口服胰岛素羧甲基壳聚糖纳米粒的制备及评价

目的:研制一种生物利用度高且具有缓释作用的口服胰岛素制剂。方法:通过钙离子交联制备羧甲基壳聚糖纳米粒,采用正交试验优化纳米粒制备条件,以透射电镜观察纳米粒形态,激光粒度分析仪测定粒度,高效液相色谱法测定纳米粒包封率和载药量,并对胰岛素的体外释放性能进行考察。结果:优化工艺制备的纳米粒外观形态圆整,平均粒径为(256.1±11.2)nm,包封率为(45±0.41)%,载药量为(17.2±0.33)%,药理相对生物利用度为14.71%。结论:口服载胰岛素羧甲基壳聚糖纳米粒具有降血糖作用和显著的缓释作用,药理相对生物利用度高。     

pH-responsive thiolated chitosan nanoparticles for oral low-molecular weight heparin delivery: in vitro and in vivo evaluation

The aim of present study was to investigate a pH-responsive and mucoadhesive nanoparticle system for oral bioavailability enhancement of low-molecular weight heparin (LMWH). The thioglycolic acid (TGA) was first covalently attached to chitosan (CS) with 396.97?±?54.54?μmol thiol groups per gram of polymer and then the nanoparticles were prepared with thiolated chitosan (TCS) and pH-sensitive polymer hydroxypropyl methylcellulose phthalate (HPMCP) by ionic cross-linking method. The obtained nanoparticles were characterized for the shape, particle size, zeta potential, drug entrapment efficiency and loading capacity. In vitro results revealed the acid stability of pH-responsive nanoparticles, which had a significant control over LMWH release and could effectively protect entrapped drugs in simulated gastric conditions. By the attachment of the thiol ligand, an improvement of permeation-enhancing effect on freshly excised carp intestine (1.86-fold improvement) could be found. The mucoadhesive properties were evaluated using fluorescently labeled TCS or CS nanoparticles. As compared with the controls, a significant improvement of mucoadhesion on rat intestinal mucosa was observed in TCS/HPMCP nanoparticles via confocal laser scanning microscopy. The activated partial thromboplastin time (APTT) was significantly prolonged and an increase in the oral bioavailability of LMWH was turned out to be pronounced after oral delivered LMWH-loaded TCS/HPMCP nanoparticles in rats, which suggested enhanced anticoagulant effects and improved absorption of LMWH. In conclusion, pH-responsive TCS/HPMCP nanoparticles hold promise for oral delivery of LMWH.     

Preparation of aminoglycoside-loaded chitosan nanoparticles using dextran sulphate as a counterion

The objective of this study was to apply the specific acid-catalysed hydrolysis of ethyl acetate to completing solvent extraction during an emulsion-based microencapsulation process. The dispersed phase consisting of poly-D,L-lactide-co-glycolide and ethyl acetate was emulsified in an acid catalyst containing aqueous phase. Catalytic hydrolysis of ethyl acetate led to its continual leaching from the dispersed phase of the emulsion, thereby triggering microsphere hardening with high efficiency. Ketoprofen was successfully encapsulated into microspheres via this technique, and liquid chromatography–mass spectrometry showed that its structural integrity was preserved during microencapsulation. Compared to typical solvent extraction approaches, the acid-catalysis technique helped minimize the consumption of a quench liquid. Also, the resultant microspheres displayed excellent dispersibility and decreased propensity for aggregation. Furthermore, the new method provided better drug encapsulation efficiency and lower levels of residual ethyl acetate in microspheres. In conclusion, the acid-catalysis approach had great potential for the preparation of versatile microspheres and nanoparticles.     

