Preparation, characterization and anticoagulation of curcumin-eluting controlled biodegradable coating stents.

Curcumin is pharmaceutically active in many ways, having properties including anticoagulation, anti-proliferation, anti-inflammatory, and may be used to fabricate drug-eluting stents to treat in-stent restenosis after stent implantation. Here we describe our investigations of curcumin-eluting PLGA coatings formed using the biodegradable polymer PLGA (polylactic acid-co-glycolic acid) as drug carrier and uniformly fabricated on the surface of 316L stainless steel stents by an ultrasonic spray method. Three doses were explored--low dose ( approximately 140 microg per stent or 115 microg/cm(2)), moderate dose ( approximately 280 microg per stent or 230 microg/cm(2)), and high dose ( approximately 490 microg per stent or 408 microg/cm(2)). Pre- and post-expansion morphologies of the stent coating were examined by optical microscopy (OM) and scanning electron microscopy (SEM), indicating that the coating not only was very smooth and uniform but also had the ability to withstand the compressive and tensile strains imparted without cracking from the stent during the expansion process. Atomic force microscopy (AFM) images indicated the topography of the PLGA-only and moderate dose curcumin-eluting stent that showed an average roughness below 1 nm; no drug particles could be seen on the stent surface, indicating that curcumin can be mixed with PLGA at the molecular level using an ultrasonic atomization spray method. The structure of the coating films was characterized by Fourier Transform Infrared (FTIR) spectroscopy and X-ray electron spectroscopy (XPS), with results suggesting that there was no chemical reaction between curcumin and the drug. The results of in vitro measurements of drug release from curcumin-eluting stents showed that all the curcumin-eluting stents studied exhibited a nearly linear sustained-release profile with no significant burst releases within the measurement period. The in vitro anticoagulation behavior of curcumin-eluting stents was investigated by static platelet adhesion and APTT (activated partial thromboplastin time) tests, revealing that the anticoagulation properties of curcumin-eluting stents are superior to those for stainless steel stents and PLGA-only-coated stents. The anticoagulation behavior of curcumin stents improved significantly as the drug dose was increased.     

Amorphous oxide--a platform for drug delivery.

Usually, a drug is loaded onto the metallic surface of a medical device by applying a polymer layer containing the drug. Unfortunately, polymer coatings on the metallic surface may exhibit numerous problems after implantation, such as late thrombosis, inflammation, and restenosis. Current research was conducted to investigate whether a suitable oxide layer can be used as a polymer-free platform for drug loading, especially for cardiovascular stents. The loading of heparin onto, as well as eluting of heparin from, the amorphous oxide film on the 316LVM stainless steel wire was confirmed by experimental studies using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), electron spectroscopy for chemical analysis (ESCA), high-performance liquid chromatography (HPLC), and activated clotting time (ACT). Evidence shows that amorphous oxide can be an ideal substitute for the polymer coating of drug-loaded stents to minimize metallic corrosion, inflammation, late-thrombosis, and restenosis.     

类细胞膜仿生药物缓释涂层冠状动脉支架材料

背景:金属冠状动脉支架植入后发生再狭窄的概率高达20%～30%,为了降低再狭窄发生率,在863项目支持下,探索新型药物涂层支架治疗冠状动脉狭窄的可能性.目的:将约物涂层支架植入小猪冠状动脉狭窄模型,观察其安全性和有效性,以及与金属裸支架的差异性.设计、时间及地点:随机对照,动物实验于2003-11/2004-04在阜外心血管病医院完成.材料:由单体2-(甲基丙烯酰氧基)乙基-2-(三甲基氨基)乙基磷酸酯、甲基丙烯酸十八酯、甲基丙烯酸羟丙酯和甲基丙烯酸(三甲氧)硅基丙酯合成了一种新型类细胞膜涂层材料.方法:21只猪随机分为3组:裸支架组,涂层携载雷帕霉素(120 μ g,支架)组,单纯涂层支架组.将支架预装到输送系统,使用Toshiba CSⅡ型C臂成像仪造影条件下,将药物支架置入小型猪冠状动脉血管,每只猪置入2枚支架.主要观察指标:使用图像分析仪检测管腔直径,管腔面积,支架上平均内膜厚度,支架间平均内膜厚度,内膜面积,面积再狭窄百分比,损伤指数.结果:置入后28 d时,涂层携载雷帕霉素组和裸支架组相比,支架上内膜厚度、支架间内膜厚度、新生内膜面积差异均有显著性意义(P＜0.05),其中新生内膜面积涂层携载雷帕霉素组比裸支架组减少了44.87%:虽面积狭窄百分比差异无显著性意义,但P值(0.053)接近0.05;且涂层携载雷帕霉素组无再狭窄发生.结论;涂层携载雷帕霉素支架可显著抑制支架置入后血管内膜增生和再狭窄发生.     

