Rhenium-188-Labeled DTPA: a new radiopharmaceutical for intravascular radiation therapy

Balloon angioplasty is a standard treatment for artherosclerotic coronary artery disease. However, its clinical value is reduced by a high restenosis rate. A new concept in preventing restenosis is the use of a liquid-filled balloon containing a beta-emitting radioisotope. In this study, we performed biodistribution studies of Re-188 perrhenate and Re-188 diethylenetriaminopentaacetate (DTPA) to assess the resulting organ dose values in the event of balloon rupture if these agents are used for the clinical inhibition of restenosis after percutaneous transluminal coronary angioplasty (PTCA). After injecting Re-188 preparations intravenously, rats were killed at 10 min, 30 min, 60 min, 2 h, and 6 h ( n =5 per group). Tissue concentrations were calculated and expressed as percent injected dose per gram or per milliliter (%ID/g or %ID/mL). In addition, urine excretion and thyroid gland uptake were evaluated in rats ( n=5 per group) with a gamma camera after administration of 37 MBq (1 mCi) of each agent. Our data showed that both agents were excreted primarily via urine. However, the excretion of Re-188 DTPA was much faster than that of Re-188 perrhenate via the urinary system. The biodistribution data revealed that radioactivity levels in the stomach and the thyroid gland were high in the perrhenate group but low in the Re-188 DTPA group. The concentration levels in other tissues including lung, liver, testis, muscle, and blood were low throughout this study for both agents. The thyroid radiation value in the Re-188 perrhenate group was 0.163 mGy/MBq, which was much higher than that of the Re-188 DTPA group (0.0167 mGy/MBq). The stomach radiation value was as high as 0.127 mGy/MBq for Re-188 perrhenate, compared with 0.013 mGy/MBq for Re-188 DTPA. In conclusion, in the event of balloon rupture, the release of Re-188 DTPA results in lower radiation doses than Re-188 perrhenate, especially to the thyroid gland and the stomach. Our data suggest that Re-188 DTPA is a useful radiopharmaceutical for endovascular irradiation.     

An immunohistochemical and immunoelectron microscopic study of adhesion molecules in synovial pannus formation in rheumatoid arthritis

To investigate the mechanism of synovial pannus formation in rheumatoid arthritis, immunohistochemical and immunoelectron microscopic studies with monoclonal antibodies against the adhesion molecules, CD54 (ICAM-1), CD 11a (LFA-1), CDw49a (VLA-1), CDw49b (VLA-2), CDw49c (VLA-3), Cdw49d (VLA-4) and CDw49e (VLA-5), were carried out to determine the pattern of distribution of these molecules at the rheumatoid synovial cartilage junction. Treatment with anti-ICAM-1 resulted in membrane staining of most of the macrophages and fibroblasts infiltrating the synovial tissue and bordering the pannus-cartilage junction, suggesting the possibility that ICAM-1 may function to facilitate the adhesion of synovial type A cells bearing ICAM-1 to type B cells of the pannus. ICAM-1-positive macrophages and fibroblasts were often found to be in contact with lymphoid cells, suggesting also that a cellular immune reaction occurs in the formation of the pannus. In addition, VLA-3, VLA-4 and, particularly, VLA-5 were the predominant1 integrins expressed by rheumatoid synovial pannus. Since these three integrins all function as fibronectin receptors, it is possible that the fibronectin-rich environment of the rheumatoid cartilage surface effectively traps pannus cells expressing high levels of these molecules. The VLA-5 molecule was found in a pericellular and interterritorial matrix distribution in the present study, strongly suggesting that a recepfor-ligand interaction between VLA-5 and cartilage matrix may occur at the early stage of pannus formation. Furthermore, an increase in1 integrin may be necessary for the growth of the pannus and also for the upregulation of the VLA molecules, leading secondarily to increased attachment.     

