Somatostatin receptor-binding peptides suitable for tumor radiotherapy with Re-188 or Re-186. Chemistry and initial biological studies

Somatostatin derivative peptides previously designed for radiodiagnostic purposes (99mTc P829 or 99mTc depreotide) were reoptimized for radiotherapy of tumors with rhenium radioisotopes. An optimized pharmacophore peptide P1839 was derived by in vitro binding affinity assay to AR42J rat pancreatic tumor cell membranes. Peptides with chelating domains and their oxorhenium(V) complexes were tested in vitro for binding to NCI H69 human SCLC tumor membranes. Further optimization entailed radiolabeling with 99mTc and biodistribution in an AR42J xenograft mouse model. Kidney uptake was decreased substantially by removing positively charged residues. Neutral N3S diamide amine thiol chelators with no adjacent positive charges had the best overall properties. Substituting an aromatic amino acid into the chelator approximately doubled the tumor uptake. The final optimized peptide P2045 (39) radiolabeled with 99mTc exhibited increased tumor uptake ( approximately 25 %ID/g at 1.5 h), lower kidney uptake ( approximately 4.8 %ID/g at 1.5 h), and extensive urinary excretion (59 %ID at 1.5 h). Finally, comparison biodistribution studies between 99mTc and 188Re (39) showed a good correlation between the two metal complexes and demonstrated prolonged tumor retention (> or =24 h).     

New antiangiogenic strategies for the treatment of proliferative synovitis

Angiogenesis inhibition, which has been extensively studied for the treatment of various malignancies, is beginning to emerge as a new potential therapy for proliferative synovitis, particularly rheumatoid arthritis (RA). The rheumatoid pannus, the site of inflammation and joint destruction in the rheumatoid synovium, relies on the development of new vasculature to sustain its growth. A host of mediators have been shown to induce angiogenesis at the site of the inflamed synovium; these include vascular endothelial growth factor, fibroblast growth factor, integrin alpha(V)beta3, angiopoietin, prosta-glandin E1 and prostaglandin E2, and matrix metalloproteinases. In addition, hypoxia at the site of synovial inflammation contributes to angiogenesis stimulation. Several naturally-occurring inhibitors exist, such angiostatin and endostatin. There are a number of drugs undergoing study in the treatment of proliferative synovitis, which capitalise on the correlation between angiogenesis inhibition and the reduction of signs and symptoms of RA. Paclitaxel and an anti-integrin alpha(V)beta3 antibody, LM-609, are currently in clinical trials. Other drugs that may inhibit angiogenesis in RA include TNP-470 (formerly called AGM-1470), PPI-2458, PTK-787, bevacizumab and thalidomide. Many of these drugs have shown promise for the treatment of oncologic disorders, and are now being evaluated for the treatment of proliferative synovitis.     

阿托伐他汀钙泊洛沙姆188固体分散体的制备及表征

目的:制备阿托伐他汀钙泊洛沙姆188(AC-P188)固体分散体,并对其进行表征。方法:以P188和聚乙二醇6000(PEG6000)为载体材料,采用溶剂挥发法制备AC-P188固体分散体,以载药率、水中溶解度、体外累积释放度为指标,采用单因素试验筛选处方中P188、PEG6000用量;利用差示扫描量热(DSC)法、X射线衍射(XRD)仪、傅里叶红外光谱(FT-IR)仪考察所制固体分散体中的晶型变化。结果:处方为0.5 g AC,4 g P188,4 g PEG6000;所制AC-P188固体分散体的载药率为89.97%,水中溶解度为1.57 mg/ml,体外累积释放度为92.69%;表征结果显示,AC可能以分子或无定形态均匀分散于载体中,AC与载体材料之间可能以氢键形式缔合。结论:成功制得AC-P188固体分散体,为提高阿托伐他汀钙的溶出和生物利用度提供了一定的理论基础。     

