Docetaxel-loaded nanoparticles based on star-shaped mannitol-core PLGA-TPGS diblock copolymer for breast cancer therapy

A star-shaped biodegradable polymer, mannitol-core poly(d,l-lactide-co-glycolide)-d-α-tocopheryl polyethylene glycol 1000 succinate (M-PLGA-TPGS), was synthesized in order to provide a novel nanoformulation for breast cancer chemotherapy. This novel copolymer was prepared by a core-first approach via three stages of chemical reaction, and was characterized by nuclear magnetic resonance, gel permeation chromatography and thermogravimetric analysis. The docetaxel-loaded M-PLGA-TPGS nanoparticles (NPs), prepared by a modified nanoprecipitation method, were observed to be near-spherical shape with narrow size distribution. Confocal laser scanning microscopy showed that the uptake level of M-PLGA-TPGS NPs was higher than that of PLGA NPs and PLGA-TPGS NPs in MCF-7 cells. A significantly higher level of cytotoxicity was achieved with docetaxel-loaded M-PLGA-TPGS NPs than with commercial Taxotere®, docetaxel-loaded PLGA-TPGS and PLGA NPs. Examination of the drug loading and encapsulation efficiency proved that star-shaped M-PLGA-TPGS could carry higher levels of drug than linear polymer. The in vivo experiment showed docetaxel-loaded M-PLGA-TPGS NPs to have the highest anti-tumor efficacy. In conclusion, the star-like M-PLGA-TPGS copolymer shows potential as a promising drug-loaded biomaterial that can be applied in developing novel nanoformulations for breast cancer therapy.     

Nanostructural control of the release of macromolecules from silica sol–gels

The therapeutic use of biological molecules such as growth factors and monoclonal antibodies is challenging in view of their limited half-life in vivo. This has elicited the interest in delivery materials that can protect these molecules until released over extended periods of time. Although previous studies have shown controlled release of biologically functional BMP-2 and TGF-β from silica sol–gels, more versatile release conditions are desirable. This study focuses on the relationship between room temperature processed silica sol–gel synthesis conditions and the nanopore size and size distribution of the sol–gels. Furthermore, the effect on release of large molecules with a size up to 70 kDa is determined. Dextran, a hydrophilic polysaccharide, was selected as a large model molecule at molecular sizes of 10, 40 and 70 kDa, as it enabled us to determine a size effect uniquely without possible confounding chemical effects arising from the various molecules used. Previously, acid catalysis was performed at a pH value of 1.8 below the isoelectric point of silica. Herein the silica synthesis was pursued using acid catalysis at either pH 1.8 or 3.05 first, followed by catalysis at higher values by adding base. This results in a mesoporous structure with an abundance of pores around 3.5 nm. The data show that all molecular sizes can be released in a controlled manner. The data also reveal a unique in vivo approach to enable release of large biological molecules: the use more labile sol–gel structures by acid catalyzing above the pH value of the isoelectric point of silica; upon immersion in a physiological fluid the pores expand to reach an average size of 3.5 nm, thereby facilitating molecular out-diffusion.     

Commentary to the recently published review “Drug pipeline in neurodegeneration based on transgenic mice models of Alzheimer's disease” by Li,Evrahimi and Schluesener. Ageing Res. Rev. 2013 Jan;12(1):116–40

Li and colleagues summarized the most frequently used Alzheimer's disease (AD) mouse models available for drug testing and the mediating effects of the different compounds. With almost 300 cited publications, authors present the research community's effort of the last 10 years in finding a new drug for the treatment of AD.Some of the transgenic mouse lines mentioned by Li and colleagues are discussed only very briefly. Since we are convinced that a couple of these models indeed have a great value for AD research and the development of new AD drugs we will subsequently describe a few of them in more detail.A suitable mouse model of AD does not only have to mimic major hallmarks of AD that are modifiable by different test substances as mentioned by the authors; they also have to be translational to clinical trials in humans. For the following discussion, we will therefore also include information on clinical trials of drugs previously tested in the different transgenic mice.     

