Gadolinium-DTPA as a contrast agent in MRI: initial clinical experience in 20 patients

Magnetic resonance imaging (MRI) was performed in 20 patients before and after intravenous administration of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) in a dose of 0.1 mmol/kg. Twelve of the patients had clinical and histologic diagnoses of cerebral tumor, six had hepatic tumors, one had hepatic cysts, and one had transitional cell carcinoma of the bladder. Contrast enhancement was seen with all tumors, but not with the hepatic cysts. The degree of enhancement was greater than that seen with computed tomography (CT) in 13 cases, equal to it in six, and less in one. Contrast enhancement was detectable as long as 18 hr after injection of Gd-DTPA in one case of cerebral tumor. The margin between cerebral tumor and peritumoral edema could be delineated with contrast-enhanced MRI to the degree possible with contrast-enhanced CT. In the liver isointense enhancement was seen with saturation-recovery (SR), inversion-recovery (IR), and spin-echo (SE) sequences although not with all three sequences simultaneously. In general IR sequences were most sensitive for display of the contrast agent, but the enhancement often decreased the difference between abnormal and normal tissue. No short-term side effects were encountered and no significant change was seen in urea, creatinine, electrolytes, liver function tests, blood coagulation, or urine testing after injection of Gd-DTPA. Although much more work will be required to evaluate this contrast agent, these initial experiences are very promising.     

Gadolinium-DTPA as a contrast agent in magnetic resonance imaging of the brain

Summary One hundred patients with CT-proven intracranial disease have been studied by magnetic resonance imaging (MRI) before and after intravenous injection with Gadolinium-DTPA (Gd-DTPA), in order to assess the role and clinical efficacy of Gd-DTPA. T₂-weighted spin echo sequences, although sensitive to the detection of intracranial disease, in general fail to differentiate macroscopic tumour from oedema. Following Gd-DTPA, T₁-weighted spin echo sequences in primary tumours demonstrated a variable degree of contrast enhancement unrelated to histological type. Small tumours, especially acoustic neuromas and meningiomas in the posterior fossa, were rendered more conspicuous. Optimum time for scanning was between five and 25 min following injection for all lesions except those adjacent to normal enhancing structures such as nasal/sinus mucosa and pituitary gland when delayed scans up to 45 min were necessary. No differences were observed between the 0.1 and 0.2 mmol/kg Gd-DTPA concentrations used and no complications attributable to Gd-DTPA were detected. Clinical advantages of Gd-DTPA include shorter scan times, macroscopic tumour/oedema separation and improved detection of certain tumours, particularly acoustic neuromas.     

Gadolinium-DTPA as a contrast agent in MR imaging--theoretical projections and practical observations

The theoretical basis for the use of paramagnetic agents to enhance proton relaxation is described. Factors of importance in the design of contrast agents are considered. Measurements of changes in T1 and T2 in vitro due to Gd3+-diethylenetriamine pentaacetic acid (DTPA) are used to predict changes in the intensity of transverse magnetisation seen with different sequences in magnetic resonance imaging. The use of Gd3+-DTPA in clinical cases is illustrated.     

Gadolinium-DTPA: a new contrast agent for magnetic resonance imaging

Gd-DTPA-dimeglumine is a new contrast agent for magnetic resonance imaging. Its safety and efficacy in man were evaluated in 20 volunteers and 60 patients. For determination of tolerance of Gd-DTPA, blood and urine samples were taken and blood pressure, pulse rate, and ECG were recorded before and after injection. The results of these analyses showed no clinically relevant changes. In MR imaging of intracranial lesions Gd-DTPA serves as an indicator of function or disfunction of the blood-brain-barrier, because its pharmacokinetic behavior is very similar to that of urographic iodinated contrast media used now for X-ray CT. And so by using Gd-DTPA it is possible to differentiate between neoplastic tissue and perifocal edema, to determine the extension of tumor infiltration, and to detect tumor recurrence.     

Nitrogen-filled liposomes as a vascular US contrast agent: preliminary evaluation.

Liposomes with a mean diameter of 1-2 microns were made to entrap nitrogen gas and tested as an ultrasound (US) contrast agent. The gas-filled liposomes, or Aerosomes (ImaRx Pharmaceutical, Tucson) were tested in vitro for size, stability, reflectivity, and acoustic characterization, and were tested in vivo for acute toxicity in mice and for cardiac imaging in rabbits after intravenous injection. Aerosomes have much greater reflectivity and higher attenuation than do standard liposomes and retain their acoustic properties after storage in aqueous media for several months. The interpolated median lethal dose of Aerosomes is approximately 2.5 mmol of lipid per kilogram, and the imaging dose is under 5 mumol of lipid per kilogram, yielding a potential therapeutic index of over 500 to 1. Postcontrast US images showed sustained enhancement of all four cardiac chambers as well as enhancement in the aorta, vena cava, and hepatic veins. Aerosomes hold promise as a contrast agent for cardiac and blood-pool imaging. Further work is in progress to characterize and develop this novel US contrast agent.     