Silicon-carbide coated coronary stents have low platelet and leukocyte adhesion during platelet activation.

BACKGROUND: Stent thrombosis and restenosis are of great clinical significance. We constructed a closed loop in vitro heparinized whole human blood circulation model for testing hemocompatibility of coronary stents. This model allows evaluation of human blood activation by blood-stent interaction in a well-controlled setting. Until now these interactions were studied in the highly coagulable pig coronary artery model. METHODS: We evaluated activation of the coagulation system and blood components by uncoated, heparin-coated, and silicon-carbide coated tantalum stents. The effects, measured by biochemical assays, were compared with stainless-steel stents. Also the inhibitory effect on platelet activation by indomethacin equal to the oral effect of 325 mg acetylsalicylic acid daily, was measured and visualized by scanning electron microscopy. RESULTS: Both activation of the coagulation system and platelets were counteracted by indomethacin, suggesting an important role for platelets in activation of the coagulation system in this model. Despite platelet activation by all stents, the SiC-coated tantalum stent demonstrates a significantly lower GpIIIa receptor-mediated platelet adhesion at the stent surface (21.7 x 10(3) counts per second/mg stent weight) compared to all other stents (stainless-steel 54.0, heparin-coated 95.7 and uncoated 76.2 x 10(3) cps/mg). Also activated leukocytes demonstrated a significantly lower CD11b receptor-mediated adhesion at the SiC-coated stent (37.0 x 10(3) cps/mg) than at the stainless-steel stent (114.5 x 10(3) cps/mg). CONCLUSIONS: Data from this in vitro circulation study show a significantly lower platelet and leukocyte adhesion at the surface of the SiC-coated tantalum stent than at the surface of stainless-steel stents or uncoated and heparin-coated tantalum stents.     

Design of an intravaginal ring for the controlled delivery of 17 beta-estradiol as its 3-acetate ester.

Suitable ester prodrugs of 17beta-estradiol are identified, thus permitting effective sustained and controlled estrogen replacement therapy (ERT) from an elastomeric, silicone intravaginal ring (IVR). IVR devices of reservoir design were prepared by blending silicone elastomer base with n-propylorthosilicate (cross-linker) and 10% w/w of 17beta-estradiol or an ester prodrug, the mix being activated with 0.5% w/w stannous octoate and cured at 80 degrees C for 2 min. A rate-controlling membrane was similarly prepared, without the active agent. IVR devices were of cross-sectional diameter 9 mm, outer diameter 54 mm, with core cross-sectional diameter of 2 mm and core length varied as required. Sink conditions were evident for the 17beta-estradiol esters in 1.0% aqueous benzalkonium chloride solution. The low release rates into 0.9% w/v saline of the lipophilic valerate and benzoate esters were due to their intrinsically low aqueous solubilities. In vivo, these esters failed to raise plasma estradiol above baseline levels in postmenopausal human volunteers, despite good in vitro release characteristics under sink conditions. The best release rates under sink conditions, in combination with substantial aqueous solubilities as indicated by the release rates into saline, were observed for the acetate and propionate esters. A combination of drug release characteristics, short plasma half-life and a toxicologically acceptable hydrolysis product indicated that 17beta-estradiol-3-acetate was the prodrug of choice for IVR delivery of ERT. In vivo, an IVR device releasing 100 microg/day of estradiol as its 3-acetate ester maintained over 84 days a circulating plasma concentration in the region of 300 pmoll(-1), within the clinically desirable range for ERT.     