Combining ibuprofen and acetaminophen for acute pain management after third-molar extractions: Translating clinical research to dental practice

BackgroundEffective and safe drug therapy for the management of acute postoperative pain has relied on orally administered analgesics such as ibuprofen, naproxen and acetaminophen, or N-acetyl-p-aminophenol (APAP), as well as combination formulations containing opioids such as hydrocodone with APAP. The combination of ibuprofen and APAP has been advocated in the last few years as an alternative therapy for postoperative pain management. The authors conducted a critical analysis to evaluate the scientific evidence for using the ibuprofen-APAP combination and propose clinical treatment recommendations for its use in managing acute postoperative pain in dentistry.Types of Studies ReviewedThe authors used quantitative evidence-based reviews published by the Cochrane Collaboration to determine the relative analgesic efficacy and safety of combining ibuprofen and APAP. They found additional articles by searching the Ovid MEDLINE, PubMed and http://ClinicalTrials.gov databases.ConclusionsThe results of the quantitative systematic reviews indicated that the ibuprofen-APAP combination may be a more effective analgesic, with fewer untoward effects, than are many of the currently available opioid-containing formulations. In addition, the authors found several randomized controlled trials that also indicated that the ibuprofen-APAP combination provided greater pain relief than did ibuprofen or APAP alone after third-molar extractions. The adverse effects associated with the combination were similar to those of the individual component drugs.Practical ImplicationsCombining ibuprofen with APAP provides dentists with an additional therapeutic strategy for managing acute postoperative dental pain. This combination has been reported to provide greater analgesia without significantly increasing the adverse effects that often are associated with opioid-containing analgesic combinations. When making stepwise recommendations for the management of acute postoperative dental pain, dentists should consider including ibuprofen-APAP combination therapy.     

Adverse drug and device reactions in the oral cavity: Surveillance and reporting

BackgroundAccording to the U.S. Centers for Disease Control and Prevention, 48 percent of Americans (roughly 144 million people) used at least one prescribed medication in the preceding month; 11 percent used five or more. The authors describe the U.S. Food and Drug Administration's (FDA's) MedWatch program, the safety surveillance system for drugs and devices in the United States, and the dentist's role with regard to voluntary reporting of adverse effects (AEs). They also identify the most frequent AEs in the oral cavity as reported in the FDA Adverse Event Reporting System (FAERS).MethodsThe authors reviewed the literature regarding MedWatch, and they mined data in the FAERS public database for the 100 most commonly prescribed medications and their associated AEs.ResultsPharyngitis was the most common AE. Cough, dysgeusia and dysphagia also were common.ConclusionThe MedWatch program and its related databases contain useful information about AEs of pharmaceuticals and devices manifested in the oral cavity. Increased participation in the reporting of suspected adverse reactions will improve the national surveillance system and ultimately will protect patients' safety.Practical ImplicationsAs pharmaceutical consumption increases exponentially for a growing segment of the population, and as innovation in dental technology and devices flourishes, dentists have a distinct role in safeguarding patients' well-being. Promptly reporting AEs in the oral cavity improves quality of care and protects patients' well-being.     

Delivery of macromolecules across oral mucosa from polymeric hydrogels is enhanced by electrophoresis (iontophoresis)

Objective

To develop polymeric hydrogel delivery systems for iontophorseis transfer of large molecules across buccal (porcine) mucosa.

Methods

Three hydrogels (PVA, HPMC and PVA/HPMC) were prepared as stable gels (7 mm diameter/1.5 mm thick). Quantitative (8 and 36 h) assessment of porcine buccal mucosa and the three hydrogel delivery systems, using a diffusion cell in vitro model, was carried out by UV/vis spectroscopy with three model agents (3 and 10 kDa dextrans and 12 kDa parvalbumin). Passive and iontophoresis parameters were obtained. Experimental and theoretical data were compared.

Results

Iontophoresis (30 min, 1–8 h) significantly enhanced the delivery of all model agents across four single systems (hydrogels and buccal mucosa) and three sandwich systems (hydrogels on top of buccal mucosa), as confirmed by time lag factor/enhancement ratio (TLF/ER) data. The diffusion coefficients of model agents across buccal mucosa (×10⁻¹³ m² s⁻¹) were ∼100 times lower than across single hydrogels (2.97–4.80 × 10⁻¹¹ m² s⁻¹). Solubility values of all agents across hydrogels were similar, but lower across buccal mucosa. Permeability of parvalbumin was highest across PVA, and for both dextrans across PVA/HPMC. In sandwich systems TLFs were similar for all hydrogels, but significantly lower, and ERs significantly higher, than tissue alone. Experimental and theoretical TLF data were in reasonable agreement.

Significance

The in vitro data show that iontophoresis enhanced the delivery of large molecules across polymeric hydrogel systems and buccal mucosa. This creates the opportunity of new approaches to drug delivery and opens pathways to further research for delivering therapeutic agents topically and systemically.     

