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1.
Ann Pharm Fr ; 73(4): 266-76, 2015 Jul.
Article in French | MEDLINE | ID: mdl-25731664

ABSTRACT

Gadolinium chelates (GC) are contrast agents widely used to facilitate or to enable diagnosis using magnetic resonance imaging (MRI). From a regulatory viewpoint, GC are drugs. GC have largely contributed to the success of MRI, which has become a major component of clinician's diagnostic armamentarium. GC are not metabolised and are excreted by the kidneys. They distribute into the extracellular compartment. Because of its high intrinsic toxicity, gadolinium must be administered as a chelate. GC can be classified according to two key molecular features: (a) nature of the chelating moiety: either macrocyclic molecules in which gadolinium is caged in the pre-organized cavity of the ligand, or linear, open-chain molecules, (b) ionicity: Gd chelates can be ionic (meglumine or sodium salts) or non-ionic. The thermodynamic and kinetic stabilities of the various GCs differ according to these structural characteristics. The kinetic stability of macrocyclic GCs is much higher than that of linear GCs and the thermodynamic stability of ionic GCs is generally higher than that of non-ionic GC, thus leading to a lower risk of gadolinium dissociation. This class of drugs has enjoyed an excellent reputation in terms of safety for a long time, until a causal link with a recently-described serious disease, nephrogenic systemic fibrosis (NSF), was evidenced. It is acknowledged that the vast majority of NSF cases are related to the administration of some linear CG in renally-impaired patients. Health authorities, worldwide, released recommendations which drastically reduced the occurrence of new cases.


Subject(s)
Contrast Media/chemistry , Contrast Media/toxicity , Gadolinium/chemistry , Gadolinium/toxicity , Magnetic Resonance Imaging/methods , Animals , Chelating Agents , Humans
2.
Atherosclerosis ; 228(2): 339-45, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23582588

ABSTRACT

PURPOSE: The aim of this study was to compare the ability of (18)F-FDG PET and iron contrast-enhanced MRI with a novel USPIO (P904) to assess change in plaque inflammation induced by atorvastatin and dietary change in a rabbit model of atherosclerosis using a combined PET/MR scanner. MATERIALS AND METHODS: Atherosclerotic rabbits underwent USPIO-enhanced MRI and (18)F-FDG PET in PET/MR hybrid system at baseline and were then randomly divided into a progression group (high cholesterol diet) and a regression group (chow diet and atorvastatin). Each group was scanned again 6 months after baseline imaging. R2* (i.e. 1/T2*) values were calculated pre/post P904 injection. (18)F-FDG PET data were analyzed by averaging the mean Standard Uptake Value (SUVmean) over the abdominal aorta. The in vivo imaging was then correlated with matched histological sections stained for macrophages. RESULTS: (18)F-FDG PET showed strong FDG uptake in the abdominal aorta and P904 injection revealed an increase in R2* values in the aortic wall at baseline. At 6 months, SUVmean values measured in the regression group showed a significant decrease from baseline (p = 0.015). In comparison, progression group values remained constant (p = 0.681). R2* values showed a similar decreasing trend in the regression group suggesting less USPIO uptake in the aortic wall. Correlations between SUVmean or Change in R2* value and macrophages density (RAM-11 staining) were good (R(2) = 0.778 and 0.707 respectively). CONCLUSION: This experimental study confirms the possibility to combine two functional imaging modalities to assess changes in the inflammation of atherosclerotic plaques. (18)F-FDG-PET seems to be more sensitive than USPIO P904 to detect early changes in plaque inflammation.


Subject(s)
Aorta, Abdominal , Aortic Diseases/diagnosis , Atherosclerosis/diagnosis , Contrast Media , Dextrans , Fluorodeoxyglucose F18 , Inflammation/diagnosis , Magnetic Resonance Imaging , Magnetite Nanoparticles , Plaque, Atherosclerotic , Positron-Emission Tomography , Radiopharmaceuticals , Animals , Aorta, Abdominal/diagnostic imaging , Aorta, Abdominal/drug effects , Aorta, Abdominal/pathology , Aortic Diseases/diagnostic imaging , Aortic Diseases/drug therapy , Aortic Diseases/pathology , Atherosclerosis/diagnostic imaging , Atherosclerosis/drug therapy , Atherosclerosis/pathology , Atorvastatin , Disease Models, Animal , Disease Progression , Heptanoic Acids/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Inflammation/diagnostic imaging , Inflammation/drug therapy , Inflammation/pathology , Predictive Value of Tests , Pyrroles/pharmacology , Rabbits , Radiography , Time Factors
3.
Ann Pharm Fr ; 70(1): 26-34, 2012 Jan.
Article in French | MEDLINE | ID: mdl-22341006