Emerging applications for ferumoxytol as a contrast agent in MRI

Ferumoxytol is an ultrasmall superparamagnetic iron oxide (USPIO) agent initially approved by the Food and Drug Administration (FDA) as an iron replacement therapy for patients with anemia due to chronic renal failure. Recently, ferumoxytol has been investigated extensively as an intravenous contrast agent in magnetic resonance imaging (MRI). Since it causes regional T₁ and T₂* shortening in vivo, conventional pulse sequences can be used following ferumoxytol administration to demonstrate signal enhancement or loss. Ferumoxytol can be administered as a rapid bolus and has a long intravascular half‐life on the order of 14–15 hours, making it a potentially useful agent for vascular and perfusion‐weighted MRI. In comparison to other USPIOs, ferumoxytol is less limited by allergic and idiosyncratic reactions. Furthermore, since ferumoxytol is an iron‐based agent with no potential for causing nephrogenic systemic fibrosis, it may be useful as an alternative to gadolinium‐based contrast agents in patients with compromised renal function. Ferumoxytol is ultimately taken up by macrophages/the reticuloendothelial system in the liver, spleen, and lymph nodes, and this uptake mechanism is being explored as a novel imaging technique for vascular lesions, tumors, and lymph nodes. This article reviews the properties of ferumoxytol relevant to MRI as well as many of the uses for the agent currently under investigation. J. Magn. Reson. Imaging 2015;41:884–898 . © 2014 Wiley Periodicals, Inc .     

Gadolinium-DTPA as X-ray contrast medium in clinical studies

The aim of this study was to investigate the contrast effects of gadolinium (Gd) in patients undergoing digital subtraction angiography (DSA), intravenous urography (IVU) and CT. 15 patients attending for coeliac axis DSA (n = 5), abdominal CT (n = 5) and IVU (n = 5) were injected with 0.3 mmol kg-1 Gd-DTPA, the maximum approved dose. For DSA and IVU, images were categorized as being of diagnostic or non-diagnostic quality. For CT, enhancement was measured in Hounsfield Units (HU). On CT, enhancement with Gd was reproducible in all cases; average peak aortic enhancement was 75 HU but duration was short. On IVU, four of five studies yielded positive pyelograms but all nephrograms were relatively poor. On DSA, all five patients had diagnostic arteriograms and four of five indirect portograms were of diagnostic quality. In all 15 cases, enhancement was weaker than that achieved with routine dosage of iodinated agents. In conclusion, Gd chelates may be clinically useful in X-ray studies under certain circumstances on patients with contraindications to iodinated agents. Higher doses than currently approved would be potentially useful.     

Use of nutritional support formula as a gastrointestinal contrast agent for MRI.

The objective of this study was to evaluate the potential utility of a nutritional support formula to serve as a practical means of enhancing the gastrointestinal tract on abdominal MR images. Nutritional support formula (Ensure Plus) was administered to 29 patients prior to abdominal MRI. Standard T1-weighted and T2-weighted pulse sequences were performed, in addition to fat suppression and inversion recovery sequences in selected patients. Images in these patients were evaluated for degree and uniformity of gastrointestinal tract enhancement and delineation of the bowel wall and pancreas. Results were compared with those obtained in 10 control patients. Marked enhancement of gastric contents was present in nearly all patients who received nutritional support formula on both T1-weighted and T2-weighted sequences, with mild to moderate enhancement of small bowel and colon in most patients. Although gastrointestinal and respiratory motion artifacts often limited bowel wall delineation, excellent delineation of the gastric wall and pancreas was provided. Phantom experiments demonstrated that gastrointestinal tract enhancement with nutritional support formula is due to the paramagnetic trace elements, corn syrup, and lipid material it contains. Such a formula requires no preparation, is safe, inexpensive, palatable, readily available, and represents a practical means of enhancing the gastrointestinal tract on MRI.     

Iopamidol: Exploring the potential use of a well-established x-ray contrast agent for MRI.

Iopamidol is one of the most common contrast media used for diagnostic CT-based clinical protocols. Chemically, this molecule contains two pools of mobile protons (amide and alcoholic) that are in exchange with water. At 7.05 T, pH 7.4, and 312 K, the exchange rate of the alcoholic protons is too fast to affect the NMR properties of water protons, whereas the slowly exchanging amide protons induce a T(2)-shortening effect on the "bulk" water signal that is detectable when the concentration is about 12 mM. Moreover, a more pronounced contrast is observed when the amide resonances are saturated by the application of an appropriate RF irradiation field, making iopamidol a potential chemical exchange saturation transfer (CEST) agent whose effect can be detected at a concentration as low as 7 mM (at 7.05 T). The exploitation of the MRI properties of iopamidol could facilitate novel and interesting diagnostic applications for combined MRI and CT studies.     