环孢素-泊洛沙姆188固体分散体的体外评价

目的以泊洛沙姆188（F68）为载体制备环孢素（CsA）固体分散体并考察其体外溶出。方法以溶剂一熔融法制备固体分散体，以差示扫描量热法（DSC）和X．射线衍射法鉴定CsA在体系中的存在状态，以FTIR表征药物与载体的相互作用，以摇瓶法测定CsA的溶解度，按《中国药典》溶出度第三法测定CsA从物理混合物和固体分散体中的溶出。结果X-射线衍射图谱显示CsA结晶衍射峰消失，提示药物以无定形或分子状态存在于固体分散体中。FTIR结果表明药物与载体间无相互作用。药物溶解度和溶出度均随着F68比例的增加而增大，固体分散体和物理混合物60min的累积溶出百分率分别为99．32％和75．41％，两者具显著性差异（P〈0．01）。结论F68能提高CsA的溶解度和溶出度，可用来制备CsA的固体剂型。     

吡喹酮水凝胶栓剂的含量测定

目的:制备吡喹酮水凝胶栓剂,并建立其含量测定方法。方法:用紫外分光光度法测定凝胶栓剂中吡喹酮的含量。结果:吡喹酮在0.2￣1.0mg/ml(r=0.9999)浓度范围内呈良好线性关系。平均加样回收率和相对标准偏差(RSD)为(102.44±0.69)%。结论:该处方设计合理,制备工艺可靠,质量稳定。     

乳酸环丙沙星眼用即型凝胶的研制

目的 研制乳酸环丙沙星眼用即型凝胶。方法 以泊洛沙姆407为温敏型材料制备乳酸环丙沙星眼用即型凝胶,通过对胶凝温度的考察确定处方,考察了乳酸环丙沙星眼用即型凝胶的黏度,采用无膜溶出模型对药物的体外释放机制进行研究,对制剂的眼刺激性进行评价。结果 确定18%的泊洛沙姆407作为乳酸环丙沙星眼用即型凝胶的基质。药物的体外释放呈零级动力学特征,释放量取决于凝胶溶蚀量。该制剂对兔眼无刺激。结论     

左氧氟沙星热敏型眼用凝胶的研制及体外释放研究

目的:制备左氧氟沙星热敏型眼用凝胶,并对其体外释放行为进行考察。方法:以泊洛沙姆407为热敏型材料制备左氧氟沙星眼用凝胶,根据胶凝温度筛选泊洛沙姆407的最佳处方浓度,采用无膜溶出模型对该制剂的体外释放行为进行考察。结果:左氧氟沙星检测浓度线性范围为3～11μg/ml(r=0.9991,n=6),回收率为99.62%;泊洛沙姆407在处方中的最佳浓度为18%;药物释放呈零级动力学特征,释放量取决于凝胶溶蚀量。结论:该制剂制备方法简单,用药剂量易于控制,极具开发前景。     

188Re-DTPA-DG的制备及其在正常小鼠体内分布的研究

用氯化亚锡作还原剂,以^188Re标记二乙三胺五乙酸-脱氧葡萄糖（DTPA—DG）,纸层析法鉴定^188Re—DTPA-DG的放化纯度、标记稳定性。取昆明种小鼠经尾静脉注射^188Re—DTPA—DG,观察其体内分布及显像情况。结果^188Re—DTPA—DG放化纯度〉95％,室温体外稳定;^188Re—DTPA—DG在正常小鼠血液中清除快,脑、肺、小肠、肌肉未见明显分布,主要经肾脏随尿液排出体外。提示^188Re—DTPA—DG有望成为集肿瘤SPECT显像、诊断和治疗于一体的新型葡萄糖类似物。     

Preparation and first biological evaluation of novel Re-188/Tc-99m peptide conjugates with substance-P