艾灸为主治疗膝关节创伤性滑膜炎的疗效分析

目的观察艾灸及中药治疗膝关节创伤性滑膜炎的疗效。方法75例患者完全随机分为2组,观察组38例采用艾灸及中约局部治疗;对照组37例采用多功能远红外线技术局部治疗。观察2组疗效,并进行比较。结果观察组治愈23例（60．5％）,好转14例（36．8％）,总有效率97．4％（37／38）。对照组37例中,治愈6例（16．2％）,好转23例（62．2％）,总有效率78．4％（29／37）。观察组治愈率60．5％,对照组治愈率16．2％。2组治愈率与总有效率差异有统计学意义（P〈0．05）。结论艾灸及中药局部治疗膝关市创伤性滑膜炎疗效明显。     

关节镜下治疗膝关节色素沉着绒毛结节性滑膜炎的临床疗效

目的：探讨关节镜下治疗膝关节色素沉着绒毛结节性滑膜炎的临床疗效。方法从2009年3月到2013年7月,该科收治的31例色素沉着绒毛结节性滑膜炎。结果切口均无感染,均未行术后放疗。3例复发,再次行手术治疗后现均未复发。IKDC（国际膝关节评估表）、Lysholm评分术前分别是（52．77±3．87）、（51．26±4．04）,术后分别是（84．45±2．75）、（81．65±4．11）,P＜0．05,差异有统计学意义。结论关节镜微创手术对于膝关节色素沉着绒毛结节性滑膜炎安全有效,创伤小恢复快,术后复发率低。     

Rhenium-188 and copper-67 radiopharmaceuticals for the treatment of bladder cancer

The favourable nuclear properties of copper-67 and rhenium-188 for therapeutic application are described, together with methods for the chemical synthesis of a number of derivatives. Survival from invasive bladder cancer has changed little over the past 20 years. The intravesicular administration of Cu-67 or Re-188 radiopharmaceuticals in the treatment of bladder cancer offers some promise for improvement in this situation.     

Characterization of nifedipine microparticles prepared by hot air coating technique

In the present work, the Hot Air Coating (HAC) technique was used to prepare microparticulate systems containing nifedipine. Binary mixtures constituting of nifedipine and cetearyl alcohol (CA) in different proportions (30:70, 50:50, 70:30) were studied: they were homogenized by mixing or milling before spray treatment and successively subjected to a coating procedure with the HAC apparatus fed with air at 120 degrees C under a pressure of 4.5 atm. Morphology, entrapment efficiency, drug stability, thermal behaviour and the drug dissolution profile of HAC-treated and non-treated materials were examined and compared. The HAC products show the possession of physical and physico-chemical properties and dissolution behaviour different from those of the initial physical mixtures. The operative conditions employed in the spray process allow the obtaining of microparticles containing relevant percentages of the drug (at least up to 50%). Moreover, the experimental results give evidence that the milling pre-treatment of mixtures, unlike mixing, has significant effects on the properties of the lipid-coated microparticles.     

Characterization and physical stability of fast-dissolving microparticles containing nifedipine.

The suitability of a poly(sodium methacrylate, methyl methacrylate) (NaPMM), a novel mucoadhesive material, to prepare fast-dissolving microparticles containing nifedipine (NIF) in the range of 25-75% w/w was verified. Microparticles made of a low-viscosity hydroxypropylmethylcellulose (HPMC), were also prepared to compare the NIF release profile and bioadhesive properties. The release test was carried out in oversaturation conditions. The physical state of microparticles was also investigated. The formulation stability was evaluated over a 3-month period in long-term and accelerated conditions. The presence of amorphous NIF within freshly prepared microparticles was attributed to interactions between the drug and both polymers. NaPMM conferred to microparticles suitable mucoadhesive properties and significantly increased NIF dissolution rate in comparison to HPMC. Nevertheless, NIF apparent solubilities obtained by NaPMM microparticles were lower than those obtained by the HPMC set. After 3-month storage in the case of HPMC microparticles, NIF dissolution rate and supersaturation degree significantly decreased due to drug crystallization. As far as NaPMM microparticles are concerned, neither NIF dissolution rate nor apparent solubility significantly changed.     

