Magnetic resonance imaging and computational fluid dynamics (CFD) simulations of rabbit nasal airflows for the development of hybrid CFD/PBPK models

The percentages of total airflows over the nasal respiratory and olfactory epithelium of female rabbits were calculated from computational fluid dynamics (CFD) simulations of steady-state inhalation. These airflow calculations, along with nasal airway geometry determinations, are critical parameters for hybrid CFD/physiologically based pharmacokinetic models that describe the nasal dosimetry of water-soluble or reactive gases and vapors in rabbits. CFD simulations were based upon three-dimensional computational meshes derived from magnetic resonance images of three adult female New Zealand White (NZW) rabbits. In the anterior portion of the nose, the maxillary turbinates of rabbits are considerably more complex than comparable regions in rats, mice, monkeys, or humans. This leads to a greater surface area to volume ratio in this region and thus the potential for increased extraction of water soluble or reactive gases and vapors in the anterior portion of the nose compared to many other species. Although there was considerable interanimal variability in the fine structures of the nasal turbinates and airflows in the anterior portions of the nose, there was remarkable consistency between rabbits in the percentage of total inspired airflows that reached the ethmoid turbinate region (~50%) that is presumably lined with olfactory epithelium. These latter results (airflows reaching the ethmoid turbinate region) were higher than previous published estimates for the male F344 rat (19%) and human (7%). These differences in regional airflows can have significant implications in interspecies extrapolations of nasal dosimetry.     

Hybrid magnetic nanostructures (MNS) for magnetic resonance imaging applications

The development of MRI contrast agents has experienced its version of the gilded age over the past decade, thanks largely to the rapid advances in nanotechnology. In addition to progress in single mode contrast agents, which ushered in unprecedented R(1) or R(2) sensitivities, there has also been a boon in the development of agents covering more than one mode of detection. These include T(1)-PET, T(2)-PET T(1)-optical, T(2)-optical, T(1)-T(2) agents and many others. In this review, we describe four areas which we feel have experienced particular growth due to nanotechnology, specifically T(2) magnetic nanostructure development, T(1)/T(2)-optical dual mode agents, and most recently the T(1)-T(2) hybrid imaging systems. In each of these systems, we describe applications including in vitro, in vivo usage and assay development. In all, while the benefits and drawbacks of most MRI contrast agents depend on the application at hand, the recent development in multimodal nanohybrids may curtail the shortcomings of single mode agents in diagnostic and clinical settings by synergistically incorporating functionality. It is hoped that as nanotechnology advances over the next decade, it will produce agents with increased diagnostics and assay relevant capabilities in streamlined packages that can meaningfully improve patient care and prognostics. In this review article, we focus on T(2) materials, its surface functionalization and coupling with optical and/or T(1) agents.     

非损伤性功能成像技术:正电子发射断层扫描术、磁共振波谱分析和动态对比增强磁共振影像学

当前在医药工业中越来越关注将非损伤性功能成像技术作为潜在的病人体内药物作用早期检测技术。正电子发射断层扫描术可监测组织中放射标记的药物和其代谢物的绝对浓度,或者是特殊受体的配体浓度,且可以三维直观地显示它们在体内的分布。磁共振波谱分析可监测体内未标记药物的代谢转化。动态对比增强磁共振影像学可显示小分子、亲水的造影剂在血浆与组织细胞间隙间的即时分布,并可以用来检测抗血管或血管生成的化合物的作用。     

Iodinated and gadolinium contrast media in computed tomography (CT) and magnetic resonance (MR) stroke imaging

Thrombolysis has become an approved therapy for acute stroke. However, many stroke patients do not benefit from such treatment, since the presently used criteria are very restrictive, notably with respect to the accepted time window. Even so, a significant rate of intracranial hemorrhage still occurs. Conventional cerebral computed tomography (CT) without contrast has been proposed as a selection tool for acute stroke patients. Recently, more modern magnetic resonance imaging (MRI) and CT techniques, referred to as diffusion- and perfusion-weighted imaging, and perfusion-CT, have been introduced. They afford a comprehensive noninvasive survey of acute stroke patients as soon as their emergency admission, with accurate demonstration of the site of arterial occlusion and its hemodynamic and pathophysiological repercussions of the brain parenchyma. The objective of this review article is to present the advantages and drawbacks of CT, using iodinated contrast, and MRI, using gadolinium, in the evaluation of acute stroke patients.     