ABSTRACT

Due to numerous technical developments, in vivo imaging is suitable for pharmacokinetic and metabolism studies of new chemical entities as well as for evaluating their pharmacological or biological effects. MRI, nuclear medicine, X-Ray, ultrasound and optical imaging are available for both clinical and experimental imaging with even higher performance. For all these imaging modalities, diagnostic agents are useful to improve contrast and specificity. Specific targeting of biological events is addressed by molecular imaging. From a pharmacodynamic perspective, radiolabeling of a new chemical entity allows in vivo visualization quantitative measure of its biodistribution, its elimination and its specific molecular binding. Non-invasive imaging methods are useful for longitudinal investigations of biological changes. Based on nanotechnologies, specificity of drug delivery can be monitored by imaging. New developments in hybrid imaging technologies as well as multimodal contrast agents reinforce in vivo experimental and clinical proof of mechanism of new chemical entities.


Subject(s)
Diagnostic Imaging/methods , Pharmaceutical Preparations/metabolism , Contrast Media , Drug Delivery Systems , Drug-Related Side Effects and Adverse Reactions , Humans , Magnetic Resonance Imaging , Nanotechnology , Pharmacokinetics , Positron-Emission Tomography , Radiopharmaceuticals , Tissue Distribution , Ultrasonics
4.
Br J Pharmacol ; 165(4b): 1151-62, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21740412

ABSTRACT

BACKGROUND AND PURPOSE: Hyperphosphataemia is common in patients with nephrogenic systemic fibrosis (NSF). NSF has been linked to administration of gadolinium (Gd) chelates (GCs) and elevated serum phosphate levels accelerate the release of Gd from linear, non-ionic GCs but not macrocyclic GCs. Hence, we determined whether hyperphosphataemia is a cofactor or risk factor for NSF by investigating the role of hyperphosphataemia in renally impaired rats. EXPERIMENTAL APPROACH: Firstly, the clinical, pathological and bioanalytical consequences of hyperphosphataemia were investigated in subtotal nephrectomized (SNx) Wistar rats following i.v. administration of the non-ionic, linear GC gadodiamide (5 × 2.5 mmol·kg(-1) ·day(-1) ). Secondly, the effects of several GCs were compared in these high-phosphate diet fed rats. Total Gd concentration in skin, femur and plasma was measured by inductively coupled plasma mass spectrometry (ICP-MS) and free Gd(3+) in plasma by liquid chromatography coupled to ICP-MS. Relaxometry was used to measure dissociated Gd in skin and bone. KEY RESULTS: Four out of seven SNx rats fed a high-phosphate diet administered gadodiamide developed macroscopic and microscopic (fibrotic and inflammatory) skin lesions, whereas no skin lesions were observed in SNx rats treated with saline, the other GCs and free ligands or in the normal diet, gadodiamide-treated group. Unlike the other molecules, gadodiamide gradually increased the r(1) relaxivity value, consistent with its in vivo dissociation and release of soluble Gd. CONCLUSIONS AND IMPLICATIONS: Hyperphosphataemia sensitizes renally impaired rats to the profibrotic effects of gadodiamide. Unlike the other GCs investigated, gadodiamide gradually dissociates in vivo. Our data confirm that hyperphosphataemia is a risk factor for NSF.


Subject(s)
Contrast Media/adverse effects , Gadolinium DTPA/adverse effects , Hyperphosphatemia/complications , Nephrogenic Fibrosing Dermopathy/etiology , Renal Insufficiency/complications , Animals , Contrast Media/pharmacokinetics , Disease Models, Animal , Femur/metabolism , Gadolinium/blood , Gadolinium/metabolism , Gadolinium DTPA/pharmacokinetics , Hyperphosphatemia/blood , Hyperphosphatemia/metabolism , Liver/metabolism , Male , Nephrogenic Fibrosing Dermopathy/blood , Nephrogenic Fibrosing Dermopathy/metabolism , Procollagen-Proline Dioxygenase/metabolism , Rats , Rats, Wistar , Renal Insufficiency/blood , Renal Insufficiency/metabolism , Risk Factors , Skin/metabolism , Tissue Inhibitor of Metalloproteinase-1/metabolism , Transforming Growth Factor beta1/metabolism
6.
MAGMA ; 18(3): 138-43, 2005 Jul.
Article in English | MEDLINE | ID: mdl-16047191