Fluphenazine release from biodegradable microparticles: Characterization and modelling of release

Abstract

The release of actives encapsulated in biodegradable poly-lactide-co-glycolide (PLGA)-based microparticles may be diffusion controlled, dependent on polymer degradation, or may occur by a combination of drug diffusion and polymer degradation. This report applies a model, describing combined diffusional and polymer degradation-assisted drug release, to quantify the release of fluphenazine HCl (F-HCl) from PLGA microspheres. Parameters for the release process showed that both the initial drug release phase and the polymer controlled drug release phase were dependent on the F-HCl loading of the microspheres. The percentage drug released in the burst phase and the length of the lag phase were dependent on F-HCl loading. In the degradation controlled release phase, drug release was faster the higher the loading, as shown by the decrease in t_max from 27 to 10 days, as F-HCl loadings increased from 4.2 to 16.6%w/w. The presence of F-HCl was found to catalyse the degradation of PLGA polymer during particle manufacture and during dissolution. When compared to drug free microspheres, F-HCl accelerated PLGA degradation as shown by the ～5-fold increase in both PLGA degradation rate constant (k) and reduction in t_max.     

丙型肝炎治疗新药替拉瑞韦

丙型肝炎病毒（hepatitis C virus,HCV）是一种高度变异的正链RNA黄病毒,具有慢性转化率高、病变率高等特征。有研究表明,NS3/NS4A多功能蛋白酶是HCV复制所必须的,因而NS3/NS4A蛋白酶抑制剂在HCV治疗中的意义备受关注。替拉瑞韦（Telaprevir）是一种可逆的HCVNS3/NS4A蛋白酶抑制剂,动物试验和临床试验都表明它可以有效地直接攻击HCV并阻断其复制,对HCV的抑制作用持久,将成为丙型肝炎病毒的新型治疗药物。     

Characterization of DNA-lipid complexes commonly used for gene delivery.

Cationic liposomes are used to deliver genes into cells. Here we describe some poorly understood basic features of DNA-lipid complexes (lipoplexes), especially the electrostatics, stability and DNA structure of lipoplexes, and their effects on transfection (lipofection). Use of the lipophilic, pH-sensitive fluorophore 4-heptadecyl-7-hydroxycoumarin, in combination with Gouy-Chapman calculations, showed that cationic liposomes had a large positive surface potential (180-240 mV) and a high pH (10-11.5) at the location of the probe on the liposomal surface in 20 mM Hepes buffer (pH 7.4). Other electrostatic characteristics were also found, such as the existence of protonable groups of cationic or helper lipids or salt bridges between those. Addition of DNA resulted in neutralization of cationic lipids, which was lower than expected and depending on the type of lipid and the DNA/cationic lipid ratio. The liposomes containing DOTAP (N-(1-(2,3-dioleoyloxy)propyl)-N,N, N-trimethylammonium chloride) were unstable upon dilution, probably due to the high critical micellar concentration of DOTAP, 7x10(-5) M. Large instability expressed as continuous size increase was demonstrated by the time-dependent static changes in light-scattering monitored following the mixing of cationic liposomes and DNA at DNA/cationic lipid molar ratios between 0.2 and 0.8. Addition of cationic liposomes composed of 100% DOTAP or DOTAP/DOPE (1/1) liposomes, induced instantaneous transition of the plasmid DNA from the B- toward a partial C-type conformation as shown by circular dichroism (CD) spectroscopy and at certain conditions Psi--DNA could be found as well. The Psi--DNA is characterized by inter-helical interaction between parallel helices. The highest lipofection was obtained under conditions of lipoplex instability, and when the DNA was partially dehydrated and had a partial Psi-- structure.     

Characterization of antigens adsorbed to anionic PLG microparticles by XPS and TOF-SIMS

