Value of blood pool MR contrast agents in imaging of the heart and blood vessels

Magnetic resonance (MR) imaging has emerged as a new diagnostic technique for evaluation of the cardiovascular system. The diagnostic benefits of MR contrast agents have been demonstrated in the laboratory and in clinical research that has taken place during the past 12 years. Contrast agents enhance the sensitivity of MR angiography and improve early detection and characterization of myocardial and microvascular injuries. Clinically approved MR contrast agents are not confined to the intravascular space due to their small molecular size (standard extracellular MR contrast agents) and, therefore, they produce peak vascular enhancement for only a short period of time (< 30 min). In recent years remarkable progress has been seen in the development of blood pool agents for MR imaging. Impetus for creation of these agents has come in part from a growing appreciation of MR angiography. Vascular mapping has become an important application of medical imaging. Ample experimental evidence has shown that blood pool agents may play a significant role in coronary, peripheral and pulmonary angiography. In addition to their ability to increase vascular contrast, blood pool agents provide physiological information such as rate of entry, rate of accumulation and rate of elimination. In the heart, blood pool contrast agents are useful for estimating relative myocardial perfusion, discriminating between occlusive and reperfused infarction, differentiating between reversible and irreversible myocardial injury and detecting microvascular integrity. Blood pool agents are currently being investigated in humans. Initial clinical trials have demonstrated their safety and feasibility and, hopefully, future trials will demonstrate their efficacy. The purpose of this review is to focus on the rationale and value of blood pool MR contrast agents in imaging of the heart and blood vessels.     

门控心血池显像对32例正常人心室功能测定

利用放射性核素平衡法门电路心血池显像对３２例正常人的左右心室进行显像，得出左右心室功能有关参数的正常参考值并与国内报道值作了比较和分析，与年龄、心率、左右心室ＥＦ值进行了相关性分析。     

Benchtop-MRI for in vivo imaging using a macromolecular contrast agent based on hydroxyethyl starch (HES)

Magnetic resonance imaging (MRI) is a powerful non-invasive diagnostic tool in the clinical setting. However, the wide spread use of small animal MRI instruments for preclinical research purposes has been limited by the need for strong magnets operating in the range of 4.7-11.7T. To obtain such strong and homogenous magnetic fields, superconducting electromagnets cooled with liquid helium are used, which highly increases the costs for research studies. Here we report on the use of a pilot 0.5T benchtop MRI (BT-MRI) operating with a permanent magnet and designed for in vivo imaging of mice. It was used to evaluate a novel macromolecular MRI contrast agent based on a Gd-chelate of hydroxyethyl starch (Gd-HES). Images obtained by the BT-MRI showed the high contrast enhancement of Gd-HES, its longevity in the circulation, as well as its utility for tumor diagnosis, urography and angiography. These results demonstrate the potential of the new BT-MRI as a useful research tool, as well as that of Gd-HES as a new MRI contrast agent.     

Design of potent, non-toxic anticancer peptides based on the structure of the antimicrobial peptide, temporin-1CEa

Recent advances in the search for novel anticancer agents have indicated that the positively charged antimicrobial peptides have emerged as promising agents offering several advantages over the conventional anticancer drugs. As a naturally occurring, cationic, α-helical antimicrobial peptide, temproin-1CEa has been proved to exhibit a potent anticancer effect and a moderate hemolytic activity. In order to reduce the hemolytic activity of temporin-1CEa and improve its anticancer potency towards a range of human breast cancer cells, in the present study, six analogs of temporin-1CEa were rationally designed and synthesized. The amphipathicity levels and α-helical structural patterns of peptides were reserved, while their cationic property and hydrophobicity were changed. The results of MTT and hemolysis assay indicated that the analog peptides displayed an improved anticancer activity and showed an overall optimized therapeutic index. The hydrophobicity of peptides was positively correlated with their hemolytic and antitumor activities. Moreover, the data suggest a strategy of increasing the cationicity while maintaining the moderate hydrophobicity of naturally occurring amphipathic α-helical peptides to generate analogs with improved cytotoxicity against tumor cells but decreased activity against non-neoplastic cells such as human erythrocytes. This work highlights the potential for rational design and synthesis of improved antimicrobial peptides that have the capability to be used therapeutically for treatment of cancers.     