ABSTRACT

The study evaluates the tumor distribution of the rapid clearance blood pool agent (RCBPA) gadomelitol, in a breast tumor model. Different techniques were used : (1) tissue gadolinium concentrations measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES), (2) whole body quantitative autoradiography using radiolabeled [153Gd] gadomelitol and (3) dynamic contrast-enhanced MRI with compartmental analysis. An accumulation of gadomelitol in tumors compared to muscle was observed 30 min and 3 h post injection (p.i.). Thirty minutes p.i., the gadomelitol tumor distribution evaluated by autoradiography showed a marked difference between the rim and the center, whereas both areas showed comparable concentrations after 3 h. Using dynamic contrast-enhanced MRI, three phases could be observed during the 1 hour observation period: (1) rapid tumor uptake within the first few minutes post-injection (2) a progressive increase in tumor signal enhancement over 10 min and (3) a steady-state phase. Average +/- SD (n=5) transendothelial permeability K(PS) and the fractional blood volume fBV were 12.2+/-1.6 microl/min(-1)/g and 5.4+/-0.2% respectively. Due to its slow extravasation and high tumor residence time, gadomelitol may potentially be useful to improve characterization between benign versus malignant tumors using dynamic MRI.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Contrast Media/pharmacokinetics , Heterocyclic Compounds/pharmacokinetics , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Organometallic Compounds/pharmacokinetics , Animals , Humans , Image Enhancement/methods , Magnetic Resonance Imaging/methods , Metabolic Clearance Rate , Mice , Mice, Nude , Organ Specificity , Tissue Distribution
8.
Magn Reson Med ; 46(5): 932-8, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11675645

ABSTRACT

The signal-enhancing characteristics of a new monodisperse monogadolinated macromolecular MR contrast medium (P792) were evaluated for magnetic resonance angiography (MRA) of the coronary arteries. A total of 15 cardiac examinations were performed in pigs at 1.5 T using a 3D gradient-echo sequence. Images were acquired during breath-hold before and up to 35 min after IV injection of Gd-DTPA (0.3 mmol Gd/kg), Gd-BOPTA (0.2 mmol Gd/kg), and P792 (13 micromol Gd/kg). An increase in the signal-to-noise ratio (SNR) of 97% +/- 17%, 108% +/- 37%, and 109% +/- 31% in coronary arteries and of 82% +/- 19%, 82% +/- 24%, and 28% +/- 18% in myocardium, respectively, was measured during the first postcontrast acquisition. The blood-to-myocardium signal-difference-to-noise ratio (SDNR) was significantly higher for P792 than for the other Gd compounds (P <.05) for up to 15 min after injection. Qualitative assessment showed that visualization of the coronary arteries and their branches was significantly better for P792 compared to the low-molecular Gd compounds (P <.05). The blood pool contrast medium P792 is well suited for MRA of the coronary arteries.


Subject(s)
Coronary Vessels/anatomy & histology , Heterocyclic Compounds , Magnetic Resonance Angiography/methods , Meglumine/analogs & derivatives , Organometallic Compounds , Animals , Contrast Media , Gadolinium , Gadolinium DTPA , Imaging, Three-Dimensional , Swine , Swine, Miniature
9.
Invest Radiol ; 36(9): 547-53, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11547043

ABSTRACT

RATIONALE AND OBJECTIVES: To compare the pharmacokinetics of a new macromolecular iodinated contrast medium, prototype P743, with a standard contrast agent (iobitridol) for spiral computed tomography pulmonary angiography in rabbits. METHODS: Manual injection was first used to test the performance of P743 even in cases of nonoptimal bolus timing. Then a protocol was designed to compare vessel enhancement in both first-pass and delayed scans for the two contrast agents with the help of a power injector. RESULTS: With manual fast injection, the first pass of iobitridol was observed only on proximal scans. Conversely, opacification of vessels was maintained during three spiral scans with P743 under the same injection conditions. When optimal bolus timing was performed, higher vessel enhancement was observed during bolus first pass with iobitridol (iodine dosage 250 mg I/kg) compared with P743 (150 mg I/kg). However, during the postbolus phase, the decrease in attenuation values was markedly faster with iobitridol than with P743. CONCLUSIONS: This study confirmed that P743 remains more intravascular than iobitridol, which may have clinical implications for the diagnosis of pulmonary embolism, for example.