Development and in vivo evaluation of chitosan nanoparticles for the oral delivery of albumin

Albumin is used as a plasma expander in critically ill patients and for several other clinical applications mainly via intravenous infusion. Oral administration of albumin can improve patient compliance although limited oral bioavailability of proteins is still a major challenge. Although nanomaterials have been extensively utilized for improving oral delivery of proteins, albumin has been utilized only as either a model drug or as a carrier for drug delivery. In the current study, for the first time, chitosan nanoparticles have been developed and extensively optimized to improve oral bioavailability of albumin as a therapeutic protein. Several characterizations have been performed for the albumin-loaded nanoparticles (e.g. drug encapsulation efficiency, DSC, FTIR, particle size, zeta potential, morphology, release kinetics, and enzymatic stability). Nanosized spherical particles were prepared and demonstrated high stability over three months either in a powdered form or as suspensions. Sustained release of albumin over time and high enzymatic stability as compared to the free albumin were observed. In vivo, higher serum concentrations of albumin in normal rabbits and cirrhotic rats were attained following oral and intraperitoneal administrations of the albumin-loaded nanoparticles as compared to the free albumin. The nanoparticles developed in the current study might provide efficient nanovehicles for oral administration of therapeutic albumin.     

Variations of serum potassium level and risk of hyperkalemia in inpatients receiving low-molecular-weight heparin

Objectives To observe the variations of serum potassium level in patients receiving low-molecular weight heparin, assess the consequent risk of hyperkalemia and evaluate the clinical contributory factors.Methods A prospective study was performed on consecutive inpatients treated with low-molecular-weight heparin as indicated by the attending physicians. The changes of serum potassium level observed within 5–8 days were tested by univariate and multivariate analysis according to demographic and clinical variables and concomitant pharmacological therapy.Results Four hundred and sixteen patients (mean age 73 years; 64% female) were enrolled in the study over 15 months. After receiving nadroparin or enoxaparin (mean daily dosage: 76.3 anti-factor Xa unit/kg) for a median 6-day period, their mean (±SD) serum potassium level increased from 4.2±0.5 mmol/l to 4.5±0.5 mmol/l (P<0.0001). This change was significantly correlated with baseline potassium, interval between potassium samplings, history of hypertension or renal insufficiency, and marginally with aldosterone antagonist treatment. Hyperkalemia, defined as potassium exceeding 5.5 mmol/l, developed in ten patients (2.4%) and the highest value observed was 7.6 mmol/l; by multivariate logistic-regression analysis, history of diabetes was the only significant independent predictor (odds ratio 6.5; 95% C.I.=1.7–24.8).Conclusion Short-term treatment with low-molecular-weight heparin induces a significant increase in serum potassium level but the related incidence of relevant hyperkalemia is low. However, given the high absolute number of patients currently exposed to the risk in many clinical settings and the limitation of risk prediction, clinicians should prevent this life-threatening complication by a high index of suspicion and, accordingly, a quite routine monitoring of serum potassium.     

三甲基化壳聚糖卵清蛋白纳米粒的制备

目的：以N-三甲基壳聚糖盐酸盐（N—trimethyl chitosan chloride，TMC）为材料制备新型纳米粒（nanoparticles，NPs），包裹卵清蛋白（ovalbumin，OVA），以提高卵清蛋白的包封率。方法：利用TMC与三聚磷酸钠（tripolyphosphatesodium，TPP）之间的离子胶凝作用制备纳米粒；用纳米粒度及表面电位分析仪测定纳米粒的粒径及zeta电位；探讨OVA溶液的pH值及浓度，TMC溶液的浓度，TPP溶液的浓度等因素对OVA包封率的影响；用十二烷基硫酸钠一聚丙烯酰胺明胶电泳（Soldium Dodeoyl Sulfate—Polyacrylamide，SDS-PAGE）检验OVA在纳米粒制备及体外释放过程中有无降解。结果：本研究制备的TMC／OVA纳米粒为紧密球形，分布均匀，粒径约为135．4nm，zeta电位约为＋20mV；OVA的pH值及制备工艺是影响包封率的主要因素；SDS-PAGE电泳证实在纳米粒的制备及释放过程中OVA没有降解。结论：用离子胶凝法制备载蛋白多肽类疫苗的纳米粒，操作简便，采用合适的制备方法，调整处方可将包封率提高到90％以。     