疫苗生产中基于风险评估的清洗剂变更

目的 在白喉-破伤风-无细胞百日咳疫苗生产车间玻璃瓶清洗剂的变更中,引入质量风险管理,对新清洗剂进行风险分析与评估,以确保更换清洗剂对产品质量无影响。方法 运用风险评估工具对新清洗剂进行相应风险评估,根据风险级别制定风险控制措施,对新清洗剂进行验证,确认其清洗效果以及对产品的影响。结果 清洗后玻璃瓶淋洗水中细菌内毒素含量≤0.25内毒素单位/ml、总好氧微生物计数≤100菌落形成单位/ml、总霉菌酵母菌计数≤10菌落形成单位/ml、总有机碳≤1.5 μg/cm2（淋洗水和擦拭取样）、电导率≤1.3 µS/cm,结果均符合要求。结论 在变更控制中运用质量风险管理,指导变更控制措施的制定和变更内容的实施,保证了新清洗剂的风险可接受且产品质量不受变更影响。     

Development and haematotoxicological evaluation of doped hydroxyapatite based multimodal nanocontrast agent for near-infrared, magnetic resonance and X-ray contrast imaging

Multimodal molecular imaging provides both anatomical and molecular information, aiding early stage detection and better treatment planning of diseased conditions. Here, we report development and nanotoxicity evaluation of a novel hydroxyapatite nanoparticle (nHAp) based multimodal contrast agent for combined near-infrared (NIR), MR and X-ray imaging. Under optimised wet-chemical conditions, we achieved simultaneous doping of nHAp (size ～50 nm) with indocyanine green and Gd(3+) contributing to NIR contrast (～750-850 nm), paramagnetic behaviour and X-ray absorption suitable for NIR, MR and X-ray contrast imaging, respectively. Haematocompatibility studies using stem cell viability, haemolysis, platelet activation, platelet aggregation and coagulation time analysis indicated excellent compatibility of doped nHAp (D-nHAp). Further, the immunogenic function studies using human lymphocytes (in vitro) showed that D-nHAp caused no adverse effects. Collectively, our studies suggest that D-nHAp with excellent biocompatibility and multifunctional properties is a promising nanocontrast agent for combined NIR, MR and X-ray imaging applications.     

磁共振造影剂的处方筛选和稳定性研究

目的预得到超顺磁流体制剂的最优处方 ,然后对其注射液的稳定性进行了初步研究。方法运用均匀设计进行处方筛选 ,经典恒温法预测有效期。结果其注射液在 pH值为中性时比较稳定 ,光照无影响 ,有效期约 3年。结论超顺磁流体注射液的稳定性较好     

Differential effects of cyclodextrins and derivatives on the biological behavior of the myocardial perfusion imaging agent 99mTcN-NOET.

In addition to improving drug solubilization, cyclodextrins (CDs) also affect the biological behavior of the included compound. We evaluated the effects of two natural CDs beta-CD and gamma-CD, and six beta-CD derivatives, Dimeb, Trimeb, SBb, 2-HP, 6AD, and 6 MTU on the biological behavior of (99m)TcN-NOET, a technetium-99m-labeled, lipophilic compound readily detectable through radioactivity assessment. Determination of CDs' affinities for (99m)TcN-NOET indicated that the cavity size of gamma-CD was not suitable for (99m)TcN-NOET inclusion, and that beta-CD derivatization mostly resulted in decreased CDs affinities for (99m)TcN-NOET to various extents compared with the natural beta-CD. In vitro and ex vivo experiments performed on newborn rat cardiomyocytes and isolated perfused rat hearts, respectively, showed 1.7- and 2.3-fold maximal differences in (99m)TcN-NOET cellular and tissue activities. Regression analyzes indicated no significant correlation between these observed biological differences and the affinities of the eight CDs tested for (99m)TcN-NOET or for cellular membranes. In conclusion, CD derivatization often resulted in impaired affinity of the derivatives for the lipophilic compound (99m)TcN-NOET. Moreover, the in vitro and ex vivo biological behavior of (99m)TcN-NOET was greatly affected depending on the CD used for inclusion of the tracer.     

