一种新型可降解聚合物涂层-雷帕霉素洗脱支架对猪冠状动脉新生内膜增生的影响

目的:评价可降解高分子材料聚丙交酯-乙交酯(PLGA)作为支架药物载体的可行性及携带雷帕霉素的PLGA涂层支架的抗内膜增生作用。方法:在14头微型猪的3支冠状动脉分别植入钴铬合金裸支架(CoCr-BMS)、不载药的PLGA涂层支架(PCOS)和PLGA涂层雷帕霉素洗脱支架(PLGA-SES)。分别在支架植入后1个月和3个月时,复查冠状动脉造影,然后分离支架段血管行组织病理学分析。结果:共有12头动物存活,其余2头动物可能因麻醉剂相关的呼吸抑制而死亡。支架植入后1个月和3个月,不载药的PLGA涂层支架新生内膜面积和晚期管腔丢失与CoCr-BMS组相近,而PLGA-SES组则明显低于CoCr-BMS组。组织形态学示3组支架段血管损伤积分、炎症积分及再内皮化积分差异无统计学意义。结论:在猪冠状动脉支架模型中,PLGA涂层的支架设计具有良好的生物相容性和安全性;携带雷帕霉素的这种支架可抑制新生内膜形成,预防支架再狭窄的发生。     

聚丙交酯-乙交酯涂层-钴基合金雷帕霉素洗脱支架对猪冠状动脉新生内膜增生的影响

目的:评价钴基合金支架平台、聚丙交酯-乙交酯(PLGA)聚合物作为携带雷帕霉素涂层的新型支架的抗内膜增殖的有效性及安全性。方法:随机在7头微型猪的3支冠状动脉置入钴基合金PLGA涂层支架(Cob-POS组)、钴基合金PLGA涂层雷帕霉素洗脱支架(Cob-SES组)、不锈钢雷帕霉素药物洗脱支架(gen1-SES组),记录支架释放前后的冠状动脉造影图像。3个月后,冠状动脉造影复查后处死动物,分离支架段血管行组织病理学分析。结果:6只动物存活,1只动物于支架释放过程中死亡,死因可能为麻醉剂所致的呼吸抑制。3组(n=6)支架段血管组织学评价示,与gen1-SES组比较,Cob-SES组新生内膜面积和最大内膜厚度均明显减少。Cob-POS和Cob-SES组支架内狭窄程度与gen1-SES组比较,均差异有统计学意义(P<0.05)。组织形态学示3组支架段血管损伤积分、炎症积分、再内皮化积分差异无统计学意义。结论:在猪冠状动脉支架模型中,钴基合金平台、PLGA涂层的支架设计显示出良好的生物相容性和安全性;携带雷帕霉素的这种支架显示出比第一代雷帕霉素支架更佳的抑制内膜增生的能力。     

骨关节结核局部药物缓释材料研究进展

抗结核药物缓释材料是近些年骨关节结核治疗领域的新热点,材料在植入骨关节结核病灶内后,作为骨替代物修复骨缺损的同时,能够长时间释放抗结核药物。笔者简要综述了骨关节结核局部药物缓释材料的相关研究进展。     

平阳霉素微球长效制剂的制备及其体内外释放

目的 制备可稳定释药平阳霉素的长效微球制剂,考察该微球制剂在体内外的释放.方法 运用复乳溶剂挥发法,以聚乳酸羟基乙酸(PLGA)共聚物为囊材,将平阳霉素包封在PLGA微球中,制备可缓释的具有较高包封率的平阳霉素PLGA微球长效制剂.将该微球制剂在体外环境和比格犬体内做药物释放试验.结果 体外释放实验证明该微球制剂可持续释放平阳霉素近28 d,将其肌肉注射到比格犬体内,可稳定缓释平阳霉素近24 d.结论 平阳霉素PLGA微球制剂制备工艺合理,肌肉注射该微球制剂在体内有缓释平阳霉素的作用.     