高脂蛋白a血症对冠状动脉支架术后再狭窄的影响

目的 探讨高血清脂蛋白(a)[LP(a)]血症与冠状动脉支架植入术后支架内再狭窄的关系.方法 对152例成功在我院行经皮冠状动脉成形术(PTCA)+支架植入术并于术后行冠状动脉造影随访的患者进行回顾性分析.分为再狭窄组(29例)和无再狭窄组(123例),检测患者血LP(a)水平,对其一般临床资料也进行调查分析.统计学采用Logistic多因素逐步回归分析.结果 2组患者在高LP(a)血症、吸烟、糖尿病比例方面差异均有统计学意义(P均<0.05).Logistic多因素逐步回归分析显示:LP(a)水平是支架术后支架内再狭窄发生的独立危险因素,RR为2.648,95%CI为1.066～6.575,P<0.05.其他因素如吸烟(P=0.023)、糖尿病(P=0.036)、支架类型(P=0.011)也与支架内再狭窄发生有关(P均<0.05).结论 高LP(a)血症是发生冠状动脉支架术后再狭窄的独立危险预测因素.     

高脂蛋白a血症对冠状动脉支架术后再狭窄的影响

目的 探讨高血清脂蛋白(a)[LP(a)]血症与冠状动脉支架植入术后支架内再狭窄的关系.方法 对152例成功在我院行经皮冠状动脉成形术(PTCA)+支架植入术并于术后行冠状动脉造影随访的患者进行回顾性分析.分为再狭窄组(29例)和无再狭窄组(123例),检测患者血LP(a)水平,对其一般临床资料也进行调查分析.统计学采用Logistic多因素逐步回归分析.结果 2组患者在高LP(a)血症、吸烟、糖尿病比例方面差异均有统计学意义(P均<0.05).Logistic多因素逐步回归分析显示:LP(a)水平是支架术后支架内再狭窄发生的独立危险因素,RR为2.648,95%CI为1.066～6.575,P<0.05.其他因素如吸烟(P=0.023)、糖尿病(P=0.036)、支架类型(P=0.011)也与支架内再狭窄发生有关(P均<0.05).结论 高LP(a)血症是发生冠状动脉支架术后再狭窄的独立危险预测因素.     

Predictive value of C-reactive protein in patients with unstable angina pectoris undergoing coronary artery stent implantation

In-stent restenosis is a major problem following coronary stent implantation, and inflammation plays an active role. We evaluated the effectiveness of the inflammatory marker C-reactive protein (CRP) as a predictor of in-stent restenosis after successful stent implantation, in 86 patients with unstable angina pectoris. Plasma CRP was measured in all patients before the procedure, and at 48 - 72 h and 1, 2 and 3 months post-procedure. An angiographic loss of 50% at follow-up was accepted as in-stent restenosis. We found negative and positive predictive values of the pre-procedural plasma CRP for determining 6-month in-stent restenosis of 34% and 61%, respectively. We also found a strong correlation between the 3-month post-procedural CRP value and 6-month in-stent restenosis; the negative and positive predictive values being 8% and 76%, respectively. In conclusion, we showed that a plasma CRP value > 3 mg/l in the third month after coronary stent implantation was a strong predictor of angiographic in-stent restenosis.     

Lipid microparticles as sustained release system for a GnRH antagonist (Antide).