Construction of amphiphilic copolymer nanoparticles based on hyperbranched poly (amine-ester) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine as drug carriers for cancer therapy

Novel amphiphilic copolymer nanoparticles (HPAE-co-PLA-DPPE) composed of hyperbranched poly (amine-ester), polylactide and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) segments were designed and synthesized that provided high encapsulation efficiency. These nanoparticles (NPs) were used to encapsulate an antitumor model drug, doxorubicin (DOX). The resulting NPs exhibited high encapsulation efficiency to DOX under an appropriate condition. In vitro release experiments revealed that the release of DOX from NPs was faster at pH 4.5 than that at pH 7.4 or pH 6.0. Confocal microscopy observation indicated that the DOX-loaded NPs can enter cells and localize in lysosomes that can be released quickly into the cytoplasm. The DOX-loaded NPs showed comparable anticancer efficacy with the free drug both in vivo and in vitro. These results demonstrate a feasible application of the hyperbranched copolymer, HPAE-co-PLA-DPPE, as a promising nanocarrier for intracellular delivery of antitumor drugs. FROM THE CLINICAL EDITOR: In this paper, the development of novel amphiphilic copolymer nanoparticles is discussed with the goal of establishing high encapsulation efficiency for chemotherapy drugs.     

Effect of nonenzymatic glycosylation on the magnetic resonance imaging (MRI) contrast agent binding to human serum albumin

Enhanced nonenzymatic glycosylation (NEG) of human serum albumin (HSA) is observed in diabetic patients. This modifies some of the physiological functions of HSA, as the binding of ligands. Some gadolinium complexes, commonly used as MRI contrast agents, have a high affinity for HSA, which enhances their efficacy. The aim of this study is to evaluate the possible influence of the NEG of HSA on its affinity for some gadolinium chelates.     

The effects of the anti-tumor agent mezerein on the cytotoxic capacity and oxidative metabolism of human blood cells

Summary Mezerein, the most active antitumor compound isolated from the daphne species of plants, has a structural similarity to phorbol myristate acetate (PMA), the major active compound isolated from croton oil. PMA is known to have tumor promoting activity and is a potent inflammatory agent. Mezerein has similarly been reported to have potent inflammatory properties but appears to be a weaker tumor promoter than PMA. While the effect of PMA on the function and metabolism of human blood cells has been extensively studied, there is little similar information concerning mezerein. Therefore, in these studies, we have compared the capacities of mezerein and PMA to activate the cytotoxic capacity and oxidative metabolism of human granulocyte (PMNs), monocyte, lymphocyte, and mononuclear cell (lymphocytes and monocytes) cultures in vitro. Mezerein stimulated the oxidative metabolism of PMNs in an identical manner to PMA as indicated by a burst in the activity of the HMPS pathway, the production of H₂O₂, hydroxyl radical and stable oxidants. Mezerein also stimulated the release of thromboxane B₂ from PMNs. Both compounds activated the oxidative metabolism of monocytes but not the oxidative metabolism of lymphocytes. The enhanced oxidative metabolism of the phagocytic cells was associated with an increased cytotoxicity against human red cells which are sensitive to oxidant damage but not against the NK resistant Raji lymphoblast cell line or the SW1116 colon tumor cell line.Of interest is that mezerein did not augment significantly the minimal cytotoxic capacity (NK activity) of mononuclear cells, monocytes or freshly isolated lymphocyte cultures against the tumor cell targets used in our experiments. However, lymphocyte cultures preincubated for 15 hours with mezerein had a marked enhancement of cytotoxicity against the tumor targets. This activation was not observed in similarly treated mononuclear cell cultures suggesting a suppressor activity of the monocytes.Our data suggest that the potent inflammatory activity of mezerein similar to PMA, may be related to its capacity to activate the oxidative and arachidonic metabolism of phagocytic cells. In addition, the capacity of mezerein to activate the cytotoxic capacity of lymphocytes may relate to its reported in vivo antitumor activity.Dr. Barton is currently a resident in Medicine at the Unviersity of Chicago.     