聚乳酸/聚乙醇酸微球控释系统研究进展

自上世纪80年代以来，生物可降懈微球控制释放系统在医学领域得到广泛应用。其除具备其他生物可降懈控释系统的优点外，还具有对特定器官、组织的靶向性。通常用作高分子载体的有聚酯类、聚α-氨基酸类以及淀粉和壳聚糖等。聚乳酸／聚乙醇酸（PLGA）为聚酯类的一种，现将其研究进展综述如下。     

氯硝柳胺控释贴膜预防日本血吸虫感染的初步试验

采用生物医用高分子研制药物控制释放系统能使药物长效化、低毒化。近年来生物医用高分子作为药物控制释放的载体 ,成为第三代药物制剂开发研究的方向 ,越来越为人们所关注。2 0世纪 70年代末 80年代初 ,国内主要研究抗癌药、麻醉药、避孕药等的缓释 ,而血吸虫病预防药物的控制释放体系国内外均鲜见文献报道。本实验以氯硝柳胺作主药 ,合成制备为具有控释功能高、生物相容性好的医用材料 ,经粘合剂扩散至皮肤表面渗透吸收的控释贴膜 ,并在室内做预防日本血吸虫感染试验。1　材料与方法氯硝柳胺粉剂 ,含量 >98% ,由安徽省淮南第三制药厂生产 …     

紫杉醇缓释剂型对人胚肺成纤维细胞增殖的抑制作用

目的建立紫杉醇、聚乳酸-羟基乙酸共聚物(PLGA)缓释系统,观察其抑制人胚肺成纤维细胞的效果,探讨用于治疗瘢痕性气道狭窄的可行性。方法采用改良溶剂蒸发法制备紫杉醇PLGA缓释微球,高效液相色谱法(HPLC法)测定其载药量、包封率,并行体外释放试验对其缓释性进行评估;采用噻唑蓝法测定空白微球及不同剂量的紫杉醇缓释微球对人胚肺成纤维细胞增殖的抑制率,对其有效性进行评价。结果紫杉醇PLGA微球形态圆整,平均粒径40μm,载药量和包封率分别为1.67%和66.8%。体外释药表明微球具有缓释性,可持续释放20天以上;20 mg微球每天释放的紫杉醇浓度在10-5mol/L左右,均在有效浓度范围内。MTT测定,不同剂量微球均可抑制HPF增殖,并且呈剂量依赖性,60 mg微球缓释液作用24 h,对HPF的抑制率可达50%以上。结论成功制备了紫杉醇缓释剂型,能够实现药物缓慢释放并可有效抑制HPF的增殖。证实局部应用该剂型在治疗瘢痕性气道狭窄方面具有潜在价值。     

聚乳酸羟基乙酸-甲状旁腺激素相关蛋白复合微球的制备 形态表征及生物相容性研究

［摘要］　目的　制备聚乳酸羟基乙酸-甲状旁腺激素相关蛋白复合微球（PLGA-PTHrP）并观察其形态表征及其生物相容性。方法　采用复乳溶剂挥发法制备空白聚乳酸羟基乙酸（PLGA）微球,通过表面浸提法将不同浓度的甲状旁腺激素相关蛋白（PTHrP）装载到PLGA微球。采用冷冻干燥法制备负载有效浓度PTHrP的PLGA微球。通过扫描电镜观察PLGA微球形态并计算微球粒径,检测PLGA-PTHrP的蛋白释放量,并绘制释放曲线。将PLGA-PTHrP与大鼠全骨髓细胞共培养,分析复合微球对细胞增殖分化的影响。结果　采用复乳溶剂挥发法制备得到的空载PLGA微球呈球形或类球形,表面较平整,平均粒径为（56.73±7.22）μm。载蛋白微球的体外蛋白质释放实验结果显示,蛋白质的释放速率在前100 h较快,释放时间可持续达300 h。载蛋白微球释放的蛋白质占蛋白质总量的87.3%。实验结果显示,PLGA-PTHrP对大鼠全骨髓细胞增殖活力无明显影响。结论　通过复乳溶剂挥发法可制备出表面较平整,粒径较均匀的PLGA空白微球,使用表面浸提法及冷冻干燥法能制备出有效的PLGA-PTHrP缓释体系,该缓释体系能在一定时间范围内实现PTHrP的缓释作用。     