低分子肝素治疗心绞痛的疗效研究

目的观察低分子肝素治疗心绞痛的疗效。方法选择符合心绞痛患者80例,随机分为治疗组A42例（低分子肝素组＋常规药物治疗）,和对照组B38例（未使用低分子肝素组）,比较两组治疗心绞痛的疗效。结果治疗组有效率95．2％,对照组有效率65．79％,两组存在显著差异。结论低分子肝素联合常规治疗药物对心绞痛患者是安全有效的治疗方法。     

低分子肝素对于人工全髋关节置换术后下肢深静脉血栓形成的预防

目的探讨人工髋关节置换术(THR)后用低分子肝素预防下肢深静脉血栓(DVT)形成的疗效和安全性。方法将2002年1月至2006年6月行人工全髋关节置换术的94例患者随机分为未用药组和用药组,其中未用药组46例,未预防性使用任何药物;用药组48例,围手术期给予低分子肝素预防性治疗。术后第7天,两组患者均行双侧下肢彩色多谱勒超声检查,了解DVT形成情况及两组术后DVT的发生率。结果未用药组中有22例DVT阳性,DVT的发生率47.8%,用药组中有9例DVT阳性,DVT的发生率18.8%,两组比较,差异有统计学意义(P<0.05)。未用药组近端DVT的发生率为19.6%,用药组近端DVT的发生率为2.1%,两组比较,差异有统计学意义(P<0.05)。用药组未发现术中术后出血增多以及药物不良反应。结论低分子肝素能显著降低人工全髋关节置换术后下肢深静脉血栓的发生率,且具有良好的安全性。     

生物素化壳聚糖纳米粒的制备及其相关性质

制备了生物素化的壳聚糖纳米粒(biotinylated chitosan nanoparticles，Bio-CS-NP)并测定其相关性质，以此作为抗癌药物的载体。制备过程为：先用磺酸琥珀酰亚胺生物素与壳聚糖反应生成生物素化的壳聚糖(biotinylated chitosan，Bio-CS)，再采用氯化钠沉淀法制备Bio-CS-NP。采用试剂盒测定Bio-CS-NP表面配体连接密度，用透射电镜和激光粒度分析仪分别检测纳米粒的形态和粒径，并比较了人肝癌HepG2细胞对Bio-CS-NP和未经生物素修饰的壳聚糖纳米粒(chitosan nanoparticles，CS-NP)的摄取情况。结果显示，Bio-CS-NP表面配体连接密度为2.2 biotin CS；纳米粒形态为圆球形，表面光滑，平均粒径为296.8 nm，多分散指数为0.155；HepG2细胞对Bio-CS-NP的摄取能力显著高于CS-NP(P<0.05)。以上研究结果表明Bio-CS-NP有望成为一种新型的药物载体，用于抗癌药物对癌细胞的主动靶向。生物素的检测方法简便、可行。     

低分子肝素治疗脓毒症的效果探讨

目的分析低分子肝素治疗脓毒症的临床效果。方法80例脓毒症患者,采取随机数字表法分为对照组与观察组,每组40例。对照组给予常规治疗,观察组在对照组基础上加用低分子肝素治疗。对比两组治疗前后凝血功能指标[凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、血小板计数(PLT)、C反应蛋白(CRP)]、急性生理学及慢性健康状况评分系统Ⅱ(APACHEⅡ)评分、随访28 d生存率及不良反应发生率。结果治疗后第7天,观察组PT、APTT短于对照组、PLT高于对照组、CRP水平低于对照组,差异有统计学意义(P<0.05)。治疗后第7天,观察组APACHEⅡ评分(12.60±4.36)分低于对照组的(18.75±9.11)分,差异有统计学意义(P<0.05)。观察组随访28 d生存率95.00%高于对照组的77.50%,差异有统计学意义(P<0.05)。两组不良反应发生率对比差异无统计学意义(P>0.05)。结论低分子肝素治疗脓毒症可有效改善凝血功能指标,患者生存率较高,同时未增加不良反应发生率,保证了用药的安全性。     