A phospholipid spin label used as a liposome-associated MRI contrast agent

Given current clinical use of phospholipid bilayer structures (liposomes/vesicles) as nontoxic drug delivery vehicles, we have addressed the possibility of employing the phospholipids themselves as MRI contrast agents. To this end we have synthesized phosphatidylcholine with a nitroxide spin label replacing one methyl residue of the choline headgroup. This material was mixed with natural phosphatidylcholine in mole ratios from 1:50 to 1:1 and used to prepare sonicated unilamellar vesicles in saline. Expected structural features of these vesicles were verified by freeze-fracture electron microscopy. Proton T1 values of saline were readily decreased to less than 0.3 s by such preparations, yielding a net relaxivity of 0.6 M-1 s-1. The approach seems to be a realistic way of firmly associating a contrast agent of minimal toxicity with ordinary liposomes/vesicles in a manner that is not subject to leakage.     

Perfusion-weighted MRI using gadobutrol as a contrast agent in a rat stroke model

The purpose of this study was to examine the new nonionic contrast agent gadobutrol in MR perfusion-weighted imaging, including the influence of different concentrations and dosages of the agent on the sensitivity to perfusion alterations. Sixteen rats were examined within 35 to 105 minutes after endovascular occlusion of the middle cerebral artery. A fast T2*-weighted fast low-angle shot (FLASH) sequence was used to acquire four images before and 16 images after bolus injection of .1, .2, .3, and .4 mmol/kg gadobutrol as .5 molar and 1.0 molar formulation. From user-defined regions, we obtained the maximum signal decrease, the relative regional cerebral blood volume, and the bolus delay. Contrast between ischemic and nonischemic regions during bolus passage increased with dose and concentration of the contrast agent. For low doses (.1 and .2 mmol/kg), the ischemic lesion could not or could barely be discerned. For higher doses (.3 and .4 mmol/kg), administration of the 1 molar contrast agent yielded a better contrast between ischemic and nonischemic tissue. Our results suggest that administration of gadobutrol at higher dosage and higher concentration increases sensitivity to perfusion alterations. These results are potentially useful for perfusion-weighted imaging of the human brain, because the volume of contrast agent will be reduced if a solution with higher concentration is used. When using contrast agents in higher concentrations for human examinations, a significant signal decrease may be achieved also with the low doses (.1–.15 mmol/kg).     

The value of gadoterate meglumine as a gastrointestinal contrast agent in MRI

To evaluate the safety and efficacy of a gadoterate meglumine formulation as an oral contrast agent, MRI (0.5 T) was performed on 29 patients with abdominal disease before and after administration of contrast material. The patients ingested 16 ml/kg of a gadoterate meglumine solution (10 g/l glucose, 2 mmol/l gadoterate meglumine) over 1 h. Fourteen per cent of patients had mild side effects related to the contrast agent. Significant hyperintense contrast enhancement was achieved for the stomach and duodenum allowing better delineation of gastric and duodenal walls, entire pancreas and spleen on T1- and T2-weighted spin echo sequences. In 5 patients more diagnostic information was available from post-contrast images compared with precontrast images. This study shows that gadoterate meglumine is a safe and well-tolerated contrast agent that improves MRI of the proximal gastrointestinal tract and upper abdomen.Presented at the European Congress of Radiology, Vienna, Austria, 15–20 September 1991 Correspondence to: Y. Miaux     

Superparamagnetic iron oxide MION as a contrast agent for sodium MRI in myocardial infarction.

An intravascular iron-based contrast agent was used as a sodium (23Na) MRI T2 relaxant in an effort to suppress the blood signal from the ventricular cavities in normal and infarcted canine myocardium in vivo. 23Na MRI signal decreases in blood were attributed to decreases in the fast (T2f) and slow (T2s) transverse relaxation components, which were quantified as a function of dose and MRI echo time (TE). In vivo 23Na MRI signal decreases up to 65% were noted in ventricular blood when imaging under dose and TE conditions of 10 mg/kg body weight and 5 ms, respectively. Contrast injection followed by subsequent 23Na MRI in canine myocardial infarction led to a clear delineation of the location of the injured tissue, as identified by postmortem triphenyltetrazolium chloride staining, and to an improvement in the contrast-to-noise ratio between the blood in the ventricular chamber and the infarcted tissue that was as high as 3.3-fold in the postcontrast images in comparison to the precontrast images.     