Lipid microparticles (LMs) as a sustained release system for a gonadotropin release hormone (GnRH) antagonist (Antide) were prepared and evaluated. Antide loaded microparticles (Antide-LMs) were obtained by a cryogenic micronization process starting from two different monoglycerides (glyceryl monobehenate and glyceryl monostearate) and using two different incorporation methods (co-melting and solvent evaporation). Antide-LMs, 2% (w/w) loading, were characterized for drug incorporation by RP-HPLC, particle size by laser diffractometry and surface morphology by scanning electron microscopy. In vitro peptide release and in vitro biological activity were also studied. Serum Antide and testosterone levels, as pharmacodynamic marker, were assessed following subcutaneous administration in rats. Antide-LMs showed a mean diameter of approximately 30 micro m and variable Antide release depending on lipid matrix and incorporation method. In vivo experiments demonstrated that detectable Antide plasma levels were present, in the case of Antide-LMs based on Compritol E ATO obtained by co-melting procedure, for at least 30 days after dosing. Testosterone levels were consistent with prolonged pharmacokinetic profiles. In vitro release of Antide from LMs correlated well with the in vivo release. In conclusion, LMs can sustain the release of Antide for at least 1 month. The levels of the initial 'burst' and the extent of the pharmacodynamic effect can be influenced by the lipid characteristics and by process conditions.     

血管内支架材料特点与缺血性脑卒中的治疗效果

背景：新型血管内支架材料是目前脑血管疾病介入治疗的研究热点.目的：分析血管内支架材料学特征及缺血性脑卒中治疗效果.方法：第一作者于2012年12月应用计算机检索数据库的相关文章,中文检索词为“缺血性脑卒中;血管内支架;支架材料;介入治疗”,检索时间范围在2003至2012年,共检索到相关文献120篇,符合纳入标准并用于分析的文献24篇.结果与结论：①金属裸支架在血液中长期存放有腐蚀、金属离子溶出和凝血性等现象,为解决金属材料存在的问题,可以通过金属支架表面改性来处理,提高金属材料的血液相溶性.②药物支架是将治疗药物涂于支架表面,使药物能够持续并高浓度的释放,防止支架置入后再狭窄.③覆膜血管内支架是在金属支架外表覆以可降解或不可降解的聚合物薄膜,抑制血管内皮增生,对血管平滑肌细胞具有良好的生物相容性,可以预防血管支架置入后再狭窄.血管内支架治疗可以降低缺血性脑卒中的风险,是一种安全有效的治疗手段,同时还可以改善缺血性脑病患者的认知功能障碍.基因及细胞种植支架材料在防治脑血管介入后再狭窄方面也具有一定优势,是血管内支架材料研究的新方向.     

Development of a novel nasal nicotine formulation comprising an optimal pulsatile and sustained plasma nicotine profile for smoking cessation.

A novel nasal formulation, in the form of a nicotine-Amberlite resin complex powder has been developed that provided an optimal combined pulsatile and sustained plasma nicotine profile for smoking cessation. The adsorption isotherms of nicotine hydrogen tartrate salt on two types of Amberlite resins (IRP69 and IR120) were evaluated and the subsequent in vitro release properties of nicotine from the nicotine-Amberlite complex powders were tested using a Franz diffusion cell. Amberlite IRP69 and Amberlite IR120 are similar cationic exchange materials with the same ion-exchange capacity but due to a smaller particle size range (10-150 microm) Amberlite IRP69 had a better flow property and a better adsorptive capacity than Amberlite IR120. The material is used as an excipient in marketed pharmaceutical formulations. The highly water soluble salt, nicotine hydrogen tartrate, displayed good adsorption onto both types of Amberlite resin. The maximum adsorption of nicotine onto Amberlite IRP69 was 1.071 mg drug per mg resin. The cumulative release of drug from nicotine hydrogen tartrate-Amberlite complex powders showed that the higher the drug loading, the faster was the rate of release of the drug. Based on these results, various nicotine hydrogen tartrate-Amberlite IRP69 powder formulations containing different ratios of free to bound drug (50% to 100% bound) and a control solution were prepared and evaluated in a sheep model by nasal administration. The nicotine plasma profiles demonstrated that an initial rapid peak plasma level of nicotine followed by a sustained elevated level could be achieved by adjusting the ratio of free to bound nicotine in the Amberlite powder formulation. The curves obtained from some of the formulations were comparable to those predicted from a computer-generated pharmacokinetic model.     