鼻泪管药栓植入术治疗泪道阻塞(附29例报告)

对29例(34只眼)泪道阻塞患者经鼻泪管植入复方药物栓剂,药栓保留50 d.34只眼均成功植入药栓(成功率100%).随访3个月,除1例在药栓保留期间中因疼痛、美容原因要求取出外,余28例均达到满意疗效,治愈率为97.06%.认为鼻泪管药栓治疗泪道阻塞不改变泪道解剖结构,是一种简单、安全、有效治疗泪道阻塞的新方法 .     

内皮祖细胞CD34抗体包被冠脉支架对猪冠状动脉再狭窄影响的研究

目的 探讨生物可降解高分子载内皮祖细胞CD34抗体支架是否可降低猪冠状动脉支架置入术后再狭窄.方法 以生物可降解高分子聚乙二醇-聚乳酸-聚谷氨酸共聚物为载体,应用N-琥珀酰亚胺基-3-(2-吡啶二硫)-丙酸酯(SPDP)方法制成内皮祖细胞CD34抗体洗脱支架.18只猪随机分为三组,即紫杉醇支架组、CD34抗体支架组、裸支架组,每组6只,将紫杉醇支架、CD34抗体支架、裸支架分别植入到各组猪的冠状动脉损伤段,4 w后处死,取出支架段血管行病理学观察及计算机图像分析血管管腔面积、内膜增生面积以及面积狭窄百分比.结果 CD34抗体支架组内膜增生面积较裸支架组减低(P＜0.05),紫杉醇支架组内膜增生面积较裸支架组也减低(P＜0.05),但较CD34抗体支架组无明显差别(P＞0.05).结论 生物可降解高分子载内皮祖细胞CD34抗体支架可明显加速支架置入术后血管内皮修复,降低再狭窄的发生.     

Chemotherapy of tuberculosis in mice using single implants of isoniazid and pyrazinamide.

OBJECTIVE: To establish the chemotherapeutic value of a depot drug preparation of isoniazid and pyrazinamide against experimental tuberculosis. DESIGN: To see whether sustained levels of pyrazinamide are available for prolonged periods after a single subcutaneous administration of a biodegradable polylactic-glycolic acid (PLGA) polymer containing the drug, studies were done to ascertain whether a single administration of isoniazid and pyrazinamide in separate PLGA polymers could offer chemotherapeutic protection against a heavy intravenous challenge of susceptible mice with a virulent strain of Mycobacterium tuberculosis similar to that rendered by daily administration of the two drugs for 8 weeks. RESULTS: Even with three times the daily dose of pyrazinamide contained in the single PLGA polymer implant, no abnormally high (burst) levels of the drug were evident after administration, but sustained levels of the drug were seen up to 54 days. The chemotherapeutic activity of the single PLGA polymer implants was similar to that obtained with standard oral treatment with the two drugs given daily for the entire 8 weeks, as judged by mortality and colony forming unit (CFU) counts of tubercle bacilli from lungs and spleen. CONCLUSION: Treatment with single implants of the PLGA polymer containing anti-mycobacterial drugs offers a strong possibility of circumventing the compliance problem.     