The chemical composition of the surface of anionic PLG microparticles before and after adsorption of vaccine antigens was measured using X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (TOF-SIMS). The interfacial distributions of components will reflect underlying interactions that govern properties such as adsorption, release, and stability of proteins in microparticle vaccine delivery systems. Poly(lactide-co-glycolide) microparticles were prepared by a w/o/w emulsification method in the presence of the anionic surfactant dioctyl sodium sulfosuccinate (DSS). Ovalbumin, lysozyme, a recombinant HIV envelope glyocoprotein and a Neisseria meningitidis B protein were adsorbed to the PLG microparticles, with XPS and time-of-flight secondary mass used to analyze elemental and molecular distributions of components of the surface of lyophilized products. Protein (antigen) binding to PLG microparticles was measured directly by distinct elemental and molecular spectroscopic signatures consistent with amino acids and excipient species. The surface sensitive composition of proteins also included counter ions that support the importance of electrostatic interactions being crucial in the mechanism of adsorptions. The protein binding capacity was consistent with the available surface area and the interpretation of previous electron and atomic force microscope images strengthened by the quantification possible by XPS and the qualitative identification possible with TOF-SIMS. Protein antigens were detected and quantified on the surface of anionic PLG microparticles with varying degrees of efficiency under different adsorption conditions such as surfactant level, pH, and ionic strength. Observable changes in elemental and molecular composition suggest an efficient electrostatic interaction creating a composite surface layer that mediates antigen binding and release.     

健膝汤联合关节镜治疗膝关节慢性滑膜炎的临床研究

目的探讨健膝汤联合关节镜治疗膝关节慢性滑膜炎的效果。方法膝关节慢性滑膜炎患者136例采用随机数字表法分为两组,68例患者采用关节镜治疗为对照组,68例患者采用健膝汤联合关节镜治疗为观察组,于治疗前后行VAS评分、Lysholm评分,比较两组治疗前后炎症因子改变、相关指标改善、临床疗效、并发症。结果治疗后,两组炎症因子(IL-6,TNFα,CRP)、浮髌试验阳性率、VAS评分降低。两组膝关节屈曲度、Lysholm评分增加。观察组炎症因子(IL-6,TNFα,CRP)、浮髌试验阳性率、VAS评分、并发症发生率低于对照组。观察组膝关节屈曲度、Lysholm评分、总有效率高于对照组(P<0.05)。结论健膝汤联合关节镜是治疗膝关节慢性滑膜炎的有效方法,可降低炎症水平,缓解疼痛,改善临床病症,疗效显著且安全性高。     

Characterization of protein-loaded poly(epsilon-caprolactone) microparticles based on a factorial design

This study was designed to systematically investigate the characteristics of bovine serum albumin (BSA) loaded poly(epsilon-caprolactine) (PCL) microparticles based on a 2(4) factorial experiment. The influences of polyvinyl pyrrolidone (PVP) concentration, BSA/PCL ratio, w/o/o/o ratio, and PEG/PCL ratio on the surface morphology, particle size, as well as the yield of microparticles, encapsulation efficiency of BSA, and in vitro release properties were evaluated. The microparticles were prepared by the w/o/o/o solvent evaporation method. The structure of BSA retained its integrity using this technique. The mean particle sizes of BSA-loded microparticles were in the range of 20-50 microm, and a highly porous morphology existed in these microparticles, irrespective of the formulations. The production yields of microparticles were in the range of 52.1-89.0%, and the encapsulation efficiencies were in the range of 13.8-68.3%. The burst release of BSA was in the range of 6.9-69.0%. The volume ration of the multi-phases significantly affected the encapsulation efficiency of BSA in PCL microparticles, and the initial amount of BSA encapsulated by PCL in terms of BSA/PCL ratio significantly affected the amount of BSA released at the end of 14 days (p < 0.05).     

肺癌治疗策略浅谈

<正>肺癌是世界范围内最常见的恶性肿瘤之一。根据世界卫生组织2000年的年报,1999年死于肺癌的人数达119．3万(男性86．0万,女性33．3万),占世界总死亡人数的2．1％,居癌症死亡的首位。根据     

曲安奈德与臭氧联合治疗创伤性膝关节滑膜炎

目的 探求并观察一种治疗创伤性膝关节滑膜炎简便有效的方法.方法 采用曲安奈德与臭氧联合运用膝关节内注射治疗创伤性膝关节滑膜炎98例,根据患膝的疼痛、肿胀、关节积液等指标的改善程度分为优、良、可、差.结果 本组患者经过 3～6周治疗,随访 4～12周,优60例,良29例,可7例,差2例.总优良率90.8 %,全组部分患者除局部胀痛外未见明显不良反应.结论 通过本组98例患者疗效观察,两种药物的关节腔内注射能迅速缓解疼痛,减轻肿胀及积液,改善关节功能,是一种值得推广的方法.     