Modulatory effects of estrogen and progesterone on colorectal hyperalgesia in the rat

The contribution of estrogen and progesterone to colorectal hyperalgesia was examined in female rats. The electromyogram recorded from the abdominal wall (visceromotor response, vmr) and the discharge of lumbosacral dorsal horn neurons to colorectal distention (CRD) were measured in intact female, ovariectomized (OVx) and estradiol replaced OVx (E2; 50mug, 48h) rats with and without colonic inflammation. Colorectal hyperalgesia was transient in intact rats, but persisted at least 4h in E2 and OVx rats. The magnitude of hyperalgesia in E2 rats was greater than OVx which was greater than intact rats. Dorsal horn neurons that responded to CRD with an Abrupt (on and off with stimulus) excitatory discharge showed similar sensitivity to estradiol as the vmr following colonic inflammation. In contrast, inflammation did not increase the magnitude of response of excitatory neurons with sustained afterdischarges in any of the treatment groups. Intact female rats have a comparable plasma estrogen concentration to E2 rats, suggesting the difference in responses may have been due to antinociceptive effects of progesterone. This was tested by administering E2+/- progesterone (1mg) and measuring the vmr. Progesterone reduced the facilitation of the vmr produced by E2 before and following colonic inflammation. The present study suggests that estrogen replacement enhances visceral signal processing following colonic inflammation. Furthermore, progesterone may counteract the effects of estrogen on colorectal sensitivity.     

Preparation and in vitro and in vivo release studies of Huperzine A loaded microspheres for the treatment of Alzheimer's disease.

The purpose of this study was to prepare microspheres containing Huperzine A, which is used for patients suffering from Alzheimer's disease because of its potent anticholineestase activity, and to clarify in vitro and in vivo release characteristics of them. The preparation and in vitro and in vivo release studies of Huperzine A loaded microspheres were described. By spray drying method, Huperzine A was encapsulated successfully in the microspheres which were spherical with a non-porous and smooth surface. In vitro studies showed that the release of Huperzine A from microspheres was depended on the properties of polymers and the release medium. Counter-ionic interaction between the primary amine group of Huperzine A and the carboxylic terminal group of PLG polymers improves the encapsulation of Huperzine A, reducing the initial burst and extending the sustained release. High molecular weight of PLG polymer leads to a negative influence on sustained release of Huperzine A due to less carboxylic terminal groups. Acidic medium also reduces the initial burst and sustained the release due to decreased swelling of the polymeric matrix. In vivo experiment showed, after intramuscular injection, that the plasma concentration of Huperzine A reached the max. at 2 h, then fell rapidly to a stable and near constant level of 0.5 to 2.5 ng/ml within 2 weeks, until the drug was exhausted from the microspheres. It indicates the potential of a 2-week sustained release system of Huperzine A.     

Estrogen reduces cardiac injury and expression of beta1-adrenoceptor upon ischemic insult in the rat heart

To test the hypothesis that estrogen confers cardioprotection by suppressing the expression of beta-adrenoceptor (beta-AR), we first correlated the infarct size in response to ischemic insult and beta-AR stimulation with the expression of beta(1)-AR in sham, ovariectomized (Ovx) and estrogen replaced (Ovx + E(2)) rats. When beta-AR is being activated during ischemia, the infarct size was significantly greater in Ovx than in the sham and Ovx + E(2) rats. There is a negative correlation between the infarct size and the expression level of beta(1)-AR as revealed by Western blotting and supported by binding analysis. Incubation of ventricular myocytes from Ovx rats with estrogen at 10(-9) M for 24 and 48 h, but not 12 h, significantly reduced lactate dehydrogenase release when the myocytes are subjected to simulated ischemia. The cardioprotective effect of 24 h estrogen incubation was accompanied by a reduction in the protein expression level of beta(1)-AR, which is estrogen receptor-dependent, whereas the lack of protection of 12-h estrogen incubation was not accompanied by any alterations in the expression level of beta(1)-AR. Together, the result from present study suggested that it is most likely that the cardioprotective effect of long-term estrogen replacement is due to suppressing the enhanced expression of cardiac beta(1)-AR in the Ovx rats, which in turn reduces cardiac injury when beta-AR is activated by sympathetic hyperactivity during ischemia. Therefore, suppression of the enhanced expression of cardiac beta(1)-AR in Ovx rats represents a novel cardioprotective mechanism of estrogen replacement therapy.     