Influence of processing variables and in vitro characterization of glipizide loaded biodegradable nanoparticles

AimThe aim of this study was to develop glipizide (GPZ) loaded biodegradable nanoparticles by using a biodegradable polymer, poly(d,l-lactic-co-glycolic acid) (PLGA) as a sustained release carrier.Material and MethodsPLGA nanoparticles (PLGA NPs) were prepared by a modified emulsification solvent evaporation technique. Subsequent study shows no interaction of GPZ with PLGA (FT-IR study). Various formulation parameters such as stirring speed (300–3000 rpm), drug:polymer ratio (1:4 to 2:1), with addition of surfactants (0.5%, w/v polyvinyl alcohol/polysorbate-80) were studies for particle size, drug loading, and encapsulation efficiency.ResultThe drug entrapment efficiency, drug loading, particle size and zeta potential were investigated. The surface morphology was characterized by scanning electron microscopy (SEM). Mean particle size of nanoparticles was altered by changing the drug:polymer ratio and stirring speed. Addition of surfactants showed a promise to increase drug loading, encapsulation efficiency, and decreased particle size. The drug release pattern consisted of two phases releasing about 40% (within first 24 h) followed by a slow releasing phase (up to 90%) within next 48 h. The release data was fitted in various kinetic models (zero-order, first-order, and Higuchi's kinetics) indicated a controlled drug release. Accelerated stability studies (ICH guidelines) revealed that the GPZ-loaded nanoparticles were stable at the end of 6 months.ConclusionsThe Controlled release biodegradable nanoparticles can be prepared by selecting the proper processing variables.     

Biocompatibility of Implanted Diabetes Devices: Part 2: A Review of the Development of a Vehicle for Localized and Controlled Drug Delivery for Implantable Biosensors

A major obstacle to the development of implantable biosensors is the foreign body response (FBR) that results from tissue trauma during implantation and the continuous presence of the implant in the body. The in vivo stability and functionality of biosensors are compromised by damage to sensor components and decreased analyte transport to the sensor. This paper summarizes research undertaken by our group since 2001 to control the FBR toward implanted sensors. Localized and sustained delivery of the anti-inflammatory drug, dexamethasone, and the angiogenic growth factor, vascular endothelial growth factor (VEGF), was utilized to inhibit inflammation as well as fibrosis and provide a stable tissue–device interface without producing systemic adverse effects. The drug-loaded polylactic-co-glycolic acid (PLGA) microspheres were embedded in a polyvinyl alcohol (PVA) hydrogel composite to fabricate a drug-eluting, permeable external coating for implantable devices. The composites were fabricated using the freeze–thaw cycle method and had mechanical properties similar to soft body tissue. Dexamethasone-loaded microsphere/hydrogel composites were able to provide anti-inflammatory protection, preventing the FBR. Moreover, concurrent release of dexamethasone with VEGF induced neoangiogenesis in addition to providing anti-inflammatory protection. Sustained release of dexamethasone is required for the entire sensor lifetime, as a delayed inflammatory response developed after depletion of the drug from the composites. These studies have shown the potential of PLGA microsphere/PVA hydrogel-based composites as drug-eluting external coatings for implantable biosensors.     

High Throughput Screening of Valganciclovir in Acidic Microenvironments of Polyester Thin Films

Ganciclovir and valganciclor are antiviral agents used for the treatment of cytomegalovirus retinitis. The conventional method for administering ganciclovir in cytomegalovirus retinitis patients is repeated intravitreal injections. In order to obviate the possible detrimental effects of repeated intraocular injections, to improve compliance and to eliminate systemic side-effects, we investigated the tuning of the ganciclovir pro-drug valganciclovir and the release from thin films of poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), or mixtures of both, as a step towards prototyping periocular valganciclovir implants. To investigate the drug release, we established and evaluated a high throughput fluorescence-based quantification screening assay for the detection of valganciclovir. Our protocol allows quantifying as little as 20 ng of valganciclovir in 96-well polypropylene plates and a 50× faster analysis compared to traditional HPLC measurements. This improvement can hence be extrapolated to other polyester matrix thin film formulations using a high-throughput approach. The acidic microenvironment within the polyester matrix was found to protect valganciclovir from degradation with resultant increases in the half-life of the drug in the periocular implant to 100 days. Linear release profiles were obtained using the pure polyester polymers for 10 days and 60 days formulations; however, gross phase separations of PCL and acid-terminated PLGA prevented tuning within these timeframes due to the phase separation of the polymer, valganciclovir, or both.     