磁共振动态增强扫描在乳腺环形强化病灶的应用

目的评估MRI动态增强在乳腺环形强化病灶的诊断价值。方法回顾性分析21例乳腺患者MRI环形强化病例,所有病例均经病理证实。患者均行3D快速梯度回波序列动态增强扫并描绘制时间-信号强度曲线。结果 21例乳腺环形强化病变中,恶性病灶16例,良性病灶5例,病灶增强形态特征及时间一信号强度时间曲线在良恶性乳腺病变中差异均有统计学意差异(P0.05)。结论动态增强MRI可以作为鉴别诊断乳腺环形强化病灶的良恶性有效手段。     

Pharmaceutical applications of magnetic resonance imaging (MRI)

Magnetic resonance imaging (MRI) is a powerful imaging modality that provides internal images of materials and living organisms on a microscopic and macroscopic scale. It is non-invasive and non-destructive, and one of very few techniques that can observe internal events inside undisturbed specimens in situ. It is versatile, as a wide range of NMR modalities can be accessed, and 2D and 3D imaging can be undertaken. Despite widespread use and major advances in clinical MRI, it has seen limited application in the pharmaceutical sciences. In vitro studies have focussed on drug release mechanisms in polymeric delivery systems, but isolated studies of bioadhesion, tablet properties, and extrusion and mixing processes illustrate the wider potential. Perhaps the greatest potential however, lies in investigations of pharmaceuticals in vivo, where pilot human and animal studies have demonstrated we can obtain unique insights into the behaviour of gastrointestinal, topical, colloidal, and targeted drug delivery systems.     

Myelin imaging compound (MIC) enhanced magnetic resonance imaging of myelination

The vertebrate nervous system is characterized by myelination, a fundamental biological process that protects the axons and facilitates electric pulse transduction. Damage to myelin is considered a major effect of autoimmune diseases such as multiple sclerosis (MS). Currently, therapeutic interventions are focused on protecting myelin integrity and promoting myelin repair. These efforts need to be accompanied by an effective imaging tool that correlates the disease progression with the extent of myelination. To date, magnetic resonance imaging (MRI) is the primary imaging technique to detect brain lesions in MS. However, conventional MRI cannot differentiate demyelinated lesions from other inflammatory lesions and therefore cannot predict disease progression in MS. To address this problem, we have prepared a Gd-based contrast agent, termed MIC (myelin imaging compound), which binds to myelin with high specificity. In this work, we demonstrate that MIC exhibits a high kinetic stability toward transmetalation with promising relaxometric properties. MIC was used for in vivo imaging of myelination following intracerebroventricular infusion in the rat brain. MIC was found to distribute preferentially in highly myelinated regions and was able to detect regions of focally induced demyelination.     

Structure-stability relationships of Gd(III) ion complexes for magnetic resonance imaging

Molecular mechanical calculations and molecular dynamics simulations, based on the AMBER force field, were used to examine the molecular structures and stabilities of nine multidentate ligands and their Gd(III) ion complexes. The magnitude of various factors determining the stability of multidentate Gd(III) complexes, including the energy loss due to change of ligand conformation by complexation, the energy gain from cation-ligand attraction, and effects of intramolecular hydrogen bonding, were calculated by molecular mechanics. The fit between the Gd cation and the binding cavity in the ligands was examined by molecular graphics techniques. Intramolecular hydrogen bonds in free ligands with amide or hydroxyl as H-bond donors usually disfavor complex formation, due to disruption of hydrogen bonds during complex formation. Intramolecular hydrogen bonds may contribute to enhance complex stability if they make the desolvation energy of the free ligands smaller. The calculated complex stabilities were in reasonable agreement with experimental log K values which were available for five of the compounds. The calculated complex stabilities of two hitherto unsynthesized covalently constrained DTPA-derivatives and a DOTA-derivative bearing phenoxy groups as pendant arms indicate that these may form Gd(III) complexes with sufficient stability for use in magnetic resonance imaging techniques.     