Metabolic fate in the dog of the nitroxide moiety in a compound with potential utility as a contrast agent in MRI

Nitroxides, paramagnetic compounds with demonstrated effectiveness as contrast agents in proton magnetic resonance imaging, shorten the relaxation times of protons and therefore cause an increase in image intensity in tissues into which they distribute. In this study, the metabolic fate of the nitroxide moiety was examined in the dog using a pyrrolidine nitroxide derivative, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid, for which contrast-enhancing properties have been previously studied in animals. After radiolabeling by microwave discharge in the presence of tritium gas, the compound was administered intravenously to a dog. Ninety-four percent of the radioactivity injected was recovered in urine within 3 days; the majority (90%) was excreted during the first 6 h. The radioactivity in the urine was identified as either the unchanged nitroxide or its corresponding hydroxylamine. Neither complete reduction of the nitroxide moiety to the amine nor any other metabolic transformation was observed.     

Gd-DOTA as a gastrointestinal contrast agent for gastric emptying measurements with MRI

Current MR meal markers may interfere with gastric motility and secretion restricting the use of MRI in the measurement of gastric physiology. We therefore evaluated Gd-DOTA as a liquid phase marker, in vitro by determining dissociation, and adherence to the solids, and in vivo by simultaneous MRI (0.35 T scanner, multiple T₁-weighted sections of the upper abdomen) and double indicator (perfusion marker PEG 4000, meal marker ^99mTc-DTPA) measurements of emptying and secretion, following ingestion of 500 ml 10% glucose. In vitro Gd-DOTA was stable at a pH > 2 with < 2% dissociation at 24 h during incubation with HCI. Dissociation during incubation with HCI was linearly dependent on H⁺ concentration (0.77 < pH < 2.02). Less Gd-DOTA was absorbed onto the solid phase than ^99mTc-DTPA (25% cf 36%). in vivo Gd-DOTA marked gastric contents provided strong positive contrast. Similar emptying curves were observed with both MRI and double-indicator techniques (r = 0.987, P < 0.001). Gd-DOTA has the potential to be a useful liquid phase contrast agent in MR studies on gastric function.     

Ytterbium-DTPA. A potential intravascular contrast agent

Ytterbium-DTPA was evaluated as a potential intravascular contrast agent. Ytterbium-DTPA was synthesized from ytterbium oxide and diethylene triamine penta-acetic acid (DTPA). CT scans of increasing concentrations of ytterbium and iodine showed that at 125 kVp, ytterbium was denser than an equal concentration of iodine. The LD50 of intravenous ytterbium-DTPA was 10 mM/kg (1.73 g ytterbium/kg) in rats. In enhanced CT scans and pulmonary angiography in dogs, ytterbium was visibly denser than iodine, and CT Hounsfield units showed greater enhancement of the aorta and inferior vena cava with ytterbium. The animals showed no sign of acute or delayed toxicity. Ytterbium-DTPA deserves further evaluation as a contrast agent for high kVp techniques.     

Evaluation of methemoglobin as an autologous intravascular MRI contrast agent

Methemoglobin (MetHb) was evaluated as an intravascular paramagnetic contrast agent. Methemoglobin formation was induced by 4-dimethylaminophenol (4-DMAP), causing a reduction in blood T₂* in vitro. The 4-DMAP generated metHb with a time constant of 62 s. A 4-DMAP bolus did not decrease measurably the signal intensity in the in vivo rabbit kidney in the first pass. At steady state, a MetHb concentration of 24.8 ± 2.3% resulted in a signal decrease of 9.2 ± 2.6% in the kidney. Methemoglobin is an effective vascular T₂* relaxation agent, but the formation of MetHb by 4-DMAP is too slow for first-pass imaging. A more effective conversion agent resulting in a bolus of at least 25% MetHb within 5 s would result in a detectable first-pass signal and a viable contrast technique.     

Mn-TPPS4; a potential MRI contrast agent for localizing the normal aortic wall in rabbits

The localizing potential of the Mn (III) complex of tetrakis (4-sulfonatophenyl) porphyrin (Mn-TPPS4) for the normal aortic wall was investigated in nine male New Zealand White rabbits by means of 2.0 T magnetic resonance imaging system. Fortyeight hours after intravenous administration of 0.25-0.50 mmol/kg body weight (b.w.) of Mn-TPPS4, the selective contrast enhancing effects in the normal aortic wall were observed using ECG-gated T1 weighted sequence. An intense brownish internal surface was also observed in the post-mortem aorta. These preliminary results indicate that Mn-TPPS4 might be a suitable MRI contrast agent for the localization of the normal aorta. Acute cardio-toxic effects were observed in one animal after 0.25 mmol/kg b.w. of Mn-TPPS4.