新型正性肌力活性物PHR0007对大鼠血压和心电图的影响

目的探讨新型正性肌力活性物PHR0007(三唑并二氢喹啉衍生物)对大鼠动脉血压和心电图的影响和作用机制。方法经股动脉插管连接压力换能器和用针状电极连接标准肢体导联,利用BL-420S生物机能实验系统观察给药前和静脉单用PHR0007(0.1、0.3、1.0μg.kg-1)或米力农(3.8μg.kg-1),以及合用PHR0007(0.1μg.kg-1)和米力农(3.8μg.kg-1)后1 h之内的股动脉血压和肢体标准Ⅱ导联心电图变化。结果与给药前比较,注射PHR0007后0.10~0.75 h内收缩压显著提高(P<0.05)。注射米力农后0.10~0.25 h内收缩压也明显增高(P<0.05)。合用米力农和PHR0007后0.10~0.75 h内收缩压虽然升高(P<0.05),但较单用PHR0007或米力农无明显差异(P>0.05)。0.1μg.kg-1PHR0007使心率减慢(P<0.05)。不同浓度的PHR0007使QT间期延长(P<0.05),且在低剂量更加明显。各种处理因素对舒张压和PR间期无显著性影响。结论类似米力农,PHR0007对大鼠具有强心和扩血管作用。     

彩色多普勒能量图检测子宫肌瘤血供的初步探讨

目的 探讨彩色多普勒能量图(CDE)检测子宫肌瘤血供的临床意义。方法 对2001年5月至2003年7月50例正常子宫妇女与55例子宫肌瘤患者分别进行彩色多普勒能量图与彩色多普勒血流显像(CDFI)对比观察。结果 正常子宫CDE血流表现为“带状”、“斑点状”,显示率为100％;CDFI表现为“短线状”、“星点状”,显示率为78％。子宫肌瘤CDE内部血流显像为“树枝状”或“网格状”,显示率为83．6％;CDFI表现为“带状”或“斑点状”,显示率为65．5％。结论 应用CDE和CDFI对照检查表明,CDE具有以下特点：(1)显示血流信号丰富,完整性好,具有“超声血管造影”的效果：(2)检测血流的敏感性高,对低流速和微小血管均可显示;(3)无混叠现象存在;(4)操作容易,获取的血流信号清晰,可以用作分析肌瘤血供灌注的客观参数。     

激光散斑成像技术测定阿魏酸对大鼠脑血流量的影响

目的：考察阿魏酸对大鼠脑血流量的影响。方法：通过激光散斑成像技术观察腹腔注射阿魏酸后对正常大鼠脑血流量的影响，并对大鼠脑动脉血流和微循环区域血流进行计算分析。结果：正常大鼠腹腔注射阿魏酸50mg·kg-1后，大鼠的脑血管（包括大小动脉和静脉）的形态无明显变化；给药50min后，大鼠脑动脉的血流量缓慢增加，最高可增加到原血流量的170%，并能维持在一个相对较高的水平1h以上；给药60min后，微循环区的血流量渐渐增加，最高可增加到原血流量的150%～160%。结论：阿魏酸能显著增加大鼠大脑动脉及微循环区的血流量，不同区域的血流增加量有所不同。其机制可能与其松弛毛细血管前后括约肌，减少血流阻力及增加心肌收缩力，增加供血量等作用有关。     