IntroductionNew ¹⁸⁸Re and ^99mTc peptide conjugates with substance- P (SP) were prepared and biologically evaluated. The radiopharmaceuticals have been labelled with the [M≡N]²⁺ (M=^99mTc, ¹⁸⁸Re) core using a combination of π-donor tridentate and π-acceptor monodentate ancillary ligands.MethodsThe new radiopharmaceuticals have been prepared through a two-step reaction by simultaneous addition of the tridentate and monodentate ligands to a vial containing a preformed [M≡N]²⁺ core. The tridentate ligand was formed by linking two cysteine residues to the terminal arginine of the undecapeptide SP, whereas the monodentate ligand was a tertiary phosphine. The preparation of the corresponding Re-188 derivative required developing a more complex chemical procedure to obtain the [Re≡N]²⁺ core in satisfactory yields. Characterization of the resulting products was obtained by chromatographic methods. Biological evaluation was performed for both Tc-99m and Re-188 derivatives by in-vitro studies on isolated cells expressing NK1-receptors. In-vivo imaging in mice was carried out using a small-animal YAP(S)PET tomograph.ConclusionNew Tc-99m and Re-188 peptide radiopharmaceuticals with SP have been prepared in high-yield and with high-specific activity. Both Tc-99m and Re-188 peptide radioconjugates exhibit high affinity for NK1 receptors, thus giving further evidence to the empirical rule that structurally related Tc-99m and Re-188 radiopharmaceuticals exhibit identical biological properties.     

Preparation,pharmacokinetics and pharmacodynamics of ophthalmic thermosensitive in situ hydrogel of betaxolol hydrochloride

Conventional ophthalmic formulations often eliminate rapidly after administration and cannot provide and maintain an adequate concentration of the drug in the precorneal area. To solve those problems, a thermosensitive in situ gelling and mucoadhesive ophthalmic drug delivery system was prepared and evaluated, the system was composed of poloxamer analogs and polycarbophil (PCP) and betaxolol hydrochloride (BH) was selected as model drug. The concentrations of poloxamer 407 (P407) (22% (w/v)) and poloxamer 188 (P188) (3.5% (w/v)) were identified through central composite design-response surface methodology (CCD-RSM). The BH in situ hydrogel (BH-HG) was liquid solution at low temperature and turned to semisolid at eye temperature. BH-HG showed good stability and biocompatibility, which fulfilled the requirements of ocular application. In vitro studies indicated that addition of PCP enhanced the viscosity of BH-HG and the release results of BH from BH-HG demonstrated a sustained release behavior of BH because of the gel dissolution. In vivo pharmacokinetics and pharmacodynamics studies indicated that the BH-HG formulation resulted in an improved bioavailability and a significantly lower intraocular pressure (IOP). The results suggested BH-HG could be potentially used as an in situ gelling system for ophthalmic delivery to enhance the bioavailability and efficacy.     

Expression and function of microRNA-188-5p in activated rheumatoid arthritis synovial fibroblasts

Activated synovial fibroblasts in rheumatoid arthritis (RASF) play a critical role in the pathology of rheumatoid arthritis (RA). Recent studies suggested that deregulation of microRNAs (miRs) affects the development and progression of RA. Therefore, we aimed to identify de-regulated miRs in RASF and to identify target genes that may contribute to the aggressive phenotype of RASF. Quantitative real-time PCR revealed a marked downregulation of miR-188-5p in synovial tissue samples of RA patients as well as in RASF. Exposure to the cytokine interleukine-1β lead to a further downregulation of miR-188-5p expression levels compared to control cells. Re-expression of miR-188-5p in RASF by transient transfection significantly inhibited cell migration. However, miR-188-5p re-expression had no effects on glycosaminoglycan degradation or expression of repellent factors, which have been previously shown to affect the invasive behavior of RASF. In search for target genes of miR-188-5p in RASF we performed gene expression profiling in RASF and found a strong regulatory effect of miR-188-5p on the hyaluronan binding protein KIAA1199 as well as collagens COL1A1 and COL12A1, which was confirmed by qRT-PCR. In silico analysis revealed that KIAA1199 carries a 3’UTR binding site for miR-188-5p. COL1A1 and COL12A1 showed no binding site in the mRNA region, suggesting an indirect regulation of these two genes by miR-188-5p. In summary, our study showed that miR-188-5p is down-regulated in RA in vitro and in vivo, most likely triggered by an inflammatory environment. MiR-188-5p expression is correlated to the activation state of RASF and inhibits migration of these cells. Furthermore, miR-188-5p is directly and indirectly regulating the expression of genes, which may play a role in extracellular matrix formation and destruction in RA. Herewith, this study identified potential novel therapeutic targets to inhibit the development and progression of RA.