Subject(s)
Contrast Media , Iodine , Iohexol/analogs & derivatives , Pulmonary Artery/diagnostic imaging , Tomography, X-Ray Computed , Angiography , Animals , Iodine Compounds , Macromolecular Substances , Organic Chemicals , Rabbits
10.
Invest Radiol ; 36(8): 445-54, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11500594

ABSTRACT

RATIONALE AND OBJECTIVES: To summarize the physicochemical characterization, pharmacokinetic behavior, and biological evaluation of P792, a new monogadolinated MRI blood-pool agent. METHODS: The molecular modeling of P792 was described. The r1 relaxivity properties of P792 were measured in water and 4% human serum albumin at different magnetic fields (20, 40, 60 MHz). The stability of the gadolinium complex was assessed. The pharmacokinetic and biodistribution profiles were studied in rabbits. Renal tolerance in dehydrated rats undergoing selective intrarenal injection was evaluated. Hemodynamic safety in rats and in vitro histamine and leukotriene B4 release were also tested. RESULTS: The mean diameter of P792 is 50.5 A and the r1 relaxivity of this monogadolinium contrast agent is 29 L x mmol(-1) x s(-1) at 60 MHz. The stability of the gadolinium complex in transmetallation is excellent. The pharmacokinetic and biodistribution profiles are consistent with that of a rapid-clearance blood-pool agent: P792 is mainly excreted by glomerular filtration, and its diffusion across normal endothelium is limited. Renal and hemodynamic safety is comparable to that of the nonspecific agent gadolinium-tetraazacyclododecane tetraacetic acid. No histamine or leukotriene B4 release was found in RBL-2H3 isolated mastocytes. CONCLUSIONS: The relaxivity of P792 at clinical field is very high for a monogadolinium complex without protein binding. The pharmacokinetic and biodistribution profiles are consistent with those of a rapid-clearance blood-pool agent. Its initial safety profile is satisfactory. Experimental and clinical studies are underway to confirm the potential of P792 in MRI.


Subject(s)
Contrast Media/chemistry , Contrast Media/pharmacokinetics , Magnetic Resonance Imaging , Acute Kidney Injury/metabolism , Animals , Disease Models, Animal , Hemodynamics/drug effects , Heterocyclic Compounds , Histamine/metabolism , Leukotriene B4/metabolism , Magnetic Resonance Spectroscopy , Molecular Structure , Organometallic Compounds , Rabbits , Rats , Tissue Distribution
11.
J Magn Reson Imaging ; 14(2): 97-105, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11477666

ABSTRACT

T1-weighted magnetic resonance imaging (MRI) was used to evaluate the potential interest of a new Gd-based contrast agent, termed P760, to characterize brain tumor heterogeneity and vascularization and to delineate regions containing permeable vessels. The C6 rat glioma model was used as a model of high-grade glioblastoma. The signal enhancement was measured as a function of time in the vascular compartment and in different regions of interest (ROIs) within the tumor after the injection of 0.02 mmol x kg(-1) of P760. The results were compared to those obtained after the injection of 0.1 mmol x kg(-1) of Gd-DOTA. We showed that P760, in spite of a Gd concentration five times smaller, produces an enhancement in the blood pool similar to that produced by Gd-DOTA. It was shown that P760 makes possible an excellent delineation of regions containing vessels with a damaged blood-brain barrier (BBB). Images acquired 5-10 minutes after P760 injection showed the location of permeable vessels more accurately than Gd-DOTA-enhanced images. The enhancement produced in the tumor by P760 was, however, less than that produced by Gd-DOTA. The extravasation and/or diffusion rate of P760 in the interstitial medium were found to be strongly reduced, compared to those found with Gd-DOTA. This study suggests that the new contrast agent has promising capabilities in clinical imaging of brain tumors.