重组Sj14-3-3,SjGST及mIL-12/聚乳酸聚乙醇酸共聚物(PLGA)缓释微球对小鼠免疫保护性的研究

目的研究聚乳酸聚乙醇酸共聚物(PLGA)微球给药系统在血吸虫病分子疫苗中的应用,并探讨rSj14-3-3,rSjGST及mIL-12作为疫苗的协同作用,及mIL-12刺激机体产生CTL和辅助性T细胞(Th)在抗血吸虫病中的作用。方法从pET28a/Sj14-3-3和GST重组质粒中诱导表达rSj14-3-3及rSjGST,过柱纯化。构建真核表达质粒pcDNA3.1(+)mIL-12,并共同包入PLGA缓释微球。对制备的微球进行体外释放,观察其释放速度。分组免疫BALB/c小鼠,进行尾蚴攻击感染实验。在攻击感染6w后,剖杀小鼠,计算各组的减虫率。结果各组的减虫率:单独rSj14-3-3组为27.6%,rSj14-3-3+PcDNA3.1(+)mIL-12组34.9%,rSj14-3-3+PcDNA3.1(+)mIL-12PLGA微球组37.5%,rSj14-3-3与rSjGST混合后+PcDNA3.1(+)mIL-12PLGA微球组38.8%;各组减卵率分别为(按以上组序)35.3%,49.1%,50.5%,和43.1%。结论PLGA微球给药系统可诱导并调节体液与细胞免疫从而增强了疫苗的抗感染,抗生殖作用。但rSj14-3-3和rSjGST抗原之间未表现出协同作用。mIL-12刺激机体产生CTL和辅助性T细胞(Th),在BALB/c鼠抗血吸虫攻击感染发挥作用,增强了疫苗保护作用。     

XIENCE V™ Stent Design and Rationale

Drug-eluting stents (DES) are a preferred treatment modality for occlusive coronary artery disease. First-generation DES have demonstrated high levels of efficacy. However, concerns have been raised over late thrombotic events. XIENCE V™ everolimus-eluting coronary stent is a second-generation DES designed to be more deliverable and safe, while maintaining efficacy in a broad patient population compared with first-generation DES. ^{1 − 3} As a drug/device combination product, the overall performance of a DES is determined by its components and how well they are integrated. XIENCE V utilizes the MULTI-LINK VISION^® stent, the antiproliferative drug everolimus, a fluorinated polymer drug carrier, poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP), and a stent-specific delivery system. A DES coating must fulfill the multiple goals of biocompatibility, controlled drug release and maintenance of the coating durability through stent crimping, and expansion in vivo. The XIENCE V coating utilizes a two-layer coating system composed of an acrylate primer and a fluorinated copolymer drug reservoir. Fluorinated polymers have a long history of use in permanent vascular implant applications. The XIENCE V fluorinated copolymer offers in vivo biocompatibility combined with excellent chemical stability and high purity. Described in this article are the design rationale and polymer selection criteria. The hemocompatibility and biocompatibility of the fluorinated polymer coating are discussed. Characterization results on drug release control, possible drug release mechanism, coating integrity, coating uniformity, and fatigue resistance are also presented.     

Controlling Acute Inflammation with Fast Releasing Dexamethasone-PLGA Microsphere/PVA Hydrogel Composites for Implantable Devices

Background

Continuous release of dexamethasone from PLGA microsphere/PVA hydrogel composites has been shown to suppress the inflammatory tissue reaction in response to subcutaneously implanted foreign material for a period of one month. The scope of the present work is to investigate whether suppressing the initial acute inflammatory phase with fast releasing dexamethasone-PLGA microsphere/PVA composites (that release the drug over a period of one week) would prevent the development of a foreign body reaction in response to implantation in the subcutaneous tissue using a rat model.