海藻酸包衣的季铵化壳聚糖纳米粒用于胰岛素口服给药的研究

本研究的目的是开发海藻酸包衣的壳聚糖纳米粒口服递送胰岛素。采用三聚磷酸钠（TPP）离子交联作用将N-[（2-羟基-3-三甲基铵）丙基]壳聚糖氯化物（HTCC）制备得到季铵化壳聚糖纳米粒（HTCC-T纳米粒）,然后在温和搅拌条件下滴加入海藻酸钠溶液,进一步形成海藻酸包衣季铵化壳聚糖纳米粒（HTCC-A纳米粒）。分别采用粒度仪、透射电镜和HPLC分析对HTCC-A纳米粒进行了粒径、zeta电位、表面形态、载药量和包封率的表征。结果表明,HTCC-A纳米粒为均匀的球形颗粒,大小为（322.2±8.5）nm,表面带有正电荷（（14.1±0.6）mV）。体外释放结果表明,在不同p H值的释放介质中,HTCC-A纳米粒的释放行为与HTCC-T纳米粒（未用海藻酸包衣）有很大的不同,这表明海藻酸包衣可以显著改善纳米粒中胰岛素的释放行为。同时,体外酶解试验和圆二色散图谱进一步证实,海藻酸包衣可以显著改善纳米粒中胰岛素结构稳定性。HTCC-A纳米粒十二指肠给药的相对药理生物利用度为8.0%±2.5%。与HTCC-T纳米粒口服给药相比,HTCC-A纳米粒的相对药理生物利用度显著增加（P〈0.05）,是HTCC-T纳米粒的2.2倍。由此可见,海藻酸包衣季铵化壳聚糖纳米粒（HTCC-A纳米粒）将可能成为一种有效的口服递送载体系统用于提高胰岛素的体内口服吸收效果。     

Topical drug delivery using chitosan nano- and microparticles

Introduction: Topical drug delivery offers important benefits for improving the therapeutic effect and reducing systemic side effects of the administered compounds. In addition, utilization of biopolymeric material-based systems can play a key role in developing new topical dosage forms and their applications. This review describes the advances that have been made, new strategies and as well as possible challenges of particular systems of chitosan used in topical drug delivery, including challenging innovations in topical usage of these systems that can make significant impact on clinical practice.

Areas covered: The main area covered is hypothesis that particulate carriers based on chitosan and its derivatives can penetrate the topical barriers from the body. For this reason, the novel studies described emphasize the fact that chitosan-based particular systems are popular that can be tailor-made according to in vitro and in vivo characterization. Such parameters, which are known to influence their in vivo performance, can be modulated by adjusting the formulation conditions of the chitosan-based particular systems for topical application.

Expert opinion: The topical application of drugs with particulate systems comprising a natural polymer, chitosan, is one of the most popular drug delivery routes. The aim of topical use of chitosan particles is to improve the drug bioavailability by prolonging the residence time of drugs applied topically or by enhancing the passing of drugs through the epithelial cells by opening the tight junctions between epithelial cells and also to reduce the side effects of the drugs.     

依达拉奉联合低分子肝素治疗进展性脑梗死疗效观察

目的 观察低分子肝素联合依达拉奉治疗进展性脑梗死的疗效.方法 将发病72 h内的进展性脑梗死患者60例随机分成低分子肝素与依达拉奉联合治疗组和单用低分子肝素治疗对照组各30例,于治疗前、后进行神经功能缺损程序评分(NIHSS)和日常生活能力量表(ADL)评分及临床疗效评定.结果 两组治疗前NIHSS、ADL评分差异均无统计学意义(均P＞0.05);治疗后7d、14 d两组NIHSS差异均有统计学意义(t=15.987、11.756,均P＜0.01),治疗后14d,两组ADL评分差异有统计学意义(=62.56,P＜0.01).治疗后14 d,治疗组显效率63.3％、总有效率83.3％,明显高于对照组的20.0％、46.7％(x2=13.695、5.769,均P＜0.01).结论 低分子肝素联合依达拉奉治疗进展性脑梗死有显著疗效.     

