survival. Conclusion: Age, hypertension, bleeding history, infection, portal vein width, and D-2 polymer are all independent risk factors for gastrointestinal bleeding and cerebral infarction, while ALB and Hb are independent protective factors.

The Lattice Distortion, Defect Evolution and Electrochemical Performance Improvement in Zn-VO2(B) Nanorods.

Cathode materials of energy storage batteries have attracted extensive attention because of the importance in deciding the rate performance and long cycle property of batteries. Herein, we report a simple and environmentally friendly solvothermal method to prepare Zn-doped VO2(B) cathode materials. The introduction of zinc ions can effectively regulate the lattice structure, surface morphology and internal defect state of Zn-VO2(B) nano materials. The sample with Zn content x = 1.5% has smaller cell volume and grain size, and higher concentration of vacancy defects. These microstructures ensure the structural stability during ion embedding process and, thus, this sample shows excellent electrochemical performances. The capacitance retention rate still maintains 88% after 1000 cycles at the current density of 0.1 A·g-1. The enhanced performances of Zn-doped VO2(B) samples may lay a foundation for the improvement of electrochemical performances of VO2(B) cathode materials for energy storage batteries in the future.

The influence of co-solvents on the stability and bioavailability of rapamycin formulated in self-microemulsifying drug delivery systems.

OBJECTIVE: This work aims to investigate the influence of various types and different contents of co-solvent on the stability and bioavailability of rapamycin formulated in self-microemulsifying drug delivery systems (SMEDDS). METHODS: A series of SMEDDS of rapamycin were prepared with different co-solvents [including PEG 400/ethanol (F1), glycerol/ethanol (F2), propylene glycol (F3), glycerol formal (F4), transcutol P (F5)]. Drug stability in aqueous media at different pH values and in vitro dispersion of SMEDDS were investigated prior to bioavailability assessment. The storage stability of rapamycin in formulations was also evaluated. RESULTS AND DISCUSSION: The AUC values of rapamycin following oral administration of F1, F3-F5 to rats were significantly higher than those of Rapamune and F0 (SMEDDS without co-solvent). Interestingly, a tendency toward increased bioavailability was seen in F1-F5, which presented the better drug stability in pH 1.2 aqueous media. However, a further increase of the content of co-solvent did not effectively improve the oral bioavailability of rapamycin. Compared with F0, F1-F5 presented significant improvement of drug storage stability. More specifically, the more--OH per unit mass co-solvent had, the better stability rapamycin presented in formulation. CONCLUSIONS: The data obtained in present study highlight the importance of co-solvents on the stability and bioavailability of rapamycin formulated in SMEDDS. Besides solubilizing drug and increasing the dispersion rate, co-solvent could markedly affect the stability of rapamycin whether in different aqueous media or during storage and contribute to the improved oral bioavailability; it can also appropriately decrease the content of surfactant without compromising the absorption of drug.

Nanocrystals of medium soluble actives--novel concept for improved dermal delivery and production strategy.

After use in oral pharmaceutical products, nanocrystals are meanwhile applied to improve the dermal penetration of cosmetic actives (e.g. rutin, hesperidin) and of drugs. By now, nanocrystals are only dermally applied made from poorly soluble actives. The novel concept is to formulate nanocrystals also from medium soluble actives, and to apply a dermal formulation containing additionally nanocrystals. The nanocrystals should act as fast dissolving depot, increase saturation solubility and especially accumulate in the hair follicles, to further increase skin penetration. Caffeine was used as model compound with relevance to market products, and a particular process was developed for the production of caffeine nanocrystals to overcome the supersaturation related effect of crystal growth and fiber formation - typical with medium soluble compounds. It is based on low energy milling (pearl milling) in combination with low dielectric constant dispersion media (water-ethanol or ethanol-propylene glycol mixtures) and optimal stabilizers. Most successful was Carbopol(®) 981 (e.g. 20% caffeine in ethanol-propylene glycol 3:7 with 2% Carbopol, w/w). Nanocrystals with varied sizes can now be produced in a controlled process e.g. 660 nm (optimal for hair follicle accumulation) to 250 nm (optimal for fast dissolution). The short term test proved stability over 2 months of the present formulation being sufficient to perform in vivo testing of the novel concept.