A novel drug-eluting stent spray-coated with multi-layers of collagen and sirolimus.

In the study, a novel drug-eluting stent for treating the coronary arterial stenosis was developed. Using a spray-coating method, aqueous bovine type I collagen and sirolimus were coated layer-by-layer alternatively onto the surface of a metallic stent and a topcoat of collagen was used as a barrier to control drug release. To prevent dissolution of the collagen matrices, the spray-coated collagen was further crosslinked by genipin, a naturally occurring crosslinking agent. The results obtained in the atomic force microscopy (AFM) examination suggested that the spray-coated collagen was tightly adhered to the surface of the stent. Additionally, the collagen coating was demonstrated by the scanning electron microscopy (SEM) to be sufficiently flexible to allow balloon expansion of the stent without cracking or peeling from the wire. The resistance against enzymatic degradation and the hemocompatibility of the collagen matrices increased significantly as their degree of crosslinking increased. All the studied sirolimus-loaded stents exhibited a nearly linear sustained-release profile (except at the end stage of release) with no significant burst releases. It was found that a topcoat of collagen on the collagen/sirolimus coated stent did slow down the release of sirolimus to some extent. Additionally, the number of layers of collagen/sirolimus coated significantly affected the duration of sirolimus released. Furthermore, the sustained-release duration of sirolimus was proportional to the actual amount of drug loaded on the stent. The aforementioned results indicated that the drug-eluting stent developed had a tightly adhered collagen coating and can be used as a drug reservoir to sustain release of sirolimus.     

Development and in vivo characterization of a novel peptide drug delivery system providing extended plasma half life

It was the aim of this study to develop a sustained parenteral peptide (DALCE) delivery system by the immobilization of DALCE to thiolated carboxymethyl dextran-cysteine (CMD-Cys) via disulfide bond formation. The resulting CMD-Cys-DALCE conjugate displayed a 22.6±7.9% (m/m) of DALCE (mean±S.D.; n=3). The conjugation of DALCE with CMD-Cys was confirmed by FTIR-ATR spectroscopy. In vitro release studies of conjugate CMD-Cys-DALCE in the presence of 2 μM/ml reduced glutathione (GSH) being also available in the plasma showed a sustained peptide release over a time period of 8 h, because of thiol/disulfide exchange reactions. For in vivo pharmacokinetic study, DALCE and CMD-Cys-DALCE were administered intravenously to male Sprague-Dawley rats at a dose of 1mg/kg. The AUC(0-8) (ng.min/ml) was determined to be 268848±924 and 40019±495 for CMD-Cys-DALCE and DALCE, respectively. The mean residence time (MRT) was determined to be 256±8 and 53.1±9.5 min for CMD-Cys-DALCE and for DALCE, respectively. CMD-Cys-DALCE showed a more than 5-fold increased elimination half-life (p<0.01), 3-fold decreased volume of distribution (p<0.01) and a 6.7-fold decreased plasma clearance rate (p<0.01) compared to DALCE. According to these findings, CMD-Cys-DALCE seems to act as prodrug by improving half-life and decreasing plasma clearance.     

鼠血管外膜涂抹雌激素抑制血管再狭窄

目的探讨局部应用雌激素对雌性去势大鼠血管成形术后再狭窄的影响及其作用机制.方法制作40只雌性大鼠去势模型,并在此基础上制作左颈总动脉血管再狭窄模型,将其随机分为去势组、去势 E(应用雌激素)组.雌激素由pluronic gelatine携带局部涂抹于实验组的血管外膜,观察不同时间点血管腔及血管壁的变化.结果PTA后7天、14天、28天,去势组血管狭窄指数最大,去势 E组与未去势组之间无显著性差异.血管成形术(PTA)后3天、7天、14天,去势组血管外膜细胞增殖指数最大,去势 E组与未去势组之间无显著性差异.结论用pluronic gelatine携带雌激素局部涂抹血管外膜是一种有效的血管再狭窄预防方法,其作用机制可能与雌激素干预血管外膜细胞的活化有关.     