Impact of chitosan composites and chitosan nanoparticle composites on various drug delivery systems: A review

Chitosan is a promising biopolymer for drug delivery systems. Because of its beneficial properties, chitosan is widely used in biomedical and pharmaceutical fields. In this review, we summarize the physicochemical and drug delivery properties of chitosan, selected studies on utilization of chitosan and chitosan-based nanoparticle composites in various drug delivery systems, and selected studies on the application of chitosan films in both drug delivery and wound healing. Chitosan is considered the most important polysaccharide for various drug delivery purposes because of its cationic character and primary amino groups, which are responsible for its many properties such as mucoadhesion, controlled drug release, transfection, in situ gelation, and efflux pump inhibitory properties and permeation enhancement. This review can enhance our understanding of drug delivery systems particularly in cases where chitosan drug-loaded nanoparticles are applied.     

Preparation and in vitro/in vivo evaluation of resveratrol-loaded carboxymethyl chitosan nanoparticles

Resveratrol (RES) is natural polyphenol with a strong biological activity, but its disadvantages, such as poor water solubility, susceptibility to oxidative decomposition and rapid metabolism in the body, which substantially restricts in vivo bioavailability, need to be resolved. This study used carboxymethyl chitosan (CMCS) as a drug carrier and utilized emulsion cross-linking to prepare RES-loaded CMCS nanoparticles (RES-CMCSNPs). A single-factor experiment was performed to optimize the preparation of these particles; in vitro and in vivo characteristics were evaluated. Spherical RES-CMCSNPs were prepared under optimal conditions, in which average particle size, potential, drug loading and encapsulation efficiency were (155.3?±?15.2) nm, (?10.28?±?6.4) mV, (5.1?±?0.8)% and (44.5?±?2.2)%, respectively. FTIR, DSC and XRD showed that RES molecules were wrapped in the nanoparticles. In vitro DPPH radical scavenging abilities showed RES-CMCSNPs were better than RES raw powder. The nanoparticles improved the solubility of RES, thereby greatly improving the antioxidant activity of the drug. In vitro release experiments of RES and RES-CMCSNPs by simulating the human gastrointestinal tract were performed, in which RES-CMCSNPs rendered better releasing effects than raw RES. Raw RES and RES-CMCSNPs results were in line with those obtained for the single-chamber model for pharmacokinetic studies in rats. Compared with the bulk drugs, the RES-CMCSNPs exhibited increased in vivo absorption, prolonged duration of action and increased relative bioavailability by 3.516 times more than those of the raw RES. In addition, the residual chloroform is less than the ICH limit for class 2 solvents.     

Advances in using chitosan-based nanoparticles for in vitro and in vivo drug and gene delivery

Importance of the field: This review aims to provide an overview of state-of-the-art chitosan-based nanosized carriers for the delivery of therapeutic agents. Chitosan nanocarriers are smart delivery systems owing to the possibility of their property alterations with various approaches, which would confer them with the possibility of spatiotemporal delivery features.

Areas covered in this review: The focus of this review is principally on those aspects that have not often been addressed in other reviews. These include the influence of physicochemical properties of chitosan on delivery mechanisms and chitosan modification with a variety of ligand moieties specific for cell surface receptors to increase recognition and uptake of nanocarriers into cells through receptor-mediated endocytosis. Multiple examples that demonstrate the advantages of chitosan-based nanocarriers over other delivery systems of therapeutic agents are highlighted. Particular emphasis is given to the alteration of material properties by functionalization or combination with other polymers for their specific applications. Finally, structural and experimental parameters influencing transfection efficiency of chitosan-based nanocarriers are presented for both in vitro and in vivo gene delivery.