3T磁共振动态配准技术灌注成像在识别肝硬化结节恶变中的应用

目的 分析3.0T磁共振(MRI)动态配准技术(DynaVIBE)灌注成像(PWI)在识别肝硬化结节恶变中的应用价值.方法 选择2014年7月至2016年6月于本院拟行手术治疗且经常规MRI检查存在可疑肝硬化结节恶变的30例患者,均作DynaVIBE PWI扫描,并与病理结果进行对照.结果 癌结节血流量(BF)为(330.15±98.36) ml·min-1·ml-1、血容量(BV)为(30.45±14.26) ml/min、肝动脉灌注量(HAP)为(210.33±50.46) ml·min-1·m1-1、肝动脉灌注指数(HPI)为(0.52±0.11)均高于肝硬化结节[(149.01 ±73.12) ml· min-1· ml-1、(17.66±6.84) ml/min、(65.71±21.55) ml·min-1·ml-1、(0.26±0.05)]与不典型增生结节[(211.54±90.25)ml· min-1·ml-1、(25.33±15.32)ml/min、(145.21±30.64)ml·min-1·m1-1、(0.44±0.06)](P＜0.05),不典型增生结节上述各参数高于肝硬化结节;同时癌结节平均通过时间(MTT)、峰值时间(TTP)[(7.46±1.79)s、(25.22±1.75)s]快于肝硬化结节[(10.24±4.76)s、(39.55±1.66)s]与不典型增生结节[(8.71±2.11)s、(35.86±1.38)s](P＜0.05),而不典型增生结节MTT、TTP快于肝硬化结节(P＜0.05).结论 PWI可直接反映肝硬化结节血流灌注情况,为良恶性肝硬化结节鉴别提供依据.     

Macrophage targeted N-(2-hydroxypropyl)methacrylamide conjugates for magnetic resonance imaging

This study describes the synthesis, characterization and in vitro evaluation of targetable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-gadolinium (Gd) chelates for enhanced magnetic resonance imaging (MRI) of macrophages. Copolymers of HPMA, methacryloylglycylglycyl-mannosamine (MA-GG-ManN), aminopropylmethacrylamide-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (APMA-DOTA), and 5-(3-(methacryloylaminopropyl)thioureidyl) fluorescein (MA-AP-FITC) were synthesized and characterized. Gd was chelated to the polymeric precursors. The conjugates were characterized for gadolinium content by inductively coupled plasma optical emission spectrometry (ICP-OES) and T1 relaxivity (r1) at room temperature and 1.5 T. The effect of ManN content on mannose receptor mediated uptake of THP-1 human macrophages was evaluated as a function of time and temperature. The polymer conjugates showed relaxivities in the range of 21.8-24.9 s(-1) mM(-1) Gd. Relaxivities of the conjugates per mM Gd were up to 7 times higher than that of a commercially available MR contrast agent Gd-DOTA. Significantly (p < 0.042) higher uptake was observed for targeted conjugates compared to nontargeted conjugates. The uptake of polymeric conjugates was time and concentration dependent and appears to be mannose receptor mediated. The increased relaxivity coupled with the ability to target these carriers to cells containing ManN receptors shows promise for the application of these agents in clinical MR imaging of macrophage mediated malignancies.     

医用核磁共振成像系统的风险故障分析及维护保养

目前,医用核磁共振成像系统与临床诊断密切相关,在疾病诊断中发挥了非常重要的作用。核磁共振成像设备制动化程度高,结构精密,所以在运行中存在潜在的风险,且易出现故障。因此,本文通过从核磁共振成像系统原理和运行程序方面分析存在的潜在风险,从电气系统、运行方面及图像方面分析常见故障,进而总结核磁共振成像设备的维护和保养方法,使操作人员熟知医用核磁共振成像系统的常见风险故障,为操作人员提供排除故障和日常维护作参考,提高临床诊断效率。     

Use of diffusion- and perfusion-weighted magnetic resonance imaging in drug development for ischemic stroke

Diffusion- and perfusion-weighted magnetic resonance imaging (DWI and PWI, respectively) are novel imaging modalities that can detect brain ischemia early in its full extent, can be performed in minutes, can be repeated easily, and allow for follow-up of the ischemic lesion size over time with good spatial and temporal resolution. We have used DWI and PWI in evaluating novel therapeutic approaches for ischemic stroke in numerous studies in the rat and lately in humans. It is now clear that DWI and PWI offer a good combination for safe and reliable evaluation of novel drugs on the size and tissue characteristics of brain ischemia. After inducing focal brain ischemia in the rat, one can first detect the presence and extent of ischemia by DWI and hypoperfusion by PWI, calculate the volume of ischemic brain tissue, and then follow the development of the ischemic lesion over time for several hours during treatment, thus detecting in vivo effects of the novel drug on brain ischemia. Successful reperfusion (either mechanically or as a result of thrombolytic therapy) can also be detected easily. DWI and PWI when performed before starting treatment can also exclude the pretreatment bias, a potential reason for false-positive studies in which proper imaging studies are not employed. Thus we can determine the in vivo efficacy (or lack of efficacy) of new therapeutic regimens (both neuroprotective and thrombolytic) rapidly, safely, and reliably by using a small sample size only, and adapt the same strategy to clinical trials.     