Subject(s)
Brain Neoplasms/diagnosis , Contrast Media/pharmacokinetics , Glioblastoma/diagnosis , Magnetic Resonance Imaging , Organometallic Compounds/pharmacokinetics , Animals , Female , Gadolinium/pharmacokinetics , Heterocyclic Compounds/pharmacokinetics , Rats , Rats, Sprague-Dawley
12.
Eur Radiol ; 11(7): 1276-84, 2001.
Article in English | MEDLINE | ID: mdl-11471624

ABSTRACT

The aim of this study was to assess MR signal enhancement patterns of carboxymethyldextran (CMD)-A2-Gd-DOTA, a new macromolecular contrast agent, in the abdomen and pelvis of New Zealand white rabbits. Nine New Zealand white rabbits underwent MRI before and following injection of 0.05 mmol/kg body weight (bw) CMD-A2-Gd-DOTA (52.1 kDa), using turbo FLASH-, dynamic FLASH 60 degrees-, T1- and T2-weighted spin-echo and turbo spin-echo sequences up to 10 days p.i. Changes in blood and tissue signal intensities (deltaSI) and relaxation rates (deltaR1) were calculated. Differences between pre- and post-contrast MRI data were compared using the Scheffé test. CMD-A2-Gd-DOTA demonstrated significant blood-pool enhancement and significant tissue enhancement on T1-weighted images, whereas no significant signal changes were observed on T2-weighted images (P < 0.05). Kidney parenchyma, pelvis and bladder demonstrated a subsequent enhancement, resembling renal elimination of the majority of the contrast agent. Liver parenchyma demonstrated a slow, delayed decay of the contrast enhancement due to storage and biodegradation of larger subfractions of the contrast agent. All tissue signal intensities were back to baseline 10 days p.i. CMD-A2-Gd-DOTA is a new macromolecular contrast agent with blood-pool effect, significant signal enhancement of abdominal organs and pelvic bone marrow, partial storage in the liver and baseline tissue signal intensities by 10 days p.i.


Subject(s)
Abdomen/anatomy & histology , Contrast Media , Image Enhancement/methods , Magnetic Resonance Imaging/methods , Organometallic Compounds , Pelvis/anatomy & histology , Analysis of Variance , Animals , Models, Animal , Organometallic Compounds/pharmacokinetics , Rabbits
13.
MAGMA ; 12(2-3): 82-7, 2001 May.
Article in English | MEDLINE | ID: mdl-11390260

ABSTRACT

The aim of this study was to validate an experimental model designed to distinguish four categories of contrast agents, non specific agents (NDA, Gd-DOTA) characterized by rapid and total extravasation; low diffusion agents (LDA, P760) characterized by delayed extravasation; and rapid (P792) and slow clearance (P717) blood pool agents (BPA) characterized by limited extravasation. Plasma and peritoneal gadolinium concentrations were simultaneously measured after intravenous injection of various contrast agents in mice. Products of each category were compared in this model.The plasma pharmacokinetic profiles were similar for Gd-DOTA and P760 (t1/2=13.3 and 13.8 min, respectively), whereas the half-lives were 22 and 1212 min for P792 and P717, respectively. The plasma clearance was inversely related to the size of the contrast agent. The intraperitoneal diffusion patterns of the various products were related to the molecular volume: C(max) per dose decreased progressively (78.7, 51.2, 44.2, 33.5 1/l) and t(max) increased (7, 15, 40, and 120 min) for Gd-DOTA, P760, P792 and P717, respectively. Nevertheless, the same quantities of Gd-DOTA and P760 (AUC ratio of 78.4 and 76.8, respectively) diffused into the peritoneum, whereas only 44.5% of P792 and 21.5% of P717 extravasated.The data obtained in this peritoneal permeability model with the various categories of contrast agents provide an estimation of the quantities of contrast agents diffusing into a permeable interstitium and may be used to predict the corresponding signal intensity, which can be measured locally.