口腔扁平苔藓患者外周血相关炎症因子表达分析

目的：观察口腔扁平苔藓（OLP）患者外周血中的炎症因子红细胞沉降率、C反应蛋白和类风湿因子的表达。方法：检测20例OLP患者（白纹组与充血糜烂组各10例）和20例类风湿性关节炎（RA）患者外周血的炎症因子血沉、C反应蛋白和类风湿因子指标。结果：OLP患者和RA患者外周血的炎症因子红细胞沉降率（t检验,12．4±10．1VS22．6±16．1,P=0．02）、C反应蛋白（￡检验,4．6±5．4VS26．9±24．7,P=0．0003）和类风湿因子Q检验,9．2±0．2VS340．4±541．7,P=0．009）指标之间均有统计学差异。而相应指标在OLP白纹组（5例男性、5例女性,年龄45．1±14．8岁）与充血糜烂组（3例男性、7例女性,年龄49．5±15．2岁）之间无统计学差异（￡检验,红细胞沉降率11．9±9．2VS12．9±11．5,P=0．83;C反应蛋白5．7±7．7VS3．6±1．0,P=0．39;类风湿因子9．1±0．06VS9．2±0．2,P=0．33）。结论：外周血红细胞沉降率、C反应蛋白和类风湿因子与OLP的炎症程度无相关性。     

上海市1999-2006年新登记老年肺结核患者死亡情况及影响因素分析

目的 描述上海市60岁及以上的老年肺结核患者的死亡情况,探讨其可能的影响因素。方法 上海市1999-2006年期间新登记并确诊的痰分枝杆菌培养阳性肺结核病患者共14589例,其中≥60周岁的老年患者共5068例（34.7%）,<60岁的非老年患者共9521例（65.3%）。研究描述了两组患者人口学、临床特征、细菌学、死亡情况等方面的特征,并以logistic回归逐步前进法鉴别老年患者中可能与死亡有关的危险因素。结果 老年患者中男性4167例,占82.2%,非老年患者中男性6699例,占70.4%（χ²=244.8, P<0.01)、老年复发患者1447例,占28.6%;非老年患者1240例,占13.0%（χ²=536.3, P<0.01);老年有合并症患者1472例,占29.0%,非老年患者1172例,占12.3%（χ²=624.2, P<0.01);老年涂阳患者4313例,占85.1%,非老年患者7625例,占80.0%（χ²=31.6, P<0.01)。两者比较差异均有统计学意义。老年患者中肺部影像学检查显示有空洞者(1480例,占29.2%)显著低于非老年患者（3120例,占32.8%）,两者比较有统计学差异（χ²=11.9, P<0.01)。老年患者病死率(668例,13.2%)显著高于非老年患者(139例,1.5%),两者比较差异有统计学意义（χ²=479.7, P<0.01)。在5068例老年组患者中,经多因素logisitic回归逐步前进法分析显示,70～<80岁(OR=1.89, 95%CI＝1.54～3.32,P<0.01)、80岁及以上 (OR=3.71, 95%CI＝2.91～4.74, P<0.01)、男性(OR=1.72, 95%CI＝1.34～2.21,P<0.01)、有合并症(OR=1.53, 95%CI＝1.28～1.83,P<0.01)、涂阳(OR=1.33, 95%CI＝1.02～1.72, P=0.03)、居住地区为郊县(OR=1.49, 95%CI＝1.24～1.79,P<0.01)和耐多药(OR=1.95, 95%CI＝1.10～3.48,P=0.02)与死亡相关。结论 上海市老年肺结核患者病死率远高于非老年患者。高龄、男性、有合并症、涂阳、居住于郊县和耐多药是死亡的危险因素。     

耐多药结核分枝杆菌对利福布汀和利福平的交叉耐药性分析

目的 对耐多药MTB临床分离株进行利福布汀和利福平交叉耐药性研究分析,为利福布汀治疗耐多药MTB提供依据.方法 在96孔板上检测利福布汀和利福平对99株耐多药MTB菌株的90％最低抑菌浓度(MIC90),交叉耐药率数据分析采用x2检验,两组间MIC比较经对数转化后采用独立样本t检验.结果 利福布汀和利福平的交叉耐药率为85.9％(85/99).利福布汀的MIC90值为≤16 mg/L,中位数为2 mg/L;利福平的MIC9o值为≥2 mg/L,中位数＞32 mg/L,利福布汀MIC90值仅为利福平的1/8 ～ 1/32.利福布汀和利福平交叉耐药率随利福平的耐药程度加大而上升,低耐利福平组和中耐利福平组的交叉耐药例数分别为0/9和5/9,而高耐利福平组几乎全部交叉耐药(98.8％,80/81).结论 利福布汀对利福平耐药MTB菌株有一定的抗菌活性,可作为利福类药物耐药结核病的可选择药物.