Methods

Dexamethasone loaded PLGA microspheres were prepared using the solvent evaporation method. In vitro release from microspheres was analyzed using USP apparatus 4 in phosphate buffered saline (PBS) at 37°C. Composites were fabricated in 18G needles by freeze-thaw cycling the PVA/microsphere dispersion. The composites were implanted in the subcutaneous tissue of anesthetized rats. The pharmacodynamic effect was evaluated by histological examination of the tissue surrounding the composites at pre-determined time points.

Results

In vitro release studies showed that most of the drug entrapped in the microspheres was released within one week. At days 3 and 8, these fast releasing dexamethasone containing composites suppressed the acute phase of inflammation but did not prevent the development of an inflammatory reaction after dexamethasone was completely released from the composites. By day 30, chronic inflammation and fibrosis were observed in the tissue surrounding the drug-containing composites. On days 3 and 8, the number of inflammatory cells in the vicinity of the dexamethasone containing composites was similar to that in normal tissue. However, the number of inflammatory cells was higher in drug-containing composites as compared to drug-free composites by day 30. This was due to the inflammation being in a more advanced stage in drug-free composites where a granulomatous reaction had already developed.

Conclusion

Fast release of dexamethasone from PLGA/PVA composites did not provide long-term protection against the foreign body reaction in response to implantation. It would appear that a sustained delivery of anti-inflammatory agents such as dexamethasone is necessary to suppress inflammation throughout the implant life-time.     

抗结核药栓填塞治疗难治性耐多药肺结核空洞的疗效研究

目的探讨抗结核药栓填塞治疗难治性耐多药肺结核空洞的临床疗效。方法在纤维支气管镜引导下，将抗结核药栓定期注入难治性耐多药肺结核空洞内，用X线胸片等方法动态观察变化。结果治疗组比对照组痰菌阴转率高，空洞闭合率高，单发空洞、干酪空洞的疗效比多发空洞、纤维空洞的疗效较好。未发现与介入药栓有关的毒副作用。结论经纤维支气管镜引导灌注抗结核药栓，是治疗难治性耐多药肺结核空洞的有效方法，无明显毒性反应，特此介绍。     

Sustained release of melatonin from poly (lactic‐co‐glycolic acid) (PLGA) microspheres to induce osteogenesis of human mesenchymal stem cells in vitro

Abstract: Melatonin promotes bone formation and prevents bone degradation via receptor‐dependent or receptor‐independent actions. The aim of this study is to encapsulate melatonin into poly (lactic‐co‐glycolic acid) (PLGA) microspheres (PLGA‐MEL‐MS) and create a melatonin sustained release system, then to evaluate its effect on the osteogenesis of human mesenchymal stem cells (hMSCs) in vitro. PLGA‐MEL‐MS were prepared by single emulsion solvent evaporation technique. Scanning electron microscopy demonstrated the incorporation of melatonin did not disturb the conventional generation of PLGA microspheres in size and morphology. In vitro drug release assay showed that PLGA‐MEL‐MS exhibited a biphasic drug release pattern: a low initial burst release effect with approximately 40% drug release at the first 3 days and a relatively retarded and continuous release with about 85% drug release over the 25 days. Cell proliferation assay demonstrated that PLGA‐MEL‐MS had no apparent effect on proliferation of human MSCs. In an osteogenesis assay, PLGA‐MEL‐MS obviously enhanced alkaline phosphatase (ALP) mRNA expression and increased ALP activity compared to that in the control group. Meanwhile, several markers of osteoblast differentiation were also significantly upregulated, including runx2, osteopontin, and osteocalcin. Furthermore, quantificational alizarin red‐based assay demonstrated that PLGA‐MEL‐MS significantly enhanced calcium deposit of hMSCs compared to the controls. Therefore, this simple melatonin sustained release system can control released melatonin to generate a microenvironment with a relatively stable concentration of melatonin for a period of time to support osteogenic differentiation of hMSCs in vitro. This suggests that this system may be used as bone growth stimulator in bone healing in vivo.