What the reader will gain: The readers will acquire knowledge of parameters influencing the properties of the chitosan-based nanocarriers for delivery of therapeutic agents (genetic material or drugs) in vitro and in vivo. They will get a better idea of the strategies to be adapted to tune the characteristics of chitosan and chitosan derivatives for specific delivery applications.

Take home message: Chitosan is prone to chemical and physical modifications, and is very responsive to environmental stimuli such as temperature and pH. These features make chitosan a smart material with great potential for developing multifunctional nanocarrier systems to deliver large varieties of therapeutic agents administrated in multiple ways with reduced side effects.     

Stimuli-responsive graphene-incorporated multifunctional chitosan for drug delivery applications: a review

Introduction: Recently, the use of chitosan (CS) in the drug delivery has reached an acceptable maturity. Graphene-based drug delivery is also increasing rapidly due to its unique physical, mechanical, chemical, and electrical properties. Therefore, the combination of CS and graphene can provide a promising carrier for the loading and controlled release of therapeutic agents.

Area covered: In this review, we will outline the advantages of this new drug delivery system (DDS) in association with CS and graphene alone and will list the various forms of these carriers, which have been studied in recent years as DDSs. Finally, we will discuss the application of this hybrid composite in other fields.

Expert opinion: The introducing the GO amends the mechanical characteristics of CS, which is a major problem in the use of CS-based carriers in drug delivery due to burst release in a CS-based controlled release system through the poor mechanical strength of CS. Many related research on this area are still not fully unstated and occasionally they seem inconsistent in spite of the intent to be complementary. Therefore, a sensitive review may be needed to understand the role of graphene in CS/graphene carriers for future drug delivery applications.     

低分子肝素钙治疗肺心病并呼吸衰竭的临床价值研究

目的探讨肺源性心脏病(肺心病)并呼吸衰竭患者运用低分子肝素钙进行治疗的临床应用价值。方法72例肺心病并呼吸衰竭患者,应用随机数字表法分为观察组和对照组,每组36例。对照组患者采取常规治疗,观察组患者在对照组上采用低分子肝素钙治疗。对比两组患者治疗前后动脉血气指标[氧分压(PaO2)、二氧化碳分压(PaCO2)及酸碱度(pH)值]及治疗效果。结果治疗前,两组患者的PaO2、PaCO2、pH值水平比较,差异无统计学意义(P>0.05);治疗后,观察组患者的PaO2(9.36±1.02)kPa明显高于对照组的(7.78±0.98)kPa,PaCO2(6.33±0.97)kPa明显低于对照组的(7.65±1.28)kPa,差异均具有统计学意义(P<0.05);两组患者pH值比较差异无统计学意义(P>0.05)。观察组患者总有效率为97.22%,显著高于对照组的83.33%,差异具有统计学意义(P<0.05)。结论针对肺心病并呼吸衰竭患者运用低分子肝素钙进行治疗,可有效改善患者的血气指标,提高治疗效果,具有较高的临床价值。     

阿司匹林联合低分子肝素钙治疗急性脑梗死的效果

目的 探讨阿司匹林联合低分子肝素钙治疗急性脑梗死的临床效果.方法 选取2012年5月～2014年5月本院收治的94例急性脑梗死患者作为研究对象,按照随机数字表法分为观察组和对照组,每组各47例.对照组患者采用肠溶阿司匹林联合胞二磷胆碱治疗,观察组患者在对照组治疗的基础上采用低分子肝素钙治疗.观察两组患者的CSS评分变化情况、临床疗效、不良反应发生情况.结果 观察组患者的治疗总有效率（97.87％）显著高于对照组（80.85％）,差异有统计学意义（P＜0.05）.两组患者治疗后1、2、3、4周的CSS评分均显著优于同组治疗前,差异有统计学意义（P＜0.05）;观察组患者治疗后不同时间段的CSS评分显著优于对照同时间段结果,差异有统计学意义（P＜0.05）.两组患者均未发生严重不良反应.结论 阿司匹林联合低分子肝素钙治疗急性脑梗死的临床效果显著,患者CSS评分改善显著,值得临床推广.