Dermal nanocrystals from medium soluble actives - physical stability and stability affecting parameters.

Nanocrystals are meanwhile applied to increase the dermal penetration of drugs, but were applied by now only to poorly soluble drugs (e.g. 1-10 µg/ml). As a new concept nanocrystals from medium soluble actives were produced, using caffeine as model compound (solubility 16 mg/ml at 20 °C). Penetration should be increased by (a) further increase in solubility and (b) mainly by increased hair follicle targeting of nanocrystals compared to pure solution. Caffeine nanocrystal production in water lead to pronounced crystal growth. Therefore the stability of nanocrystals in water-ethanol (1:9) and ethanol-propylene glycol (3:7) mixtures with lower dielectric constant D was investigated, using various stabilizers. Both mixtures in combination with Carbopol 981 (non-neutralized) yielded stable nanosuspensions over 2 months at 4 °C and room temperature. Storage at 40 °C lead to crystal growth, attributed to too strong solubility increase, supersaturation and Ostwald ripening effects. Stability of caffeine nanocrystals at lower temperatures could not only be attributed to lower solubility, because the solubilities of caffeine in mixtures and in water are not that much different. Other effects such as quantified by reduced dielectric constant D, and specific interactions between dispersion medium and crystal surface seem to play a role. With the 2 mixtures and Carbopol 981, a basic formulation composition for this type of nanocrystals has been established, to be used in the in vivo proof of principle of the new concept.

Intestinal absorption and intestinal lymphatic transport of sirolimus from self-microemulsifying drug delivery systems assessed using the single-pass intestinal perfusion (SPIP) technique and a chylomicron flow blocking approach: linear correlation with oral bioavailabilities in rats.

This work aims to investigate the impact of different amount of oil or surfactant included in self-microemulsifying drug delivery systems on the intestinal lymphatic transport of sirolimus using the single-pass intestinal perfusion (SPIP) technique and a chylomicron flow blocking approach. Male Sprague-Dawley rats were pretreated intraperitoneally with 3.0mg/kg cycloheximide or saline. One hour later, single-pass intestinal perfusion experiments in jejunum and ileum and in vivo bioavailability studies were carried out to calculate the effective permeability coefficient and pharmacokinetic parameters, respectively. Drug absorption from oil-free formulation was mostly via the portal blood. In contrast, for the SMEDDS formulations containing ≥25% MCT, the lymphatic transport of sirolimus was a major contributor to oral bioavailability. The formulation including more content of oil presented higher lymphatic transport of drug and further exhibited the increased oral bioavailability. Besides, distal ileum presented much more lymphatic transport of drug compared to proximal jejunum. Furthermore, even though the smaller droplet size of resultant microemulsions and more surfactant content also can positively influence the intestinal absorption of drug, their influences on the drug intestinal lymphatic transport were relatively weaker than that of more oil content. In addition, there was a high linear correlation between the AUC values and the mean of P(eff) values in jejunum and ileum.

Calcium pectinate gel bead intended for oral protein delivery: preparation improvement and formulation development.

Calcium pectinate gel (CPG) micrometer-sized beads (microbeads) containing insulin, as a model amphoteric protein, were prepared by ionotropic gelation technique together with an air compressor. The influences of phosphate buffer, pH as well as calcium and pectin concentrations of cross-linking solution on the characteristics and release profiles of microbeads were investigated. With the aid of compressed air flow, the mean diameters of beads were successfully decreased to micron-sized. The results showed that all the factors investigated greatly affected the entrapment efficiencies and release profiles of the microbeads. Suitable formulation concentrations should be considered and great care should be taken to maintain the pH of working solutions at or close to isoelectric point of protein loaded during the whole preparation process. Hence, CPG microbeads of perfect spherical shape, uniform sizes, enhanced mechanical strength, good entrapment efficiencies and delayed release profiles were prepared for a load of amphoteric protein and peptide drugs, without any use of organic solvents or harsh ingredients. Therefore, CPG microbeads could be a promising carrier for oral controlled-release systems of amphoteric protein and peptide drugs.