Subject(s)
Ascitic Fluid/chemistry , Contrast Media/pharmacokinetics , Heterocyclic Compounds/pharmacokinetics , Magnetic Resonance Imaging/methods , Organometallic Compounds/pharmacokinetics , Animals , Diffusion , Gadolinium/blood , Gadolinium/pharmacokinetics , Heterocyclic Compounds/blood , Male , Mice , Mice, Inbred ICR , Models, Biological , Organometallic Compounds/blood
14.
MAGMA ; 12(2-3): 121-7, 2001 May.
Article in English | MEDLINE | ID: mdl-11390267

ABSTRACT

An original MRI contrast agent, called P792, is described. P792 is a gadolinium macrocyclic compound based on a Gd-DOTA structure substituted by hydrophilic arms. The chemical structure of P792 has been optimized in order to provide (1) a high r(1) relaxivity in the clinical field for MRI: 29 mM(-1)xs(-1) at 60 MHz, (2) a high biocompatibility profile and (3) a high molecular volume: the apparent hydrodynamic volume of P792 is 125 times greater than that of Gd-DOTA. As a result of this high molecular volume, P792 presents an unusual pharmacokinetic profile, as it is a Rapid Clearance Blood Pool Agent (RCBPA) characterized by limited diffusion across the normal endothelium. The original pharmacokinetic properties of this RCBPA are expected to be well suited to MR coronary angiography, angiography, perfusion imaging (stress and rest), and permeability imaging (detection of ischemia and tumor grading). Further experimental imaging studies are ongoing to define the clinical value of this compound.


Subject(s)
Contrast Media/chemical synthesis , Contrast Media/pharmacokinetics , Gadolinium , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacokinetics , Magnetic Resonance Imaging/methods , Organometallic Compounds/chemical synthesis , Organometallic Compounds/pharmacokinetics , Animals , Contrast Media/chemistry , Heterocyclic Compounds/chemistry , Indicators and Reagents , Lethal Dose 50 , Male , Metabolic Clearance Rate , Molecular Structure , Organometallic Compounds/chemistry , Rats , Rats, Sprague-Dawley , Spectrometry, Mass, Electrospray Ionization , Tissue Distribution
15.
Magn Reson Med ; 45(5): 880-6, 2001 May.
Article in English | MEDLINE | ID: mdl-11323815

ABSTRACT

The diagnostic potential of a new rapid clearance blood pool contrast medium (P792; MW = 6.47 kDa) for the MR assessment of microvessel characteristics was assessed in 42 chemically-induced breast tumors, with comparisons to albumin-(Gd-DTPA). Microvessel characteristics, including the transendothelial permeability (K(PS)) and the fractional blood volume (fPV), were estimated by using dynamic MR data fit to a bidirectional two-compartment model. The MR-derived estimates for K(PS) and fPV using each contrast agent were compared, and assays using each contrast agent were correlated to the histologic tumor grade (SBR score) and the microvascular density (MVD) counts. Using P792-enhanced data, neither K(PS) nor fPV showed a statistically significant correlation with the tumor grade or the MVD (P >.05). Conversely, using albumin-(GdDTPA)(30), K(PS) values correlated significantly with the histologic tumor grade (r =.55; P <.0005) and the MVD (r =.34, P <.05), whereas no correlation was established for fPV. In conclusion, based on P792 data no correlation between tumor microvascular characteristics and histologic markers (SBR score or MVD) was found in this breast tumor model. Our analysis suggests that contrast media of relatively large (on the order of 90 kDa) molecular size, such as albumin-(GdDTPA)(30), are more accurate for the characterization of tumor microvessels.


Subject(s)
Magnetic Resonance Imaging/methods , Mammary Neoplasms, Experimental/blood supply , Mammary Neoplasms, Experimental/pathology , Animals , Contrast Media , Female , Gadolinium DTPA , Rats , Rats, Sprague-Dawley
16.
Radiology ; 218(3): 664-9, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11230637

ABSTRACT

PURPOSE: To evaluate gadoterate meglumine as a contrast agent for interstitial magnetic resonance (MR) lymphography in combination with an adapted fast three-dimensional (3D) MR sequence. MATERIALS AND METHODS: In 12 New Zealand White rabbits, 0.5 mL of undiluted gadoterate meglumine was injected subcutaneously into the dorsal foot pad (n = 9) or the foreleg (n = 3) bilaterally. Immediately after administration, a slight massage was performed at the injection site. Imaging was performed with a 3D spoiled gradient-recalled echo sequence (6.7/1.6 [repetition time msec/echo time msec]; field of view, 28.0 x 19.6; two signals acquired) similar to that used for 3D MR angiography. Thus, 3D maximum intensity projection images could be obtained. Images were obtained before injection and 5, 15, 30, 60, and 120 minutes after injection. RESULTS: In the hind legs, as many as four successive lymph node groups were depicted with maximum enhancement after 5-15 minutes for the popliteal lymph node group, 15-30 minutes for the inguinal lymph group, and 30-60 minutes for the iliac-paraaortal lymph node group; the iliac-paraaortal lymph node group was not consistently enhanced. In the forelegs, four successive lymph node groups, including axillary and mediastinal lymph node groups, showed marked gadolinium uptake, with maximum enhancement 5-15 minutes after injection. CONCLUSION: As a widely tested positive-enhancing T1 contrast agent with favorable safety features, gadoterate meglumine allows the depiction of three to four successive lymph node groups early after subcutaneous injection. With the sequence used, 3D MR lymphangiograms can be obtained.