Paclitaxel-loaded microparticles and implants for the treatment of brain cancer: preparation and physicochemical characterization

The aim of this study was to prepare different types of paclitaxel-loaded, PLGA-based microparticles and lipidic implants, which can directly be injected into the brain tissue. Releasing the drug in a time-controlled manner over several weeks, these systems are intended to optimize the treatment of brain tumors. The latter is particularly difficult because of the blood-brain barrier (BBB), hindering most drugs to reach the target tissue upon systemic administration. Especially paclitaxel (being effective for the treatment of ovarian, breast, lung and other cancers) is not able to cross the BBB to a notable extent since it is a substrate of the efflux transporter P-glycoprotein. Both, biodegradable microparticles as well as small, cylindrical, glycerol tripalmitate-based implants (which can be injected using standard needles) were prepared with different paclitaxel loadings. The effects of several formulation and processing parameters on the resulting drug release kinetics were investigated in phosphate buffer pH 7.4 as well as in a diethylnicotinamide (DENA)/phosphate buffer mixture. Using DSC, SEM, SEC and optical microscopy deeper insight into the underlying drug release mechanisms could be gained. The presence of DENA in the release medium significantly increased the solubility of paclitaxel, accelerated PLGA degradation, increased the mobility of the polymer and drug molecules and fundamentally altered the geometry of the systems, resulting in increased paclitaxel release rates.     

Characterization of carbamazepine-Gelucire 50/13 microparticles prepared by a spray-congealing process using ultrasounds

In this work, the utilization of a spray-congealing technique using a new ultrasonic atomizer to prepare enhanced-release, solvent-free microspheres of carbamazepine (CBZ)-Gelucire 50/13 in different drug-to-polymer ratios was considered. Scanning electron microscopy analysis showed that it was possible to obtain spherically shaped and nonaggregated microparticles; the prevalent particle size was in the range 150-250 microm and the microspheres had a good encapsulation efficiency (> 90% in the prevalent size fraction). The in vitro dissolution tests displayed a significant increase of the CBZ dissolution rate from microspheres compared with pure drug and to drug-Gelucire 50/13 physical mixture. Differential scanning calorimetry, hot stage microscopy, X-ray powder diffractometry, and diffuse reflectance Fourier transform infrared spectroscopy demonstrated phase stability of the original polymorph of CBZ in all the systems; moreover, no interactions between the drug and Gelucire 50/13 were found. The results of this study suggested that the spray-congealing technique using the ultrasonic atomizer could be considered as a new and interesting method to enhance the dissolution rate of a poorly water-soluble drug as CBZ.     

Barium titanate microparticles as potential carrier platform for lanthanide radionuclides for their use in the treatment of arthritis

Since the inception of radiation synovectomy, a host of radioactive colloids and microparticles incorporating suitable therapeutic radionuclides have been proposed for the treatment of arthritis. The present article reports the synthesis and evaluation of barium titanate microparticles as an innovative and effective carrier platform for lanthanide radionuclides in the preparation of therapeutic agents for treatment of arthritis. The material was synthesized by mechanochemical route and characterized by X‐ray diffraction, scanning electron microscopy, surface area, and particle size distribution analyses. Loading of lanthanide radionuclides (¹⁶⁶Ho, ¹⁵³Sm, ¹⁷⁷Lu, and ¹⁶⁹Er) on the microparticles was achieved in high yield (> 95%) resulting in the formulation of loaded particulates with excellent radiochemical purities (> 99%). Radiolanthanide‐loaded microparticles exhibited excellent in vitro stability in human serum. In vitro diethylene triamine pentaacetic acid challenge study indicated fairly strong chemical association of lanthanides with barium titanate microparticles. Long‐term biodistribution studies carried out after administration of ¹⁷⁷Lu‐loaded microparticles into one of the knee joints of normal Wistar rats revealed near‐complete retention of the formulation (> 96% of the administered radioactivity) within the joint cavity even 14 days post‐administration. The excellent localization of the loaded microparticles was further confirmed by sequential whole‐body radio‐luminescence imaging studies carried out using ¹⁶⁶Ho‐loaded microparticles.