Multifunctional poly (lactide-co-glycolide) nanoparticles for luminescence/magnetic resonance imaging and photodynamic therapy

Poly (lactide-co-glycolide) (PLGA) coupled with methoxy poly (ethylene glycol) (mPEG) or chlorin e6 (Ce6) was synthesized using the Steglich esterification method. PLGA-linked mPEG (PLGA-mPEG), PLGA-linked Ce6 (PLGA-Ce6), and Fe(3)O(4) were utilized to constitute multifunctional PLGA nanoparticles (～160 nm) via the multi-emulsion W(1)/O/W(2) (water-in-oil-in-water) method. The photo-sensitizing properties of Ce6 molecules anchored to PLGA nanoparticles enabled in vivo luminescence imaging and photodynamic therapy for the tumor site. The encapsulation of Fe(3)O(4) allowed high contrast magnetic resonance (MR) imaging of the tumor in vivo. Overall, PLGA nanoparticles resulted in a significant tumor volume regression for the light-illuminated KB tumor in vivo and enhanced the contrast at the tumor region, compared to that of Feridex(?) (commercial contrast agent).     

Pharmacokinetics in the rat and the dog of a nonionic nitroxide contrast agent for magnetic resonance imaging

Nitroxides are paramagnetic stable free radicals that have demonstrated effectiveness as contrast agents in proton magnetic resonance imaging (MRI). The pharmacokinetics and metabolic fate, determinants of the time course of MRI contrast enhancement, of a new nonionic pyrrolidine nitroxide derivative, TAP (2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carbonic acid-(2,3-dihydroxy-1-hydroxymethyl)-amide), were evaluated in the rat and the dog. A biexponential decline of the blood concentration of TAP was observed in both species after intravenous administration of 0.1- and 2.5-mmol/kg doses. The clearances in the rat, estimated after the low and high doses (15.4 +/- 2.0 and 15.3 +/- 1.4 mL/min.kg, respectively), were about twofold higher than those observed in two beagles (7.4 and 7.1 mL/min.kg for Dog #1 and 6.3 and 6.0 mL/min.kg for Dog #2). The hydroxylamine of TAP, formed by a one-electron reduction of the nitroxide moiety, was the only metabolite observed. This bioreduction of TAP has implications for its use as a MRI contrast agent because the diamagnetic hydroxylamine lacks contrast enhancing activity. In both animal species, the urinary recoveries of the dose as unchanged TAP and its hydroxylamine were essentially complete for the 24-h urine collections (92 to 98% and 83 to 95% for the rats and the dogs, respectively). Anticipated conjugative metabolism of the hydroxyl-containing side chain of TAP was not observed. Renal excretion of unchanged TAP was the predominant route of elimination, as renal clearance was estimated to be between 47 and 89% of total clearance in the dogs. Bioreduction in vivo was slower than that expected from the observed reduction of TAP in vitro in ascorbic acid solution and in rat liver and kidney homogenates.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging

AIM: The gastrointestinal transit of sequentially administered capsules was investigated in relation to the availability of fluid along the intestinal lumen by magnetic resonance imaging. METHODS: Water-sensitive magnetic resonance imaging was performed on 12 healthy subjects during fasting and 1 h after a meal. Specifiable non-disintegrating capsules were administered at 7, 4 and 1 h prior to imaging. RESULTS: While food intake reduced the mean fluid volumes in the small intestine (105 +/- 72 mL vs. 54 +/- 41 mL, P < 0.01) it had no significant effect on the mean fluid volumes in the colon (13 +/- 12 mL vs. 18 +/- 26 mL). The mean number of separated fluid pockets increased in both organs after meal (small intestine: 4 vs. 6, P < 0.05; large intestine: 4 vs. 6, P < 0.05). The distribution of capsules between the small and large intestine was strongly influenced by food (colon: 3 vs. 17 capsules, P < 0.01). CONCLUSIONS: The results show that fluid is not homogeneously distributed along the gut, which likely contributes to the individual variability of drug absorption. Furthermore, transport of fluid and solids through the ileocaecal valve is obviously initiated by a meal-induced gastro-ileocaecal reflex.     