Subject(s)
Contrast Media , Lymph Nodes/anatomy & histology , Magnetic Resonance Imaging/methods , Meglumine , Organometallic Compounds , Animals , Female , Rabbits
17.
Circulation ; 103(3): 415-22, 2001 Jan 23.
Article in English | MEDLINE | ID: mdl-11157694

ABSTRACT

BACKGROUND: Based on the observation that ultrasmall superparamagnetic particles of iron oxides (USPIOs) are phagocytosed by cells of the mononuclear phagocytic system, the purpose of this study was to evaluate their use as a marker of atherosclerosis-associated inflammatory changes in the vessel wall before luminal narrowing is present. METHODS AND RESULTS: Experiments were conducted on 6 heritable hyperlipidemic and 3 New Zealand White rabbits. 3D MR angiography (MRA) of the thoracic aorta was performed on all rabbits by use of a conventional paramagnetic contrast agent that failed to reveal any abnormalities. One week later, all rabbits except 1 of the hyperlipidemic animals were injected with a USPIO contrast agent (Sinerem, Guerbet) at a dose of 1 mmol Fe/kg. 3D MRA data sets collected over the subsequent 5 days showed increasing signal in the aortic lumen. Whereas the aortic wall of the control rabbits remained smooth and bright, marked susceptibility effects became evident on day 4 within the aortic walls of hyperlipidemic rabbits. Ex vivo imaging of aortic specimens confirmed the in vivo results. Histopathology documented marked Fe uptake in macrophages embedded in atherosclerotic plaque of the hyperlipidemic rabbits. Electron microscopy showed multiple cytoplasmic Fe particles in macrophages. No such changes were seen in control rabbits or in the hyperlipidemic rabbit that had not received Sinerem. CONCLUSIONS: USPIOs are phagocytosed by macrophages in atherosclerotic plaques of the aortic wall of hyperlipidemic rabbits in a quantity sufficient to cause susceptibility effects detectable by MRI.


Subject(s)
Aorta, Thoracic/pathology , Hyperlipidemias/diagnosis , Iron , Magnetic Resonance Angiography/methods , Oxides , Animals , Aorta, Thoracic/immunology , Aorta, Thoracic/ultrastructure , Arteriosclerosis/etiology , Arteriosclerosis/pathology , Contrast Media , Dextrans , Ferrosoferric Oxide , Hyperlipidemias/complications , Hyperlipidemias/genetics , Iron/analysis , Macrophages/chemistry , Macrophages/ultrastructure , Magnetite Nanoparticles , Oxides/analysis , Prussian Blue Reaction , Rabbits
18.
Invest Radiol ; 36(1): 41-9, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11176260

ABSTRACT

RATIONALE AND OBJECTIVES: To summarize the chemical synthesis, physicochemical characterization, pharmacokinetic behavior, and biological evaluation of P743, a new macromolecular iodinated contrast medium. METHODS: The synthesis and molecular modeling of the iodinated macromolecule P743 are described. The pharmacokinetic profile was established in rabbits and rats. Acute toxicity in mice, renal tolerance in normal rabbits, and renal tolerance in uninephrectomized, dehydrated rats undergoing selective intrarenal injection was evaluated. In vitro permeability effects on isolated mastocytes and on the coagulation pathways were carried out. Computed tomography vascular imaging was performed after intravenous injection of P743 (300 mg I/kg) in rabbits and compared with the nonspecific nonionic agent iobitridol. RESULTS: P743 is a monodisperse, macromolecular iodinated contrast medium. In both rabbits and rats, P743 showed a pharmacokinetic profile consistent with that of a rapid-clearance blood-pool agent. Its diffusion through the endothelium was found to be low in vitro, thus confirming early confinement of this macromolecule, unlike nonspecific contrast media. In both species, P743 was excreted by glomerular filtration. Acute toxicity disclosed no mortality at the highest volume that could be injected into mice, leading to a median lethal dose greater than 8.9 g I/kg. Renal tolerance was found to be good in both euvolemic rabbits and uninephrectomized, dehydrated rats. No histamine or leukotriene B4 release was found on RBL-2H3 isolated mastocytes. P743 did not interfere with the coagulation pathways. Imaging experiments confirmed that P743 remains in the vascular compartment for a longer time than does iobitridol, thus allowing vascular enhancement that is twice as high as that of iobitridol in the recirculation phase. CONCLUSIONS: The pharmacokinetic and imaging profiles of P743, a new, monodisperse, macromolecular blood-pool iodinated contrast medium, were consistent with those of a rapid-clearance blood-pool agent. Its initial safety profile is satisfactory. Further experimental imaging studies are required to define the clinical interest in such molecules.