Predictive value of plasma plasminogen activator inhibitor-1 for coronary restenosis: dependence on stent implantation and antithrombotic medication.

BACKGROUND: The plasmin activation system is involved in the development of restenosis after percutaneous coronary interventions (PCI). Conflicting data exist concerning the role of plasminogen activator inhibitor-1 (PAI-1) and its predictive value for restenosis. OBJECTIVES: To evaluate the fibrinolytic response to injury after PCI with or without stent implantation on different antithrombotic medications and its relation to late restenosis. PATIENTS AND METHODS: Eighty consecutive patients with successful PCI without (balloon only; n = 37) or with stent implantation (stent; n = 43) on different antithrombotic regimes (balloon only, aspirin; stent, aspirin/coumadin/dipyridamole vs. aspirin/ticlopidine). Blood samples were taken at baseline and up to 7 days after PCI and PAI-1 active antigen and tissue plasminogen activator (t-PA) antigen were determined. Restenosis was angiographically determined after 6 months. RESULTS: PCI increased both t-PA and PAI-1 levels (P < 0.001), with a significant prolonged and pronounced increase in stent vs. balloon-only patients (P < 0.05). Restenosis (stent 26%; balloon 38%) was significantly correlated to an attenuated PAI-1 increase after 24 h in the ticlopidine group (P = 0.007; restenosis, relative Delta PAI-1 + 50 +/- 28%; non-restenosis, + 139 +/- 50%), but not in the coumadin group. In the balloon-only group late restenosis (ISR) was associated with a trend for an augmented PAI-1 increase after 24 h. CONCLUSIONS: Coronary stent implantation significantly increases t-PA and PAI-1 plasma levels up to 1 week compared with balloon angioplasty alone. ISR in ticlopidine-treated patients was associated with an attenuated early PAI-1 active antigen increase. A less than 50% increase 24 h after stent implantation under ticlopidine treatment may identify patients at risk for the development of ISR.     

食管支架置入术后再狭窄的内镜治疗

目的探讨食管支架置入术后再狭窄的原因及治疗方法。方法对2003年6月～2005年6月15例经内镜治疗的食管支架置入术后再狭窄患者的临床资料进行回顾性分析。结果食管支架置入术后再狭窄发生率为17．2％（15／87），其中食物嵌顿1例，支架远端移位2例，肉芽组织形成及纤维化（granuladon and fibrosis，GF）6例，肿瘤组织过生长新生物（tumour—overgrowing，TG）6例。1例食物嵌顿者以内镜取出食物后缓解，2例GF一直接受氩等离子体凝固器（argon plasma coaguhdon，APC）治疗，其余12例均再次放置支架而解除了狭窄。结论食管支架置入术后再狭窄的原因是多种的，针对不同的原因可以采取不同的有效预防和治疗措施。     

Effects of different cellulose derivatives on drug release mechanism studied at a preformulation stage.

As a matter of fact, in vitro dissolution is well known to be the method of choice for the pharmaceutical industry to develop effective medicines. However, many experiments must be performed all along a new product life and they represent an overcharge of work for researchers. The purpose of this paper was to assess the relevance of new parameters obtained during preformulation stage by Nuclear Magnetic Resonance (NMR) experiments to better understand drug release mechanism. This study was carried out with three cellulose derivatives currently used as carrier matrices (Microcrystalline cellulose (MCC), Hydroxypropylmethyl cellulose (HPMC) and Ethyl cellulose (EC)). Granules and tablets were produced with these three excipients (60% w/w) and theophylline as drug model (40%). On the one hand, in vitro dissolution studies were performed with the rotating paddle method displaying the different release behaviour of these three matrices (immediate release for MCC, steady release for HPMC and sustained release for EC). On the other hand, the evolution of the T2m spin-spin relaxation time in NMR experiments during granules hydration was recorded. NMR findings shore up dissolution data, both depending on interactions between the matrix and water. NMR spectroscopy appears to be a valuable tool for obtaining, at an earlier stage of drug development, more information about drug release mechanism.