核磁共振弥散张量成像在脑胶质瘤诊断中的应用研究

目的 探讨MRI弥散张量成像（DTI）技术显示胶质瘤与相邻脑白质纤维束解剖关系在脑胶质瘤诊断中的意义.方法 23例脑胶质瘤患者接受术前常规头颅MRI序列检查的同时进行DTI序列扫描,应用Functool软件进行图像分析处理,分别获得各自的部分各向异性图（FA图）、彩色编码张量图及脑白质纤维束图;并测定胶质瘤肿瘤病灶区、灶周水肿区及正常白质区的平均弥散系数（MD值）、各向异性图;进行FA图像信号强度及对比度的分析研究,分析脑胶质瘤与相邻脑白质纤维束的解剖关系.结果 所有病例均成功实现包括DTI序列扫描以及FA图像生成.脑白质纤维束显示为显著的高信号结构,灰质显示为等信号,脑脊液显示为低信号,脑内肿瘤呈类圆形等低信号,灶肿瘤周围间质水肿区白质纤维束仍能在DTI的FA图上显像,DTI的FA图像对于脑白质纤维束显影的信号对比度明显优于常规的T1W图像.肿瘤病灶区和灶周水肿区与正常白质区的MD值比较差异均有统计学意义（均P＜0.05）,而肿瘤病灶区与灶周水肿区的MD值比较差异无统计学意义（P＞0.05）;3个区域的FA值比较差异均有统计学意义（均P＜0.05＝.结论 磁共振DTI技术可在活体清晰、无创、直观地显示脑胶质瘤与周围脑白质纤维束的关系,结合其他序列的MRI应用于脑胶质瘤的术前诊断,可以准确判断肿瘤和周围脑白质纤维束的毗邻关系,对脑胶质瘤术前诊断、手术方案设计以及术后神经功能障碍的预测与预防具有重要意义.     

A high relaxivity Gd(III)DOTA-DSPE-based liposomal contrast agent for magnetic resonance imaging

The field of molecular imaging aims to visualize and quantify (patho)physiological processes at the cellular and molecular level. Sensitive and site-targeted contrast agents are employed to visualize molecular constituents of processes of interest. The principal aim of this study was to develop a magnetic resonance imaging (MRI) detectable liposome with high relaxivity and stability. To this end, Gd(III)DOTA-DSPE was synthesized and incorporated in a liposomal formulation. The resulting liposomes were extensively characterized in vitro in terms of contrast agent efficiency and structural properties. The liposomes were shown to have a high longitudinal relaxivity, which is crucial for the detection of low concentration molecular markers in molecular imaging studies. We also demonstrated that Gd(III)DOTA-DSPE exhibits no detectable transmetallation upon incubation with Zn(II). This is important as it significantly contributes to the biocompatibility of the contrast agent. The present liposome preparation will serve as versatile and well characterized platform for molecular imaging and targeted drug delivery studies.     

The response of the rat liver in situ to bromobenzene--in vivo proton magnetic resonance imaging and 31P magnetic resonance spectroscopy studies

Proton magnetic resonance imaging (MRI) and 31P magnetic resonance spectroscopy (MRS) have been used to study the response of the rat liver in situ to bromobenzene, a classic hepatotoxicant. A localized region of high proton signal intensity was seen in the perihilar region of the liver 24 hr after injection of a sublethal dose of bromobenzene. The signal intensity of the entire liver was increased at 48 hr with a gradual return approaching control values by 120 hr. These results are consistent with acute hepatic edema followed by repair of the damaged tissue. In vivo 31P MRS studies of the same rat livers were performed under conditions whereby localized, quantitative spectra could be obtained without surgical intervention. Initial concentrations of the major endogenous phosphorus-containing metabolites within the livers of control rats were 2.97 +/- 0.43 mM for the phosphomonoesters (PME), 2.92 +/- 0.56 mM for inorganic phosphate, 11.3 +/- 1.0 mM for phosphodiesters (PDE), 4.09 +/- 0.54 mM for ATP, and 0.56 +/- 0.50 mM for ADP and the intracellular pH was 7.39 +/- 0.14 (mean +/- SD, n = 10). Bromobenzene was found to cause statistically significant (p less than 0.05) changes in several of these metabolites: a decrease in hepatic ATP levels (20% at 24 hr; 27% at 48 hr), a decrease in PDE levels (15% at 24 hr; 18% at 48 hr), and an increase in the PME (63% at 24 hr; 84% at 48 hr). Both the proton MRI and the 31P MRS changes have an onset of 15-20 hr and maximum effect at 25-60 hr, but the MRS changes returned to normal well before the MRI changes. The decreased ATP levels indicate deleterious effects of bromobenzene on the bioenergetic status of the liver in situ, while the increase in PME, due to a selective increase in phosphocholine, suggests the activation of a phosphatidylcholine-specific phospholipase C in response to tissue damage. Trolox C, a potent inhibitor of lipid peroxidation, prevented the bromobenzene-induced hepatic edema (i.e., the increase in proton MRI signal intensity) and the bioenergetic deterioration (i.e., the decrease in ATP levels). However, the bromobenzene-induced increase in PME levels was not prevented by Trolox C. These results indicate that the process of lipid peroxidation plays a significant role in the hepatotoxicity of bromobenzene within the intact animal.