基于支持向量机技术预测丙戊酸钠血药浓度

目的 基于支持向量机(SVM)技术,建立丙戊酸钠的血药浓度预测模型.方法 收集陆军军医大学第一附属医院2015年1月至2018年12月确诊为癫痫且服用丙戊酸钠缓释片的病人的血药浓度及16个血药浓度影响因素指标数据.利用随机数字表法将收集的206例病人共271个样本数据分为190个构成训练样本集以及81个构成测试样本集.基于SVM技术对190个训练样本进行训练,建立预测模型.再用外部验证法将81个测试样本的血药浓度模型预测值与实际观测值进行对比.结果 训练样本集和测试样本集中病人的各临床指标除胱抑素C外,其余指标差异无统计学意义(P≥0.05),训练样本集中病人胱抑素C为(1.17±1.23)mg/L,明显高于测试样本集中病人的(0.93±0.84)mg/L(P=0.012).基于SVM技术的血药浓度预测模型取得了较好的预测效果,模型预测值与实际观测值相对误差:小于5％的12个;5％～10％(含)的23个;10％～15％(含)的21个;15％～20％(含)的13个;20％～25％(含)的4个,超过25％的8个;平均相对误差为12.12％,相对误差小于20％(含)的样本占比达到85.18％.平均绝对误差为9.98 mg/L,绝对误差小于20 mg/L的样本占比达到95.06％.模型预测值与实际观测值的相关系数为0.788.结论 SVM技术在血药浓度预测方面具有良好的应用前景,基于该技术的丙戊酸钠血药浓度预测模型准确度较好,模型预测值与实际观测值的相关性较好,相对误差较小,可为临床制定个体化给药方案提供参考.     

Two future generations of blood substitutes based on polyhemoglobin-SOD-catalase and nanoencapsulation

This paper discusses our research on two new generation blood substitutes. One is based on the crosslinking of hemoglobin, superoxide dismutase(SOD) and catalase (CAT) to form polyhemoglobin–SOD–CAT. This is being investigated for use in conditions with potential problems related to ischemia–reperfusion injuries as in severe hemorrhagic shock, stroke and other conditions. The second one is based on biodegradable polymeric nanocapsules containing hemoglobin and enzymes. In this form, the hemoglobin and enzymes are separated from the external environment. Furthermore, modifications of the polymeric membrane can result in increase in circulation time.     

Studies on porphyrin related compounds and tumor tissue affinities. I. Synthesis of a carrier for tumor imaging agent, bifunctional chelating agent coupled porphyrin (ATN-2)

A carrier for a new tumor imaging agent, a bifunctional chelating agent (BCA)-coupled porphyrin (ATN-2), has been synthesized from protoporphyrin dimethyl ester in 4 steps. At first, the hydrobromination of protoporphyrin dimethyl ester is carried out to obtain a monobromo derivative. The derivative is treated with ethylene glycol. The resulting porphyrin has an ether group at the either 7- or 12-position of the ring. Metallation with GaCl3 of the porphyrin having a ethylene glycol residue affords Ga-metalloporphyrin. Final condensation of the metalloporphyrin with diethylenetriaminepentaacetic acid (DT-PA) gave BCA-coupled porphyrin (ATN-2). The chelation of ATN-2 with 111InCl3 easily afforded [111In]ATN-2. This agent was used for imaging transplantable pancreatic carcinoma in Syrian golden hamster at 72 h after postinjection. The efficacy of the new agent was compared with that of [67Ga]citrate. The images with [111In]ATN-2 were found to be clearer than those with [67Ga]citrate. Therefore, ATN-2, a carrier for 111InCl3, seems to be more useful for tumor imaging agents.