Subject(s)
Contrast Media/analysis , Contrast Media/pharmacology , Animals , Contrast Media/chemical synthesis , Iodine Compounds , Organic Chemicals , Rabbits , Rats
19.
Invest Radiol ; 35(4): 213-8, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10764089

ABSTRACT

RATIONALE AND OBJECTIVES: To mimic an MR angiographic protocol, an experimental model was developed in rabbits to determine gadolinium concentrations in blood early after injection. Contrast agents with different molecular sizes were compared. METHODS: The influence of injection parameters (injection rate, duration of injection, volume of injection, dose) was assessed, and two blood pool agents (P760, P717) were compared with the low-molecular-weight Gd-DOTA under similar conditions. RESULTS: Two main phases were identified: bolus and post-bolus. Injection parameters strongly influenced the pattern of the bolus phase, but the postbolus phase was sensitive only to the injected dose. The blood pool agents presented a bolus phase profile similar to that of Gd-DOTA, but 45 seconds after injection, 84% of P717 molecules were still present in the blood compartment, compared with 65% of P760 molecules and only 51% of Gd-DOTA molecules. CONCLUSIONS: Blood pool agents are useful for MR angiographic protocols involving the postbolus phase. In protocols in which only the bolus phase is imaged, blood pool agents provide similar data to Gd-DOTA, provided that the injection rate, iso-T1 efficiency dose, and volume are similar.


Subject(s)
Contrast Media , Gadolinium/pharmacokinetics , Heterocyclic Compounds/pharmacokinetics , Magnetic Resonance Angiography , Organometallic Compounds/pharmacokinetics , Animals , Male , Rabbits
20.
J Magn Reson Imaging ; 11(2): 182-91, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10713952

ABSTRACT

An original gadolinium chelate, termed P760, which diffuses through the vascular endothelium but at a much lower rate than nonspecific agents (NSA), is described. P760 is a gadolinium macrocyclic compound based on a DOTA structure that is substituted by hydrophilic bulky groups branched on the amino-carboxylic residues. The molecular weight is 5293, and the molecular volume, measured by light scattering, is 30 times higher (11.5 nm3) than that of gadolinium (Gd)-DOTA (0.38 nm3). The increase in molecular volume and weight has two consequences: a) higher relaxivity (r1; 24.7 mM-1.s-1 compared with 3.4 mM-1.s-1 for Gd-DOTA at 20 Mhz, 37 degrees C); and b) a lengthening of its transport rate through the endothelium. P760 presents a peculiar pharmacokinetic profile: at early times post injection, the blood concentrations are higher than those of Gd-DOTA, but after 20 minutes, the blood concentrations are equal for the two compounds. The body clearances of the products are identical (i.e., glomerular filtration rate). P760 molecules are large enough to have a restricted diffusion through the endothelium but, conversely, small enough to pass freely through the glomerular membrane. This limited extravasation has been observed in rabbits by magnetic resonance angiography or in investigations of tumor permeability. Further experimental imaging studies are needed to define the clinical interest of such properties.


Subject(s)
Contrast Media , Organometallic Compounds , Animals , Capillary Permeability , Contrast Media/chemistry , Contrast Media/pharmacokinetics , Diffusion , Endothelium, Vascular/metabolism , Gadolinium , Male , Meglumine/chemistry , Meglumine/pharmacokinetics , Mice , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacokinetics , Rabbits , Rats , Rats, Wistar , Tissue Distribution
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